Health Issues of Lead

**3**

**Chapter 1**

**Abstract**

**1. Introduction**

gestation [9].

Health

Effects of Lead on Reproductive

It has been documented that lead can cause a wide range of adverse reproductive outcomes. In men, lead can reduce the libido and affect spermatogenesis reducing the quality of sperm. Other effects in exposed men include disturbance of prostatic function and damage in serum testosterone. In pregnant women, lead can cross the placenta and impair the development of the fetus. Therefore, exposed women are at risk of suffering spontaneous abortion, premature delivery, gestational diabetes mellitus, pregnancy hypertension, preeclampsia, premature rupture of membranes, intrauterine growth restriction, low weight birth, and other pregnancy complications. In both men and women, lead has been associated with infertility. Harmful effects of this heavy metal have been observed even at low levels of exposure. Thus, exposure to lead remains a public health problem, especially for reproductive health. Some strategies should be considered to prevent harmful effects of lead on

**Keywords:** lead exposure, blood lead levels, reproductive outcomes, pregnant

Lead is one of the most dangerous toxic metals. This metal has no known beneficial function in the human body. In contrast, lead can impair every system of the human body and specially the renal, hematopoietic, neurological, and reproductive systems. Exposure to lead has been associated with a broad range of physiological, biochemical, and behavioral and harmful effects. There is evidence of several reproductive damages in humans exposed to lead. In women, lead exposure has been associated with spontaneous abortion [1], low birth weight [2], preterm delivery [3], fetal growth restriction [4], premature rupture of membranes [5], pregnancy hypertension [6], preeclampsia [7], and gestational diabetes [8]. Maternal blood lead has also been associated with a decrease in length of

With respect to men, exposure to inorganic lead has been linked to a decrease in some parameters of semen quality. Lead exposure has been considered to adversely affect spermatogenesis [10] and reduced fertility [10]. High lead concentrations in seminal plasma can reduce the sperm count [10]. Sperm motility and sperm mor-

The present chapter focuses on the harmful effects of lead on reproductive health of both men and women, due to the importance to established preventive measures to protect the health of parents and children exposed to this toxic metal.

*Osmel La Llave León and José M. Salas Pacheco*

both male and female reproductive systems.

phology also can be affected by lead [11].

complications, sperm quality, infertility, reproductive health

## **Chapter 1**

## Effects of Lead on Reproductive Health

*Osmel La Llave León and José M. Salas Pacheco*

## **Abstract**

It has been documented that lead can cause a wide range of adverse reproductive outcomes. In men, lead can reduce the libido and affect spermatogenesis reducing the quality of sperm. Other effects in exposed men include disturbance of prostatic function and damage in serum testosterone. In pregnant women, lead can cross the placenta and impair the development of the fetus. Therefore, exposed women are at risk of suffering spontaneous abortion, premature delivery, gestational diabetes mellitus, pregnancy hypertension, preeclampsia, premature rupture of membranes, intrauterine growth restriction, low weight birth, and other pregnancy complications. In both men and women, lead has been associated with infertility. Harmful effects of this heavy metal have been observed even at low levels of exposure. Thus, exposure to lead remains a public health problem, especially for reproductive health. Some strategies should be considered to prevent harmful effects of lead on both male and female reproductive systems.

**Keywords:** lead exposure, blood lead levels, reproductive outcomes, pregnant complications, sperm quality, infertility, reproductive health

## **1. Introduction**

Lead is one of the most dangerous toxic metals. This metal has no known beneficial function in the human body. In contrast, lead can impair every system of the human body and specially the renal, hematopoietic, neurological, and reproductive systems. Exposure to lead has been associated with a broad range of physiological, biochemical, and behavioral and harmful effects. There is evidence of several reproductive damages in humans exposed to lead. In women, lead exposure has been associated with spontaneous abortion [1], low birth weight [2], preterm delivery [3], fetal growth restriction [4], premature rupture of membranes [5], pregnancy hypertension [6], preeclampsia [7], and gestational diabetes [8]. Maternal blood lead has also been associated with a decrease in length of gestation [9].

With respect to men, exposure to inorganic lead has been linked to a decrease in some parameters of semen quality. Lead exposure has been considered to adversely affect spermatogenesis [10] and reduced fertility [10]. High lead concentrations in seminal plasma can reduce the sperm count [10]. Sperm motility and sperm morphology also can be affected by lead [11].

The present chapter focuses on the harmful effects of lead on reproductive health of both men and women, due to the importance to established preventive measures to protect the health of parents and children exposed to this toxic metal.

## **2. Lead exposure and male reproductive health**

Exposure to lead has been associated to several reproductive dysfunctions in men, such as decreased libido, impairment of spermatogenesis, and chromosomal damage, among others. However, studies about the relationship between lead exposure and male reproductive damage have shown inconsistent results. Most of the studies have analyzed the relationship between blood lead and semen quality due to the correlation observed between semen lead and blood lead [12]. Some studies have reported reduction in sperm count, morphology, and motility in men exposed to lead [13].

The effects of lead on sperm quality have been frequently studied in occupationally exposed individuals. National Institute for Occupational Safety and Health (OSHA) recommends that blood lead levels (BLL) above 40 μg/dL require health intervention. Nevertheless, studies in men without occupational exposure also showed evidence of the effects of lead on fertility. In a prospective, double-blind study carried out to evaluate the impact of seminal plasma lead levels on fertility, seminal plasma lead below this threshold value was associated with adverse effects on in vitro fertilization rates. In this survey, semen donors who participated in an artificial insemination program were included. Sperm lead concentrations were also negatively correlated with mannose receptors and mannose-induced acrosome reactions, the two biomarkers of sperm function [14]. These results show that increased lead concentrations in semen can harm male fertility.

Although most studies on the relationship between lead and infertility have been carried out in occupationally exposed workers, alterations in semen concentration of lead have been also observed in men without occupational exposure, probably due to other sources of exposure such as environment and foods. In a prospective and randomized clinical study carried out in men from infertile couples without occupational exposure to lead, a negative correlation between semen lead concentration and sperm count was observed in semen samples collected after 3–5 days of abstinence [10]. These results provide evidence that lead from environment and diet can also affect semen quality and, therefore, male fertility.

Several studies have evaluated the effect of lead exposure on the endocrine system. In lead smelting workers without clinical symptoms of lead poisoning, a decrease in serum testosterone (T) and an increase in steroid-binding globulin (SGG) levels were observed [15–18]. It is considered that lead impairs the majority of the endocrine glands. The analysis of the effect of long-term exposure to lead on thyroid function in exposed workers showed a negative association with T4 and FT4, and the depressed thyroid function was especially observed when the exposure was the most intensive [18]. In a group of workers occupationally exposed to lead from three battery factories, concentrations of FSH and LH were higher in comparison with a control group of non-exposed men, which constitutes an indicator that lead exposure alters testicular function [19]. From the biochemical point of view, it is considered that lead first causes testicular damage, and long-term exposure alters the hypothalamic-pituitary axis [17, 18, 20].

However, the results on this topic cannot be considered conclusive. In a study of the relationship between lead exposure and sex hormone levels in 133 men who had worked, at least for 6 months, in a battery manufacturing plant, BLL was measured, and endocrine system function was assessed by measuring testosterone, free testosterone, follicle stimulated hormone (FSH), and luteinizing hormone (LH). Workers were classified into two groups based on OSHA BLL standard: with BLL lower than 40 μg/dl and those with BLL equal or higher than 40 μg/dL. Statistical analysis showed no significant association between blood lead concentrations (BLC) and the sex hormone values. The authors concluded that lead exposure is not related to changes in male hormone levels [21]. In contrast, the evaluation of sperm count,

**5**

*Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

sperm morphology, and hormonal levels (LH and FSH) of individuals attended in an infertility clinic in Iran showed negative significant correlations with BLL, while

Despite some contradictory results, there is a growing concern about the harmful effects of lead on male fertility, semen quality, and hormonal levels [15, 22]. Experiments in animal models have demonstrated that lead contributes to decreased male reproductive function [23]. In humans, lead exposure has been also associated with male endocrine dysfunction [24]. It is considered that oxidative stress plays an important role on male infertility. Lower total antioxidant capacity (TAC) and vitamin E concentrations were observed in seminal plasma of infertile men in comparison with fertile subjects [25]. In addition, there were significant differences between compared groups in accumulation of malondialdehyde. Moreover, concentration of malondialdehyde negatively correlated with sperm motility and morphology. On the basis of these results, it is suggested that seminal antioxidants and blood

The effect of lead on reproductive health may vary due to the length of exposure. Taking into account the above-mentioned points, in a cross-sectional study of male workers, the effects of current and long-term occupational lead exposures on several biomarkers of male reproductive health were evaluated [11]. Semen and blood samples from male employees of a lead smelter were obtained, and concentrations of testosterone, follicle stimulated hormone, luteinizing hormone, and blood lead were determined. A decreasing trend in total sperm count was observed in relation to the increase in BLL. In addition, total motile sperm count, sperm concentration, and total sperm count showed an inverse relationship with long-term lead exposure. Nevertheless, lead exposure was not associated to sperm motility, sperm morphol-

The effects of lead exposure on male reproductive function have also been studied in animals. Experiments in mouse have shown that lead can interfere with the binding of androgens [26], suppress follicle stimulating hormone production [27], affect the function of Sertoli cell, and increase the lactate production, which constitute an essential substrate for spermatogenesis [28]. Lead exposure has been also associated with decreases in the activity of testicular oxidizing enzymes [29] and in the synthesis of testicular RNA in rats [28]. A study conducted in rats showed a positive correlation between blood lead and levels of lead in epididymal sperm and demonstrated that lead can cause generation of reactive oxygen species in sperm, which led to oxidative stress and, therefore, impairment of sperm function [30]. Epidemiological data indicate that exposure to lead can cause prostate diseases in adult males. In a study, blood lead in patients suffering from prostate cancer (PCA), patients with benign prostate hyperplasia (BPH), and a control group of men living in similar socioeconomic conditions was examined [31]. Results indicated significant higher concentrations of lead in blood in PCA and BPH males in comparison with controls. In addition, patients with PCA and BPH had significantly lower blood levels of zinc and copper than the comparative group. It is well known that Zn has an essential role in the regulation of prostate epithelium homeostasis and in ejaculation [32]. Zinc is a cofactor for many enzymes and an essential metal for the integrity of cellular membrane [33]. Lead can displace zinc ions at the proteins, provoking the inhibition of the enzymes. The displacement of zinc by lead in seminal fluid could determine the effects of prostate function, leading to decreased fertility [32]. Some authors consider that the main effect of lead on the male reproductive system is the alteration of the reproductive hormonal axis and the hormonal control of spermatogenesis, instead of the direct effect on the seminiferous tubules of the testes [23, 34]. Moreover, there is evidence that the blood-testis barrier acts as a protection for the testis cells against the harmful effects of lead [35, 36]. On the other

no correlation between BLC and sperm morphology was found [22].

antioxidants can be used as biomarkers of sperm quality.

ogy, or serum concentrations of reproductive hormones.

#### *Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

*Lead Chemistry*

**2. Lead exposure and male reproductive health**

Exposure to lead has been associated to several reproductive dysfunctions in men, such as decreased libido, impairment of spermatogenesis, and chromosomal damage, among others. However, studies about the relationship between lead exposure and male reproductive damage have shown inconsistent results. Most of the studies have analyzed the relationship between blood lead and semen quality due to the correlation observed between semen lead and blood lead [12]. Some studies have reported reduction in sperm count, morphology, and motility in men exposed to lead [13]. The effects of lead on sperm quality have been frequently studied in occupation-

ally exposed individuals. National Institute for Occupational Safety and Health (OSHA) recommends that blood lead levels (BLL) above 40 μg/dL require health intervention. Nevertheless, studies in men without occupational exposure also showed evidence of the effects of lead on fertility. In a prospective, double-blind study carried out to evaluate the impact of seminal plasma lead levels on fertility, seminal plasma lead below this threshold value was associated with adverse effects on in vitro fertilization rates. In this survey, semen donors who participated in an artificial insemination program were included. Sperm lead concentrations were also negatively correlated with mannose receptors and mannose-induced acrosome reactions, the two biomarkers of sperm function [14]. These results show that

Although most studies on the relationship between lead and infertility have been carried out in occupationally exposed workers, alterations in semen concentration of lead have been also observed in men without occupational exposure, probably due to other sources of exposure such as environment and foods. In a prospective and randomized clinical study carried out in men from infertile couples without occupational exposure to lead, a negative correlation between semen lead concentration and sperm count was observed in semen samples collected after 3–5 days of abstinence [10]. These results provide evidence that lead from environment and

Several studies have evaluated the effect of lead exposure on the endocrine system. In lead smelting workers without clinical symptoms of lead poisoning, a decrease in serum testosterone (T) and an increase in steroid-binding globulin (SGG) levels were observed [15–18]. It is considered that lead impairs the majority of the endocrine glands. The analysis of the effect of long-term exposure to lead on thyroid function in exposed workers showed a negative association with T4 and FT4, and the depressed thyroid function was especially observed when the exposure was the most intensive [18]. In a group of workers occupationally exposed to lead from three battery factories, concentrations of FSH and LH were higher in comparison with a control group of non-exposed men, which constitutes an indicator that lead exposure alters testicular function [19]. From the biochemical point of view, it is considered that lead first causes testicular damage, and long-term

However, the results on this topic cannot be considered conclusive. In a study of the relationship between lead exposure and sex hormone levels in 133 men who had worked, at least for 6 months, in a battery manufacturing plant, BLL was measured, and endocrine system function was assessed by measuring testosterone, free testosterone, follicle stimulated hormone (FSH), and luteinizing hormone (LH). Workers were classified into two groups based on OSHA BLL standard: with BLL lower than 40 μg/dl and those with BLL equal or higher than 40 μg/dL. Statistical analysis showed no significant association between blood lead concentrations (BLC) and the sex hormone values. The authors concluded that lead exposure is not related to changes in male hormone levels [21]. In contrast, the evaluation of sperm count,

increased lead concentrations in semen can harm male fertility.

diet can also affect semen quality and, therefore, male fertility.

exposure alters the hypothalamic-pituitary axis [17, 18, 20].

**4**

sperm morphology, and hormonal levels (LH and FSH) of individuals attended in an infertility clinic in Iran showed negative significant correlations with BLL, while no correlation between BLC and sperm morphology was found [22].

Despite some contradictory results, there is a growing concern about the harmful effects of lead on male fertility, semen quality, and hormonal levels [15, 22]. Experiments in animal models have demonstrated that lead contributes to decreased male reproductive function [23]. In humans, lead exposure has been also associated with male endocrine dysfunction [24]. It is considered that oxidative stress plays an important role on male infertility. Lower total antioxidant capacity (TAC) and vitamin E concentrations were observed in seminal plasma of infertile men in comparison with fertile subjects [25]. In addition, there were significant differences between compared groups in accumulation of malondialdehyde. Moreover, concentration of malondialdehyde negatively correlated with sperm motility and morphology. On the basis of these results, it is suggested that seminal antioxidants and blood antioxidants can be used as biomarkers of sperm quality.

The effect of lead on reproductive health may vary due to the length of exposure. Taking into account the above-mentioned points, in a cross-sectional study of male workers, the effects of current and long-term occupational lead exposures on several biomarkers of male reproductive health were evaluated [11]. Semen and blood samples from male employees of a lead smelter were obtained, and concentrations of testosterone, follicle stimulated hormone, luteinizing hormone, and blood lead were determined. A decreasing trend in total sperm count was observed in relation to the increase in BLL. In addition, total motile sperm count, sperm concentration, and total sperm count showed an inverse relationship with long-term lead exposure. Nevertheless, lead exposure was not associated to sperm motility, sperm morphology, or serum concentrations of reproductive hormones.

The effects of lead exposure on male reproductive function have also been studied in animals. Experiments in mouse have shown that lead can interfere with the binding of androgens [26], suppress follicle stimulating hormone production [27], affect the function of Sertoli cell, and increase the lactate production, which constitute an essential substrate for spermatogenesis [28]. Lead exposure has been also associated with decreases in the activity of testicular oxidizing enzymes [29] and in the synthesis of testicular RNA in rats [28]. A study conducted in rats showed a positive correlation between blood lead and levels of lead in epididymal sperm and demonstrated that lead can cause generation of reactive oxygen species in sperm, which led to oxidative stress and, therefore, impairment of sperm function [30].

Epidemiological data indicate that exposure to lead can cause prostate diseases in adult males. In a study, blood lead in patients suffering from prostate cancer (PCA), patients with benign prostate hyperplasia (BPH), and a control group of men living in similar socioeconomic conditions was examined [31]. Results indicated significant higher concentrations of lead in blood in PCA and BPH males in comparison with controls. In addition, patients with PCA and BPH had significantly lower blood levels of zinc and copper than the comparative group. It is well known that Zn has an essential role in the regulation of prostate epithelium homeostasis and in ejaculation [32]. Zinc is a cofactor for many enzymes and an essential metal for the integrity of cellular membrane [33]. Lead can displace zinc ions at the proteins, provoking the inhibition of the enzymes. The displacement of zinc by lead in seminal fluid could determine the effects of prostate function, leading to decreased fertility [32].

Some authors consider that the main effect of lead on the male reproductive system is the alteration of the reproductive hormonal axis and the hormonal control of spermatogenesis, instead of the direct effect on the seminiferous tubules of the testes [23, 34]. Moreover, there is evidence that the blood-testis barrier acts as a protection for the testis cells against the harmful effects of lead [35, 36]. On the other


#### **Figure 1.**

*Some effects of lead on male reproductive system.*

hand, some researchers pay more attention to the impairment of sperm parameters, such as volume of ejaculation, sperm density, abnormal morphology, sperm count, and motility, by the toxic effect of lead [10, 14, 22, 37].

Although the mechanisms by which lead affects male reproductive health are still unclear, there is no doubt that this toxic metal can jeopardize fertility in men due to alterations in semen quality, in the function of reproductive hormones, or both (see **Figure 1**). Despite conflicting reported results, there is growing evidence that lead exposure, even at low levels, can impair male reproductive health. Future research should deepen the analysis concerning these issues.

## **3. Lead exposure and female reproductive health**

It is well known that lead has harmful effects on female reproductive system. Women at reproductive age are at risk of suffering some health disorders due to the toxic effects of this metal. Occupational exposure to lead is more frequent in men compared to women. However, there are some reports on the harmful effects of lead suffered by women who work in places where lead or some lead compounds are used. In a study conducted to determine the effects of occupational exposure on bone and lead blood levels, women who were former workers at a smelter were compared with a cohort of women with no-known occupational exposure. Higher levels of lead in blood and tibia were found in the exposed group. In addition, the difference in bone lead levels between compared groups was significantly higher than the difference in BLCs [38]. In accord with these findings, a study carried out in Mexico showed that women who work with lead have greater probability to have BLCs above the CDC recommended value of 5 μg/dL compared to non-exposed women [39].

It is necessary to consider that women can be exposed to lead not only at work but also through the clothes, shoes, and work instruments that are taken home by the cohabitants who work in places where lead is used. Higher BLCs in pregnant women who live with someone who is exposed to lead at work in comparison with those who live in houses where nobody works in places that lead is used have been observed [40]. In addition, lead exposure may occur when women use some cosmetics, such as surma or kolh, and other beauty products [41–43].

Women can also be exposed to lead by pica habit, an eating disorder that consists of the consumption of non-food items without nutritional value. Among the most harmful types of pica is the consumption of soil, paint chips, and pottery. Pregnant women consuming these items put both themselves and the fetus at risk of lead poisoning [44, 45]. In Mexican, women who were recognized that they used to eat soil had significantly higher BLL compared to those who did not have this habit [40]. In one study in New York, pica behavior among lead-poisoned pregnant women (BLL ≥ 20 μg/dL) was 9%. The most common practice among them was

**7**

**Figure 2.**

*Harmful effects of lead on female reproductive health.*

*Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

(29.5 μg/dL vs. 23.8 μg/dL) [45].

eating soil (64.6%). The probability of having BLLs ≥40 μg/dL among women who reported pica was three times higher in comparison with those women who did not report this habit. In addition, pica-reporting women had a mean peak of BLL during pregnancy significantly higher compared to those who did not report pica

In addition to the effects of lead on women's fertility, a wide range of published reports refers to the damage caused by this heavy metal during pregnancy (see **Figure 2**). Prenatal exposure to lead can cause several obstetric complications and adverse pregnancy outcomes [46]. Lead absorbed into the body, mainly by ingestion or inhalation, enters the bloodstream and accumulates in soft organs (mostly in brain, liver, and kidney) and bones [47, 48]. It is considered that lead in bone represents approximately 95% of the total body burden in adults [47]. During pregnancy, the demand of calcium rises, and lead stored in bone can replace the calcium and recirculate in the bloodstream, becoming an endogenous source of exposure [16, 48–50]. Lead from the blood can cross the placenta and impair the development of the fetus [51, 52]. Therefore, lead-exposed women are at risk of suffering various pregnancy complications, such as spontaneous abortion [1, 53], preterm delivery [54, 55], GDM [8, 56], pregnancy hypertension [57–59], preeclampsia [60–64], premature rupture of membranes [65, 66], intrauterine growth restriction [67], and low weight birth [68, 69], among others. Although some researchers have failed to demonstrate the relationship between lead and abortion [70, 71], a study conducted in Mexico showed evidence that, even low-to-moderate lead exposure, below 30 μg/dL of blood lead can increase the risk of spontaneous abortion [1]. In this case, the range of BLLs in pregnant women was 1.4–29 μg/dL. Those lead concentrations can be considered common in general population in many countries, and lower to those observed in occupationally exposed women. It is considered that the mechanism by which lead induces abortion is related to the direct transmission of the metal to the developing fetus due to

the demineralization of bones during pregnancy [72, 73].

Several studies have confirmed that pregnant women exposed to lead have more

probability of having a preterm delivery compared with non-exposed women. Nevertheless, results are still inconsistent. In a prospective cohort study carried out in China, maternal urinary lead was measured and adjusted by creatinine, and newborns were classified as preterm birth and early term birth. The mean urinary lead levels were significantly higher in preterm births. In addition, among all newborns, an increase in maternal urinary lead was associated with a decrease in gestational age [3].

## *Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

*Lead Chemistry*

**Figure 1.**

hand, some researchers pay more attention to the impairment of sperm parameters, such as volume of ejaculation, sperm density, abnormal morphology, sperm count,

Although the mechanisms by which lead affects male reproductive health are still unclear, there is no doubt that this toxic metal can jeopardize fertility in men due to alterations in semen quality, in the function of reproductive hormones, or both (see **Figure 1**). Despite conflicting reported results, there is growing evidence that lead exposure, even at low levels, can impair male reproductive health. Future

It is well known that lead has harmful effects on female reproductive system. Women at reproductive age are at risk of suffering some health disorders due to the toxic effects of this metal. Occupational exposure to lead is more frequent in men compared to women. However, there are some reports on the harmful effects of lead suffered by women who work in places where lead or some lead compounds are used. In a study conducted to determine the effects of occupational exposure on bone and lead blood levels, women who were former workers at a smelter were compared with a cohort of women with no-known occupational exposure. Higher levels of lead in blood and tibia were found in the exposed group. In addition, the difference in bone lead levels between compared groups was significantly higher than the difference in BLCs [38]. In accord with these findings, a study carried out in Mexico showed that women who work with lead have greater probability to have BLCs above the CDC recommended value of 5 μg/dL compared to non-exposed women [39]. It is necessary to consider that women can be exposed to lead not only at work but also through the clothes, shoes, and work instruments that are taken home by the cohabitants who work in places where lead is used. Higher BLCs in pregnant women who live with someone who is exposed to lead at work in comparison with those who live in houses where nobody works in places that lead is used have been observed [40]. In addition, lead exposure may occur when women use some

cosmetics, such as surma or kolh, and other beauty products [41–43].

Women can also be exposed to lead by pica habit, an eating disorder that consists of the consumption of non-food items without nutritional value. Among the most harmful types of pica is the consumption of soil, paint chips, and pottery. Pregnant women consuming these items put both themselves and the fetus at risk of lead poisoning [44, 45]. In Mexican, women who were recognized that they used to eat soil had significantly higher BLL compared to those who did not have this habit [40]. In one study in New York, pica behavior among lead-poisoned pregnant women (BLL ≥ 20 μg/dL) was 9%. The most common practice among them was

and motility, by the toxic effect of lead [10, 14, 22, 37].

*Some effects of lead on male reproductive system.*

research should deepen the analysis concerning these issues.

**3. Lead exposure and female reproductive health**

**6**

eating soil (64.6%). The probability of having BLLs ≥40 μg/dL among women who reported pica was three times higher in comparison with those women who did not report this habit. In addition, pica-reporting women had a mean peak of BLL during pregnancy significantly higher compared to those who did not report pica (29.5 μg/dL vs. 23.8 μg/dL) [45].

In addition to the effects of lead on women's fertility, a wide range of published reports refers to the damage caused by this heavy metal during pregnancy (see **Figure 2**). Prenatal exposure to lead can cause several obstetric complications and adverse pregnancy outcomes [46]. Lead absorbed into the body, mainly by ingestion or inhalation, enters the bloodstream and accumulates in soft organs (mostly in brain, liver, and kidney) and bones [47, 48]. It is considered that lead in bone represents approximately 95% of the total body burden in adults [47]. During pregnancy, the demand of calcium rises, and lead stored in bone can replace the calcium and recirculate in the bloodstream, becoming an endogenous source of exposure [16, 48–50]. Lead from the blood can cross the placenta and impair the development of the fetus [51, 52]. Therefore, lead-exposed women are at risk of suffering various pregnancy complications, such as spontaneous abortion [1, 53], preterm delivery [54, 55], GDM [8, 56], pregnancy hypertension [57–59], preeclampsia [60–64], premature rupture of membranes [65, 66], intrauterine growth restriction [67], and low weight birth [68, 69], among others.

Although some researchers have failed to demonstrate the relationship between lead and abortion [70, 71], a study conducted in Mexico showed evidence that, even low-to-moderate lead exposure, below 30 μg/dL of blood lead can increase the risk of spontaneous abortion [1]. In this case, the range of BLLs in pregnant women was 1.4–29 μg/dL. Those lead concentrations can be considered common in general population in many countries, and lower to those observed in occupationally exposed women. It is considered that the mechanism by which lead induces abortion is related to the direct transmission of the metal to the developing fetus due to the demineralization of bones during pregnancy [72, 73].

Several studies have confirmed that pregnant women exposed to lead have more probability of having a preterm delivery compared with non-exposed women. Nevertheless, results are still inconsistent. In a prospective cohort study carried out in China, maternal urinary lead was measured and adjusted by creatinine, and newborns were classified as preterm birth and early term birth. The mean urinary lead levels were significantly higher in preterm births. In addition, among all newborns, an increase in maternal urinary lead was associated with a decrease in gestational age [3].


## **Figure 2.**

*Harmful effects of lead on female reproductive health.*

Lead can displace calcium because they both have similar chemical characteristics and follow analogous metabolic pathways [74]. It has been recognized that when lead crosses from the bloodstream to the placenta, the growth of the fetus can be impaired due to the interference of lead with calcium metabolism [68, 69]. The evaluation of prenatal exposure to lead has shown inverse association between maternal urine lead levels and preterm low birth weight [68]. Other studies analyzed the relationship between the levels of lead in tibia and patella and birth weight, considering that bone lead is a better biomarker to estimate the effect of lead on the fetus compared to blood lead [75, 76].

In a study conducted to evaluate the relationship between lead exposure and birth weight in Mexican women, lead levels were measured in maternal venous blood, umbilical cord, and tibia and patella. The weight of newborns was determined within the first 12 hours of delivery. Although all biomarkers of lead exposure were negatively associated with a decreased size of newborns, this association resulted statistically significant only for tibia lead levels [75]. Similar results were observed in the analysis of the relationship between maternal lead burden and early postnatal growth in a cohort of breastfed newborns [75]. In this study, maternal BLL measured at 1 month postpartum and maternal bone lead levels were significantly associated with infant BLL. Moreover, infant BLL and maternal patella lead level were inversely associated with weight gain. The weight gain from birth to the first month of life was 142 g lower in infants with BLL ≥ 10 compared to those with lower BLCs.

There is growing evidence that lead is a risk factor for gestational diabetes mellitus. Experiments with rats have demonstrated that lead exposure can induce glucose intolerance and hyperglycemia [8]. But epidemiological studies showed contradictory results. In women at 22–28 weeks of gestation, slightly mean BLCs were observed compared to those without GDM, but this difference was not statistically significant. The geometric mean BLCs were 6.13 ng/g in women with GDM and 6.05 ng/g in women without GDM. Based on this result, authors suggested that lead at these low levels of exposure is not associated with the risk of suffering GDM [77]. In contrast, in a French mother-child prospective cohort study, blood lead was associated with IGT, supporting the evidence that maternal exposure to lead is a risk factor for GDM [56]. Further studies have to be performed to confirm the deleterious effect of lead on metabolic processes and, particularly, on the development of GDM.

A large number of investigations provide evidence that exposure to lead is associated with hypertension in adults [78–81]. For this reason, the question of whether lead is associated with gestational hypertension (GH) and preeclampsia (PE) has gained a great importance in recent years.

In a cohort of pregnant women in Los Angeles, California, blood and bone lead were assessed in the 3rd trimester and post-delivery, and the prevalence of hypertension was measured [82]. The relationship of both biomarkers with GH was analyzed. After adjusting by covariables, no significant association between BLLs in 3rd trimester and hypertension was observed. Nevertheless, calcaneus bone lead was significantly associated with the risk of hypertension.

In a cross-sectional study with Maltese Caucasian women at third trimester of gestation, significantly higher BLCs in hypertensive women compared to normotensive women were observed [83]. Moreover, BLL showed a positive relationship with systolic and diastolic blood pressure.

The relationship between BLL at mid-pregnancy and blood pressure was assessed in a study carried out in pregnant women of two French municipalities [83]. In this study, hypertensive women had significantly higher BLL than normotensive women. Additionally, lowest frequency of hypertension was observed among women in the lowest quartile of BLL. These findings are in accord with

**9**

*Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

cantly associated with preeclampsia.

due to the increase of intracellular calcium ions [63, 90].

**4. Effects of gender on lead toxicity**

elucidate these inconsistencies.

lead in blood.

those observed in Nigeria, in which the impact of lead on pregnancy outcomes was investigated [84]. Significantly higher frequency of hypertension was observed in women with BLL ≥ 10 μg/dL compared to those who had lower concentrations of

The findings on the association of lead exposure with GH led to investigate if this toxic metal could be considered a risk factor for preeclampsia, a pregnancy disorder characterized by high blood pressure and proteinuria detected after 20 weeks of gestation [85]. In a cross-sectional study that included women between 29 and 43 weeks of gestation, significantly higher concentrations of lead in red blood cells of pregnant women diagnosed with preeclampsia were found compared to those without hypertension. Furthermore, women with severe preeclampsia had also higher blood cell lead concentrations than mild preeclamptic women [61]. In contrast, in a case-control study conducted in women without occupational exposure, BLCs measured within 24 hours of delivery did not differ between women with preeclampsia and normotensive group, but a significant difference between the groups was observed with respect to umbilical cord lead (UCB) concentration [64]. In addition, the ratio of umbilical cord lead to whole blood lead was signifi-

Despite the contradictory results of some studies, the majority of those supported the hypothesis that lead can cause preeclampsia. Some possible mechanisms have been suggested to explain the roll of lead in the development of this pregnancy disorder. It is considered that lead increases the circulating levels of endothelin, a vasoactive substance that causes constriction of the blood vessels, leading to the increase of blood pressure [63]. Lead also interferes in the increase of reactive oxygen species reducing the serum levels of nitric oxide (NO) and other vasodilator substances [86–89]. From the molecular point of view, lead causes inhibition of membrane adenosine triphosphatases (ATPases), which produces vasoconstriction

The influence of sex in the effect of lead on health is a controversial subject. Although sex differences regarding exposure, absorption, and metabolism of lead have been reported by certain researchers [91, 92], the results are not conclusive. In a prospective cohort, the effects of gender differences in the relationship between lead exposure and neurodevelopmental toxicity were analyzed [91]. Lead levels were determined in maternal blood in early and late pregnancy, in cord blood at birth, and in children's blood at 2, 3, and 5 years old. As a result, significant association between lead concentrations at late pregnancy and the risk of behavioral problems was observed in males, while blood lead measured in 2- and 5-year-old children was associated with an increased risk of behavioral problems in females. According to previous data, early in life, the susceptibility to neurotoxic effect of lead is higher in boys than in girls. On the other hand, experimental data suggest that susceptibility to immunotoxic effects of lead is higher in females [92]. More research is needed to

The biological effects of lead exposure in human also appear to be different according to the gender. In a study carried out in Japan, the authors aimed to determine the effects of gender on porphyrin metabolic disorders induced by lead exposure [93]. Blood lead, plasma delta-aminolevulinic acid (ALA), urinary ALA, and urinary coproporphyrin (CP) were determined in exposed workers. Although no significant differences in blood lead concentrations between male and female workers were observed, women had higher plasma ALA concentrations, as well as

#### *Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

*Lead Chemistry*

Lead can displace calcium because they both have similar chemical characteristics and follow analogous metabolic pathways [74]. It has been recognized that when lead crosses from the bloodstream to the placenta, the growth of the fetus can be impaired due to the interference of lead with calcium metabolism [68, 69]. The evaluation of prenatal exposure to lead has shown inverse association between

In a study conducted to evaluate the relationship between lead exposure and birth

weight in Mexican women, lead levels were measured in maternal venous blood, umbilical cord, and tibia and patella. The weight of newborns was determined within the first 12 hours of delivery. Although all biomarkers of lead exposure were negatively associated with a decreased size of newborns, this association resulted statistically significant only for tibia lead levels [75]. Similar results were observed in the analysis of the relationship between maternal lead burden and early postnatal growth in a cohort of breastfed newborns [75]. In this study, maternal BLL measured at 1 month postpartum and maternal bone lead levels were significantly associated with infant BLL. Moreover, infant BLL and maternal patella lead level were inversely associated with weight gain. The weight gain from birth to the first month of life was

142 g lower in infants with BLL ≥ 10 compared to those with lower BLCs.

There is growing evidence that lead is a risk factor for gestational diabetes mellitus. Experiments with rats have demonstrated that lead exposure can induce glucose intolerance and hyperglycemia [8]. But epidemiological studies showed contradictory results. In women at 22–28 weeks of gestation, slightly mean BLCs were observed compared to those without GDM, but this difference was not statistically significant. The geometric mean BLCs were 6.13 ng/g in women with GDM and 6.05 ng/g in women without GDM. Based on this result, authors suggested that lead at these low levels of exposure is not associated with the risk of suffering GDM [77]. In contrast, in a French mother-child prospective cohort study, blood lead was associated with IGT, supporting the evidence that maternal exposure to lead is a risk factor for GDM [56]. Further studies have to be performed to confirm the deleterious effect of lead on metabolic processes and, particularly, on the develop-

A large number of investigations provide evidence that exposure to lead is associated with hypertension in adults [78–81]. For this reason, the question of whether lead is associated with gestational hypertension (GH) and preeclampsia (PE) has

In a cohort of pregnant women in Los Angeles, California, blood and bone lead were assessed in the 3rd trimester and post-delivery, and the prevalence of hypertension was measured [82]. The relationship of both biomarkers with GH was analyzed. After adjusting by covariables, no significant association between BLLs in 3rd trimester and hypertension was observed. Nevertheless, calcaneus bone lead

In a cross-sectional study with Maltese Caucasian women at third trimester of gestation, significantly higher BLCs in hypertensive women compared to normotensive women were observed [83]. Moreover, BLL showed a positive relationship

The relationship between BLL at mid-pregnancy and blood pressure was assessed in a study carried out in pregnant women of two French municipalities [83]. In this study, hypertensive women had significantly higher BLL than normotensive women. Additionally, lowest frequency of hypertension was observed among women in the lowest quartile of BLL. These findings are in accord with

maternal urine lead levels and preterm low birth weight [68]. Other studies analyzed the relationship between the levels of lead in tibia and patella and birth weight, considering that bone lead is a better biomarker to estimate the effect of

lead on the fetus compared to blood lead [75, 76].

**8**

ment of GDM.

gained a great importance in recent years.

with systolic and diastolic blood pressure.

was significantly associated with the risk of hypertension.

those observed in Nigeria, in which the impact of lead on pregnancy outcomes was investigated [84]. Significantly higher frequency of hypertension was observed in women with BLL ≥ 10 μg/dL compared to those who had lower concentrations of lead in blood.

The findings on the association of lead exposure with GH led to investigate if this toxic metal could be considered a risk factor for preeclampsia, a pregnancy disorder characterized by high blood pressure and proteinuria detected after 20 weeks of gestation [85]. In a cross-sectional study that included women between 29 and 43 weeks of gestation, significantly higher concentrations of lead in red blood cells of pregnant women diagnosed with preeclampsia were found compared to those without hypertension. Furthermore, women with severe preeclampsia had also higher blood cell lead concentrations than mild preeclamptic women [61]. In contrast, in a case-control study conducted in women without occupational exposure, BLCs measured within 24 hours of delivery did not differ between women with preeclampsia and normotensive group, but a significant difference between the groups was observed with respect to umbilical cord lead (UCB) concentration [64]. In addition, the ratio of umbilical cord lead to whole blood lead was significantly associated with preeclampsia.

Despite the contradictory results of some studies, the majority of those supported the hypothesis that lead can cause preeclampsia. Some possible mechanisms have been suggested to explain the roll of lead in the development of this pregnancy disorder. It is considered that lead increases the circulating levels of endothelin, a vasoactive substance that causes constriction of the blood vessels, leading to the increase of blood pressure [63]. Lead also interferes in the increase of reactive oxygen species reducing the serum levels of nitric oxide (NO) and other vasodilator substances [86–89]. From the molecular point of view, lead causes inhibition of membrane adenosine triphosphatases (ATPases), which produces vasoconstriction due to the increase of intracellular calcium ions [63, 90].

## **4. Effects of gender on lead toxicity**

The influence of sex in the effect of lead on health is a controversial subject. Although sex differences regarding exposure, absorption, and metabolism of lead have been reported by certain researchers [91, 92], the results are not conclusive. In a prospective cohort, the effects of gender differences in the relationship between lead exposure and neurodevelopmental toxicity were analyzed [91]. Lead levels were determined in maternal blood in early and late pregnancy, in cord blood at birth, and in children's blood at 2, 3, and 5 years old. As a result, significant association between lead concentrations at late pregnancy and the risk of behavioral problems was observed in males, while blood lead measured in 2- and 5-year-old children was associated with an increased risk of behavioral problems in females. According to previous data, early in life, the susceptibility to neurotoxic effect of lead is higher in boys than in girls. On the other hand, experimental data suggest that susceptibility to immunotoxic effects of lead is higher in females [92]. More research is needed to elucidate these inconsistencies.

The biological effects of lead exposure in human also appear to be different according to the gender. In a study carried out in Japan, the authors aimed to determine the effects of gender on porphyrin metabolic disorders induced by lead exposure [93]. Blood lead, plasma delta-aminolevulinic acid (ALA), urinary ALA, and urinary coproporphyrin (CP) were determined in exposed workers. Although no significant differences in blood lead concentrations between male and female workers were observed, women had higher plasma ALA concentrations, as well as

higher excretion of urine ALA and CP in comparison with men. The mechanism that could explain this difference is still unclear.

With respect to the reproductive system, health damages in female have been observed even at very low levels of exposure. In a study carried out in Taiwan, the relationship between low-level lead exposure and risk of infertility was evaluated [94]. The average lead concentration in infertile women (3.5 μg/dL) was significantly higher than in a control group (2.78 μg/dL). Furthermore, women with BLL >2.5 μg/dL had a threefold higher risk of infertility than those with BLL ≤ 2.5 μg/dL. In contrast, the harmful effects of lead in male reproductive system have been detected at higher levels of exposure than those in female. The importance of finding explanation of gender effects for lead and other environmental toxic substances was discussed by the Society for Women's Health Research in a roundtable at the National Institute of Environmental Health Sciences in October 2002 [95].

Despite the above-mentioned results, gender differences in susceptibility to lead poisoning have been considered in few investigations. Some studies have included gender as a confounding factor in the relationship between lead exposure and health impairment [96]. However, in other investigations, differences between male and female in regard to the harmful effects of lead have not been found.

According to the results of the investigations, the following differences between men and women regarding lead exposure can be highlighted:


In summary, gender difference should be considered an important factor for a better evaluation of the harmful effects of lead on health. Further research is needed to better understand the role of sex as a modifier of the effects of lead exposure.

### **5. Lead exposure and children's reproductive system**

Lead is considered to be able to affect the development of children's reproductive system. There is evidence that both paternal and maternal lead exposure can cause a detrimental impact on the structure and function of gametes, which might cause adverse effects on newborn's health [97]. Embryos and fetus are extremely

**11**

**health**

vessels, among others [106].

and the danger it poses to their health.

*Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

and reach the fetus [51, 52].

lead may delay the timing of male puberty.

sensitive to environmental toxicants. Exposure to lead during pregnancy is known to be able to impair fetal development, since lead can cross the placental barrier

Lead is known to affect testosterone levels in adults, leading to reproductive dysfunction. Low levels of testosterone can reduce semen quality in men and increase genital malformations [98]. In contrast, high levels of testosterone in women are associated with higher frequency of polycystic ovary syndrome (POS) [99] and puberty disorders [100]. In spite of this, there are few studies that have focused on the relationship between lead exposure and androgen hormone levels in children. One of the few longitudinal studies on this issue was carried out in Russia [101]. This study evaluated the impact of organochlorine chemicals and lead in growth and pubertal timing in 516 boys. Children were enrolled in the study at the age of 5–7 years and were followed up until the age of 18–19 years. Lead exposure was negatively associated with growth during puberty. In addition, it was suggested that

In a study carried out to evaluate the relationship between blood metal concentrations and testosterone levels in the USA, children and adolescents' concentrations of lead, cadmium, mercury, and selenium in blood, as well as serum testosterone levels, were determined [102]. Although no significant association between blood lead and total testosterone (TT) was observed, the concentrations of TT were significantly higher for girls in the fourth quartile compared to those in the first quartile. On the other hand, in a prospective study conducted in Mexico City, maternal patella lead and early childhood blood lead were inversely associated with breast growth in girls [103]. Furthermore, an increase in girl's maternal patella lead was associated with later age of menarche. In addition, blood lead during childhood negatively associated with pubic hair growth in girls. No associations were observed in boys.

**6. Preventive strategies to avoid harmful effects of lead on reproductive** 

The fact that lead exposure is related to a wide range of adverse effects on reproductive health is accepted by most researchers nowadays. The main source of exposure remains occupational. But there is no doubt that, in recent years, the environmental exposure to lead has decreased, especially in developed countries like the United State, Canada, and others [104]. A main role in this reduction is attributed to the elimination of leaded gasoline [105]. Nevertheless, the risk of lead poisoning still remains, mainly in developing countries, due to some sources of exposure, such as lead paint, cosmetics, traditional medicines, electronic waste, and glazed ceramic

It is very difficult to dispense with lead due to its uses in a wide range of industrial lines, such as smelting, manufacturing and recycling of car batteries, and lead crystal glassware. However, in recent years, there has been an increase in the diffusion of the damage that lead can cause and the measures that must be taken to protect people's health. The identification of risk factors for having high BLLs has contributed to reduce the prevalence and severity of lead poisoning. In a way, the results of research have helped people to become aware of the toxicity of this metal

Health interventions in last decades have led to a decrease in lead exposure. In spite of this, it is necessary to increase protection measures, especially for women and children. To date, there is no exposure lead level that can be considered safe. Although the CDC established 5 μg/dL as the reference value for BLLs in children, epidemiological research has demonstrated that even at lower lead concentrations

#### *Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

*Lead Chemistry*

higher excretion of urine ALA and CP in comparison with men. The mechanism

With respect to the reproductive system, health damages in female have been observed even at very low levels of exposure. In a study carried out in Taiwan, the relationship between low-level lead exposure and risk of infertility was evaluated [94]. The average lead concentration in infertile women (3.5 μg/dL) was significantly higher than in a control group (2.78 μg/dL). Furthermore, women with BLL >2.5 μg/dL had a threefold higher risk of infertility than those with BLL ≤ 2.5 μg/dL. In contrast, the harmful effects of lead in male reproductive system have been detected at higher levels of exposure than those in female. The importance of finding explanation of gender effects for lead and other environmental toxic substances was discussed by the Society for Women's Health Research in a roundtable at the National Institute of Environmental Health Sciences in October 2002 [95].

Despite the above-mentioned results, gender differences in susceptibility to lead poisoning have been considered in few investigations. Some studies have included gender as a confounding factor in the relationship between lead exposure and health impairment [96]. However, in other investigations, differences between male

According to the results of the investigations, the following differences between

• Generally, in non-exposed individuals, blood lead levels are higher in males

• Damages to female reproductive health can occur at lower levels of exposure

• The risk of suffering behavioral problems in relation to prenatal lead exposure

• The susceptibility to neurotoxic effects of lead appears to be higher in boys

• From the biological point of view, porphyrin metabolic disorders induced by

• The impairment in the synthesis and function of hormones has been observed in both genders. But, little is known about the differences between male and female

regarding the mechanisms by which lead affects the reproductive system.

In summary, gender difference should be considered an important factor for a better evaluation of the harmful effects of lead on health. Further research is needed to better understand the role of sex as a modifier of the effects of lead exposure.

Lead is considered to be able to affect the development of children's reproductive system. There is evidence that both paternal and maternal lead exposure can cause a detrimental impact on the structure and function of gametes, which might cause adverse effects on newborn's health [97]. Embryos and fetus are extremely

• The susceptibility to immunotoxic effects of lead is higher in females.

and female in regard to the harmful effects of lead have not been found.

men and women regarding lead exposure can be highlighted:

at early childhood is higher in females.

lead exposure affect females more than males.

**5. Lead exposure and children's reproductive system**

than in females.

than in men.

than in girls.

that could explain this difference is still unclear.

**10**

sensitive to environmental toxicants. Exposure to lead during pregnancy is known to be able to impair fetal development, since lead can cross the placental barrier and reach the fetus [51, 52].

Lead is known to affect testosterone levels in adults, leading to reproductive dysfunction. Low levels of testosterone can reduce semen quality in men and increase genital malformations [98]. In contrast, high levels of testosterone in women are associated with higher frequency of polycystic ovary syndrome (POS) [99] and puberty disorders [100]. In spite of this, there are few studies that have focused on the relationship between lead exposure and androgen hormone levels in children. One of the few longitudinal studies on this issue was carried out in Russia [101]. This study evaluated the impact of organochlorine chemicals and lead in growth and pubertal timing in 516 boys. Children were enrolled in the study at the age of 5–7 years and were followed up until the age of 18–19 years. Lead exposure was negatively associated with growth during puberty. In addition, it was suggested that lead may delay the timing of male puberty.

In a study carried out to evaluate the relationship between blood metal concentrations and testosterone levels in the USA, children and adolescents' concentrations of lead, cadmium, mercury, and selenium in blood, as well as serum testosterone levels, were determined [102]. Although no significant association between blood lead and total testosterone (TT) was observed, the concentrations of TT were significantly higher for girls in the fourth quartile compared to those in the first quartile. On the other hand, in a prospective study conducted in Mexico City, maternal patella lead and early childhood blood lead were inversely associated with breast growth in girls [103]. Furthermore, an increase in girl's maternal patella lead was associated with later age of menarche. In addition, blood lead during childhood negatively associated with pubic hair growth in girls. No associations were observed in boys.

## **6. Preventive strategies to avoid harmful effects of lead on reproductive health**

The fact that lead exposure is related to a wide range of adverse effects on reproductive health is accepted by most researchers nowadays. The main source of exposure remains occupational. But there is no doubt that, in recent years, the environmental exposure to lead has decreased, especially in developed countries like the United State, Canada, and others [104]. A main role in this reduction is attributed to the elimination of leaded gasoline [105]. Nevertheless, the risk of lead poisoning still remains, mainly in developing countries, due to some sources of exposure, such as lead paint, cosmetics, traditional medicines, electronic waste, and glazed ceramic vessels, among others [106].

It is very difficult to dispense with lead due to its uses in a wide range of industrial lines, such as smelting, manufacturing and recycling of car batteries, and lead crystal glassware. However, in recent years, there has been an increase in the diffusion of the damage that lead can cause and the measures that must be taken to protect people's health. The identification of risk factors for having high BLLs has contributed to reduce the prevalence and severity of lead poisoning. In a way, the results of research have helped people to become aware of the toxicity of this metal and the danger it poses to their health.

Health interventions in last decades have led to a decrease in lead exposure. In spite of this, it is necessary to increase protection measures, especially for women and children. To date, there is no exposure lead level that can be considered safe. Although the CDC established 5 μg/dL as the reference value for BLLs in children, epidemiological research has demonstrated that even at lower lead concentrations

### *Lead Chemistry*

adverse health effects can occur. With respect to females, adverse reproductive outcomes have been observed also at BLLs below 5 μg/dL, decrease in delta-aminolevulinic acid dehydratase (ALAD) activity has been detected in pregnant women at mean blood lead ≥2.2 μg/dL [107], and damages in female reproductive system have been reported at BLLs above 2.5 μg/dL [95]. Some prevention strategies should be considered for protection of the toxic effects of lead. Preventive measures should include at least the following:


## **7. Conclusions**

There is enough evidence that lead exposure can harm reproductive health of both men and women. The harmful effects of lead have been mostly observed in occupationally exposed people. Nevertheless, in recent decades, research has demonstrated that these damages can occur at levels of lead formerly considered harmless. Most observed effects on male reproductive system are related to the direct impact of lead on semen quality, such as volume of ejaculation, sperm density, abnormal morphology, sperm count, and motility. In addition, lead can alter the concentrations of some male reproductive hormones, such as follicle stimulating hormones, testosterone, and luteinizing hormone.

In women, prenatal exposure to lead, even at very low levels of exposure, has shown to be harmful for both the mother and the fetus. Thus, any level of lead exposure could be associated with adverse reproductive outcomes. Lead has been associated with a wide range of adverse outcomes, including spontaneous abortion, intrauterine growth restriction, premature delivery, stillbirths, pregnancy hypertension, preeclampsia, and low birth weight, among others.

Several recent studies have suggested hypothesis related to the mechanisms by which lead affects male and female reproductive health. However, more research is

**13**

**Author details**

Mexico

Osmel La Llave León\* and José M. Salas Pacheco

provided the original work is properly cited.

The authors declare no conflicts of interest.

Institute of Scientific Research at Juarez University of Durango State, Durango,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

needed to clarify these mechanisms. In conclusion, lead exposure remains a health problem for both male and female reproductive health. It is important to implement protective measures to avoid the harmful effects of this toxic metal on reproductive

The authors are grateful to researchers, managers, and technicians, who contributed and collaborated in this research. The authors are grateful to researchers Eloisa Esquivel, Gonzalo García Vargas, Ada Sandoval Carrillo, Edna Mendez Hernandez, and Francisco Castellanos Juárez for the assistance in the preparation of this chapter. The authors would also like to recognize the Council of Science and Technology

of the State of Durango (COCYTED) for the support to their investigations.

\*Address all correspondence to: ollave56@yahoo.es; olallavel@ujed.mx

*Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

health of both men and women.

**Acknowledgements**

**Conflict of interest**

## *Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

needed to clarify these mechanisms. In conclusion, lead exposure remains a health problem for both male and female reproductive health. It is important to implement protective measures to avoid the harmful effects of this toxic metal on reproductive health of both men and women.

## **Acknowledgements**

*Lead Chemistry*

include at least the following:

sources

**7. Conclusions**

exposed population

adverse health effects can occur. With respect to females, adverse reproductive outcomes have been observed also at BLLs below 5 μg/dL, decrease in delta-aminolevulinic acid dehydratase (ALAD) activity has been detected in pregnant women at mean blood lead ≥2.2 μg/dL [107], and damages in female reproductive system have been reported at BLLs above 2.5 μg/dL [95]. Some prevention strategies should be considered for protection of the toxic effects of lead. Preventive measures should

• Developing public awareness campaigns to identify sources of health exposure

• Screening of lead exposure for all pregnant women by means of diagnosis tests,

• Keeping children and pregnant women with BLL ≥ 5 μg/dL out of exposure

• Requiring employers to take measures to reduce lead levels in workplaces

• To carry out a review of regulations to ensure greater protection for the

• Increasing environmental monitoring (lead in air, soil, water, etc.) to detect

• Searching for new biomarkers, with high sensitivity and specificity, to assess

There is enough evidence that lead exposure can harm reproductive health of both men and women. The harmful effects of lead have been mostly observed in occupationally exposed people. Nevertheless, in recent decades, research has demonstrated that these damages can occur at levels of lead formerly considered harmless. Most observed effects on male reproductive system are related to the direct impact of lead on semen quality, such as volume of ejaculation, sperm density, abnormal morphology, sperm count, and motility. In addition, lead can alter the concentrations of some male reproductive hormones, such as follicle stimulat-

In women, prenatal exposure to lead, even at very low levels of exposure, has shown to be harmful for both the mother and the fetus. Thus, any level of lead exposure could be associated with adverse reproductive outcomes. Lead has been associated with a wide range of adverse outcomes, including spontaneous abortion, intrauterine growth restriction, premature delivery, stillbirths, pregnancy hyper-

Several recent studies have suggested hypothesis related to the mechanisms by which lead affects male and female reproductive health. However, more research is

• Evaluation of risk factors for all pregnant women in their prenatal care

• Education of childbearing age women to avoid sources of lead exposure

such as blood lead, ALAD activity, and urine ALA

• Requiring exposed workers to use protective means

any deviation from established standards

the exposure and effects of lead in the body

ing hormones, testosterone, and luteinizing hormone.

tension, preeclampsia, and low birth weight, among others.

**12**

The authors are grateful to researchers, managers, and technicians, who contributed and collaborated in this research. The authors are grateful to researchers Eloisa Esquivel, Gonzalo García Vargas, Ada Sandoval Carrillo, Edna Mendez Hernandez, and Francisco Castellanos Juárez for the assistance in the preparation of this chapter. The authors would also like to recognize the Council of Science and Technology of the State of Durango (COCYTED) for the support to their investigations.

## **Conflict of interest**

The authors declare no conflicts of interest.

## **Author details**

Osmel La Llave León\* and José M. Salas Pacheco Institute of Scientific Research at Juarez University of Durango State, Durango, Mexico

\*Address all correspondence to: ollave56@yahoo.es; olallavel@ujed.mx

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Borja-Aburto VH, Hertz-Picciotto I, Rojas-Lopez M, Farias P, Rios C, Blanco J. Blood lead levels measured prospectively and risk of spontaneous abortion. American Journal of Epidemiology. 1999;**150**:590-597

[2] Irgens A, Krüger K, Skorve AH, Irgens LM. Reproductive outcome in offspring of parents occupationally exposed to lead in Norway. American Journal of Industrial Medicine. 1998;**34**:431-437. DOI: 10.1002/ (SICI)1097-0274(199811)34:5<431::AID-AJIM3>3.0.CO;2-T

[3] Cheng L, Zhang B, Huo W, Cao Z, Liu W, Liao J, et al. Fetal exposure to lead during pregnancy and the risk of preterm and early-term deliveries. International Journal of Hygiene and Environmental Health. 2017;**220**:984-989. DOI: 10.1016/j. ijheh.2017.05.006

[4] Rahman A, Kumarathasan P, Gomes J. Infant and mother related outcomes from exposure to metals with endocrine disrupting properties during pregnancy. Science of the Total Environment. 2016;**569-570**:1022-1031. DOI: 10.1016/j.scitotenv.2016.06.134

[5] Huang S, Xia W, Sheng X, Qiu L, Zhang B, Chen T, et al. Maternal lead exposure and premature rupture of membranes: A birth cohort study in China. BMJ Open. 2018;**8**:1-7. DOI: 10.1136/bmjopen-2018-021565

[6] Sowers M, Jannausch M, Scholl T, Li W, Kemp FW, Bogden JD. Blood lead concentrations and pregnancy outcomes. Archives of Environmental Health. 2002;**57**:489-495

[7] Bede-Ojimadu O, Amadi CN, Orisakwe OE. Blood lead levels in women of child-bearing age in sub-Saharan Africa: A systematic review. Frontiers in Public Health. 2018;**6**:1-18. DOI: 10.3389/fpubh.2018.00367

[8] Tyrrell JB, Hafida S, Stemmer P, Adhami A, Leff T. Lead (Pb) exposure promotes diabetes in obese rodents. Journal of Trace Elements in Medicine and Biology. 2017;**39**:221-226. DOI: 10.1016/j.jtemb.2016.10.007

[9] Cantonwine D, Hu H, Sánchez BN, Lamadrid-Figueroa H, Smith D, Ettinger AS, et al. Critical windows of fetal lead exposure. Journal of Occupational and Environmental Medicine. 2010;**52**:1106-1111. DOI: 10.1097/jom.0b013e3181f86fee

[10] Wu HM, Lin-Tan DT, Wang ML, Huang HY, Lee CL, Wang HS, et al. Lead level in seminal plasma may affect semen quality for men without occupational exposure to lead. Reproductive Biology and Endocrinology. 2012;**10**:1. DOI: 10.1186/1477-7827-10-91

[11] Alexander BH, Checkoway H, Van Netten C, Muller CH, Ewers TG, Kaufman JD, et al. Semen quality of men employed at a lead smelter. Occupational and Environmental Medicine. 1996;**53**:411-416. DOI: 10.1136/ oem.53.6.411

[12] Debnath B, Ibrahim M, Fatima P. Study of blood lead and semen lead concentration in male infertility. Pulse. 2011;**4**:10-13. DOI: 10.3329/pulse. v4i1.6956

[13] Hosni H, Selim O, Abbas M, Fathy A. Semen quality and reproductive endocrinal function related to blood lead levels in infertile painters. Andrologia. 2013;**45**:120-127. DOI: 10.1111/j.1439-0272.2012.01322.x

[14] Benoff S, Centola GM, Millan C, Napolitano B, Marmar JL, Hurley IR. Increased seminal plasma lead levels adversely affect the fertility potential of sperm in IVF. Human Reproduction. 2003;**18**:374-383. DOI: 10.1093/humrep/ deg020

**15**

10.1007/BF03345710

[21] Haghighi KS, Aminian O, Chavoshi F, Bahaedini LS, Soltani S, Najarkolaei FR. Relationship between blood lead level and male reproductive

*Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

[15] Erfurth EM, Gerhardsson L, Nilsson A, Rylander L, Schütz A, Skerfving S, et al. Effects of lead on the endocrine system in lead smelter workers. Archives of Environmental Health. 2001;**56**:449-455. DOI: 10.1080/00039890109604481

hormones in male lead exposed workers of a battery factory: A cross-sectional study. International Journal of Reproductive Biomedicine.

10.9790/0853-1509044954

DOI: 10.1136/oem.48.7.485

[25] Benedetti S, Tagliamonte MC, Catalani S, Primiterra M, Canestrari F, Stefani S De, et al. Differences in blood and semen oxidative status in fertile and infertile men, and their relationship with sperm quality. Reproductive Biomedicine Online 2012;**25**:300-306. DOI: 10.1016/j.rbmo.2012.05.011

[26] Goyer RA, Clarkson T. Toxic effects of metals. In: Klaassen C, editor. Essentials of Toxicology. 6th ed. New York: McGraw-Hill; 2001. p. 811-867

[27] Wiebe JP, Salhanick AI, Myers KI. Life Sciences. Vol. 32. USA: Pergamon

[28] Batarseh LI, Welsh MJ, Brabec MJ. Effect of lead acetate on sertoli cell lactate production and protein synthesis in vitro. Cell Biology and Toxicology. 1986;**2**:283-292. DOI: 10.1007/

[29] Winder C. Reproductive and chromosomal effects of occupational

exposure to lead in the male.

Press; 2005. pp. 1997-2005

BF00122696

biolreprod37.5.1135

[22] Al-Omary HL, Alawa ZM, Jaafar I. Environmental lead exposure and male infertility. IOSR Journal of Dental and Medical Sciences. 2016;**15**:49-54. DOI:

[23] Sokol RZ. Hormonal effects of lead acetate in the male rat: Mechanism of action1. Biology of Reproduction. 1987;**37**:1135-1138. DOI: 10.1095/

[24] Ng TP, Goh HH, Ng YL, Ong HY, Ong CN, Chia KS, et al. Male endocrine functions in workers with moderate exposure to lead. British Journal of Industrial Medicine. 1991;**48**:485-491.

2013;**11**:673-676

[16] Gulson BLL, Jameson CWW, Mahaffey KRR, Mizon KJJ, Korsch MJJ, Vimpani G. Pregnancy increases mobilization of lead from maternal skeleton. The Journal of Laboratory and Clinical Medicine. 1997;**130**:51-62. DOI:

10.1016/S0022-2143(97)90058-5

[17] Rodamilans M, Osaba MJM, To-Figueras J, Fillat FR, Marques JM, Pérez P, et al. Lead toxicity on endocrine testicular function in an occupationally

exposed population. Human & Experimental Toxicology. 1988;**7**:125- 128. DOI: 10.1177/096032718800700203

[18] Tuppurainen M, Wägar G,

sjweh.1934

Kurppa K, Sakari W, Fröseth B, Alho J, et al. Thyroid function as assessed by routine laboratory tests of workers with long-term lead exposure. Scandinavian Journal of Work, Environment & Health. 1988;**14**:175-180. DOI: 10.5271/

[19] Nigg JT, Elmore AL, Natarajan N, Friderici KH, Nikolas MA. Variation in an iron metabolism gene moderates the association between blood lead levels and attention-deficit/hyperactivity disorder in children. Psychological Science. 2016;**27**:257-269. DOI: 10.1177/0956797615618365

[20] Doumouchtsis KK, Doumouchtsis SK, Doumouchtsis EK, Perrea DN. The effect of lead intoxication on endocrine functions. Journal of Endocrinological Investigation. 2009;**32**:175-183. DOI:

## *Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

[15] Erfurth EM, Gerhardsson L, Nilsson A, Rylander L, Schütz A, Skerfving S, et al. Effects of lead on the endocrine system in lead smelter workers. Archives of Environmental Health. 2001;**56**:449-455. DOI: 10.1080/00039890109604481

[16] Gulson BLL, Jameson CWW, Mahaffey KRR, Mizon KJJ, Korsch MJJ, Vimpani G. Pregnancy increases mobilization of lead from maternal skeleton. The Journal of Laboratory and Clinical Medicine. 1997;**130**:51-62. DOI: 10.1016/S0022-2143(97)90058-5

[17] Rodamilans M, Osaba MJM, To-Figueras J, Fillat FR, Marques JM, Pérez P, et al. Lead toxicity on endocrine testicular function in an occupationally exposed population. Human & Experimental Toxicology. 1988;**7**:125- 128. DOI: 10.1177/096032718800700203

[18] Tuppurainen M, Wägar G, Kurppa K, Sakari W, Fröseth B, Alho J, et al. Thyroid function as assessed by routine laboratory tests of workers with long-term lead exposure. Scandinavian Journal of Work, Environment & Health. 1988;**14**:175-180. DOI: 10.5271/ sjweh.1934

[19] Nigg JT, Elmore AL, Natarajan N, Friderici KH, Nikolas MA. Variation in an iron metabolism gene moderates the association between blood lead levels and attention-deficit/hyperactivity disorder in children. Psychological Science. 2016;**27**:257-269. DOI: 10.1177/0956797615618365

[20] Doumouchtsis KK, Doumouchtsis SK, Doumouchtsis EK, Perrea DN. The effect of lead intoxication on endocrine functions. Journal of Endocrinological Investigation. 2009;**32**:175-183. DOI: 10.1007/BF03345710

[21] Haghighi KS, Aminian O, Chavoshi F, Bahaedini LS, Soltani S, Najarkolaei FR. Relationship between blood lead level and male reproductive hormones in male lead exposed workers of a battery factory: A cross-sectional study. International Journal of Reproductive Biomedicine. 2013;**11**:673-676

[22] Al-Omary HL, Alawa ZM, Jaafar I. Environmental lead exposure and male infertility. IOSR Journal of Dental and Medical Sciences. 2016;**15**:49-54. DOI: 10.9790/0853-1509044954

[23] Sokol RZ. Hormonal effects of lead acetate in the male rat: Mechanism of action1. Biology of Reproduction. 1987;**37**:1135-1138. DOI: 10.1095/ biolreprod37.5.1135

[24] Ng TP, Goh HH, Ng YL, Ong HY, Ong CN, Chia KS, et al. Male endocrine functions in workers with moderate exposure to lead. British Journal of Industrial Medicine. 1991;**48**:485-491. DOI: 10.1136/oem.48.7.485

[25] Benedetti S, Tagliamonte MC, Catalani S, Primiterra M, Canestrari F, Stefani S De, et al. Differences in blood and semen oxidative status in fertile and infertile men, and their relationship with sperm quality. Reproductive Biomedicine Online 2012;**25**:300-306. DOI: 10.1016/j.rbmo.2012.05.011

[26] Goyer RA, Clarkson T. Toxic effects of metals. In: Klaassen C, editor. Essentials of Toxicology. 6th ed. New York: McGraw-Hill; 2001. p. 811-867

[27] Wiebe JP, Salhanick AI, Myers KI. Life Sciences. Vol. 32. USA: Pergamon Press; 2005. pp. 1997-2005

[28] Batarseh LI, Welsh MJ, Brabec MJ. Effect of lead acetate on sertoli cell lactate production and protein synthesis in vitro. Cell Biology and Toxicology. 1986;**2**:283-292. DOI: 10.1007/ BF00122696

[29] Winder C. Reproductive and chromosomal effects of occupational exposure to lead in the male.

**14**

*Lead Chemistry*

**References**

[1] Borja-Aburto VH, Hertz-Picciotto I, Rojas-Lopez M, Farias P, Rios C, Blanco J. Blood lead levels measured prospectively and risk of spontaneous

[8] Tyrrell JB, Hafida S, Stemmer P, Adhami A, Leff T. Lead (Pb) exposure promotes diabetes in obese rodents. Journal of Trace Elements in Medicine and Biology. 2017;**39**:221-226. DOI:

[9] Cantonwine D, Hu H, Sánchez BN, Lamadrid-Figueroa H, Smith D, Ettinger AS, et al. Critical windows of fetal lead exposure. Journal of Occupational and Environmental Medicine. 2010;**52**:1106-1111. DOI: 10.1097/jom.0b013e3181f86fee

[10] Wu HM, Lin-Tan DT, Wang ML, Huang HY, Lee CL, Wang HS, et al. Lead level in seminal plasma may affect semen quality for men without occupational exposure to lead. Reproductive Biology and Endocrinology. 2012;**10**:1. DOI:

10.1186/1477-7827-10-91

oem.53.6.411

v4i1.6956

deg020

[11] Alexander BH, Checkoway H, Van Netten C, Muller CH, Ewers TG, Kaufman JD, et al. Semen quality of men employed at a lead smelter. Occupational and Environmental Medicine. 1996;**53**:411-416. DOI: 10.1136/

[12] Debnath B, Ibrahim M, Fatima P. Study of blood lead and semen lead concentration in male infertility. Pulse. 2011;**4**:10-13. DOI: 10.3329/pulse.

[13] Hosni H, Selim O, Abbas M, Fathy A. Semen quality and reproductive endocrinal function related to blood lead levels in infertile painters. Andrologia. 2013;**45**:120-127. DOI: 10.1111/j.1439-0272.2012.01322.x

[14] Benoff S, Centola GM, Millan C, Napolitano B, Marmar JL, Hurley IR. Increased seminal plasma lead levels adversely affect the fertility potential of sperm in IVF. Human Reproduction. 2003;**18**:374-383. DOI: 10.1093/humrep/

10.1016/j.jtemb.2016.10.007

abortion. American Journal of Epidemiology. 1999;**150**:590-597

[2] Irgens A, Krüger K, Skorve AH, Irgens LM. Reproductive outcome in offspring of parents occupationally exposed to lead in Norway. American Journal of Industrial Medicine. 1998;**34**:431-437. DOI: 10.1002/

(SICI)1097-0274(199811)34:5<431::AID-

[3] Cheng L, Zhang B, Huo W, Cao Z, Liu W, Liao J, et al. Fetal exposure to lead during pregnancy and the risk of preterm and early-term deliveries. International Journal of Hygiene and Environmental Health. 2017;**220**:984-989. DOI: 10.1016/j.

[4] Rahman A, Kumarathasan P, Gomes J. Infant and mother related outcomes from exposure to metals with endocrine disrupting properties during pregnancy. Science of the Total Environment. 2016;**569-570**:1022-1031. DOI: 10.1016/j.scitotenv.2016.06.134

[5] Huang S, Xia W, Sheng X, Qiu L, Zhang B, Chen T, et al. Maternal lead exposure and premature rupture of membranes: A birth cohort study in China. BMJ Open. 2018;**8**:1-7. DOI: 10.1136/bmjopen-2018-021565

[6] Sowers M, Jannausch M, Scholl T, Li W, Kemp FW, Bogden JD. Blood lead concentrations and pregnancy outcomes. Archives of Environmental

Health. 2002;**57**:489-495

[7] Bede-Ojimadu O, Amadi CN, Orisakwe OE. Blood lead levels in women of child-bearing age in sub-Saharan Africa: A systematic review. Frontiers in Public Health. 2018;**6**:1-18. DOI: 10.3389/fpubh.2018.00367

AJIM3>3.0.CO;2-T

ijheh.2017.05.006

Reproductive Toxicology. 1989;**3**:221-233. DOI: 10.1016/0890-6238(89)90016-6

[30] Hsu PC, Liu MY, Hsu CC, Chen LY, Guo YL. Lead exposure causes generation of reactive oxygen species and functional impairment in rat sperm. Toxicology. 1997;**122**:133-143. DOI: 10.1016/S0300-483X(97)00090-5

[31] Siddiqui MK, Srivastava S, Mehrotra PK. Environmental exposure to lead as a risk for prostate cancer. Biomedical and Environmental Sciences. 2002;**15**:298-305

[32] Verze P, Cai T, Lorenzetti S. The role of the prostate in male fertility, health and disease. Nature Reviews. Urology. 2016;**13**:379-386. DOI: 10.1038/ nrurol.2016.89

[33] Kelada SN, Shelton E, Kaufmann RB, Khoury MJ. δ-Aminolevulinic acid dehydratase genotype and lead toxicity: A HuGE review. American Journal of Epidemiology. 2001;**154**:1-13. DOI: 10.1126/science.3.53.32

[34] Vigeh M, Saito H, Sawada S. Lead exposure in female workers who are pregnant or of childbearing age. Industrial Health. 2011;**49**:255-261. DOI: 10.2486/indhealth.MS1192

[35] Xu B, Chia SE, Tsakok M, Ong CN. Trace elements in blood and seminal plasma and their relationship to sperm quality. Reproductive Toxicology. 1993;**7**:613-618

[36] El-Zohairy EA, Youssef AF, Abul-Nasr SM, Fahmy IM, Salem D, Kahil AK, et al. Reproductive hazards of lead exposure among urban Egyptian men. Reproductive Toxicology. 1996;**10**:145-151. DOI: 10.1016/0890-6238(95)02057-8

[37] Robins TG, Bornman MS, Ehrlich RI, Cantrell AC, Pienaar E, Vallabh J, et al. Semen quality and fertility of men

employed in a South African lead acid battery plant. American Journal of Industrial Medicine. 1997;**32**:369-376. DOI: 10.1002/(SICI)1097- 0274(199710)32:4<369::AID-AJIM8>3.0.CO;2-P

[38] Popovic M, McNeill FE, Chettle DR, Webber CE, Lee CV, Kaye WE. Impact of occupational exposure on lead levels in women. Environmental Health Perspectives. 2005;**113**:478-484. DOI: 10.1289/ ehp.7386

[39] La-Llave-León O, Salas Pacheco JM, Estrada Martínez S, Esquivel Rodríguez E, Castellanos Juárez FX, Sandoval Carrillo A, et al. The relationship between blood lead levels and occupational exposure in a pregnant population. BMC Public Health. 2016;**16**:1231. DOI: 10.1186/ s12889-016-3902-3

[40] La-Llave-Leon O, Estrada-Martinez S, Salas-Pacheco JM, Pena-Elosegui R, Duarte-Sustaita J, Rangel JLC, et al. Blood Lead levels and risk factors in pregnant women from Durango, Mexico. Archives of Environmental & Occupational Health. 2011;**66**:107-113. DOI: 10.1080/19338244.2010.511311

[41] Kaličanin B, Velimirović D. A study of the possible harmful effects of cosmetic beauty products on human health. Biological Trace Element Research. 2016;**170**:476-484. DOI: 10.1007/s12011-015-0477-2

[42] Nourmoradi H, Foroghi M, Farhadkhani M, Dastjerdi MV. Assessment of lead and cadmium levels in frequently used cosmetic products in Iran. Journal of Environmental and Public Health. 2013;**2013**:2-7. DOI: 10.1155/2013/962727

[43] Al-Saleh I, Al-Enazi S, Shinwari N. Assessment of lead in cosmetic products. Regulatory Toxicology and Pharmacology.

**17**

bone.2016.05.005

*Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

2009;**54**:105-113. DOI: 10.1016/j.

for gestation. Reproductive Toxicology. 2009;**27**:190-195. DOI: 10.1016/j.

[52] Gundacker C, Hengstschläger M. The role of the placenta in fetal exposure to heavy metals. Wiener Medizinische Wochenschrift. 2012;**162**:201-206. DOI:

[53] Hertz-Picciotto I. The evidence that lead increases the risk for spontaneous

Industrial Medicine. 2000;**38**:300-309. DOI: 10.1002/1097-0274(200009)38: 3<300::AID-AJIM9>3.0.CO;2-C

[55] Taylor CM, Golding J, Emond AM. Adverse effects of maternal lead levels on birth outcomes in the ALSPAC study: A prospective birth cohort study. BJOG: An International Journal of Obstetrics and Gynaecology. 2015;**122**:322-328. DOI: 10.1111/1471-0528.12756

[56] Soomro MH, Baiz N, Huel G, Yazbeck C, Botton J, Heude B, et al. Exposure to heavy metals during pregnancy related to gestational diabetes mellitus in diabetes-free mothers. Science of the Total

Environment. 2019;**656**:870-876. DOI:

[58] Vigeh M, Yokoyama K, Mazaheri M, Beheshti S, Ghazizadeh S, Sakai T, et al. Relationship between increased

10.1016/j.scitotenv.2018.11.422

[57] Wells EM, Navas-Acien A, Herbstman JB, Apelberg BJ, Silbergeld EK, Caldwell KL, et al. Low-level lead exposure and elevations in blood pressure during pregnancy. Environmental Health Perspectives. 2011;**119**:664-669. DOI: 10.1289/

ehp.1002666

reprotox.2008.12.006

10.1007/s10354-012-0074-3

abortion. American Journal of

[54] Vigeh M, Yokoyama K, Seyedaghamiri Z, Shinohara A, Matsukawa T, Chiba M, et al. Blood lead at currently acceptable levels may cause preterm labour. Occupational and Environmental Medicine. 2011;**68**:231- 234. DOI: 10.1136/oem.2009.050419

[44] Phipps A, Fels H, Burns MS, Gerstenberger SL. Lead poisoning due to geophagia: The consumption of miniature pottery. Open Journal of Pediatrics. 2012;**02**:60-66. DOI: 10.4236/

[45] Thihalolipavan S, Candalla BM, Ehrlich J. Examining pica in NYC pregnant women with elevated blood lead levels. Maternal and Child Health Journal. 2013;**17**:49-55. DOI: 10.1007/

[46] Bellinger DC. Teratogen update: Lead and pregnancy. Birth Defects Research Part A – Clinical and

[47] Barry PS, Mossman DB. Lead concentrations in human tissues. British Journal of Industrial Medicine. 1970;**27**:339-351. DOI: 10.1136/oem.

[48] Rădulescu A, Lundgren S. A pharmacokinetic model of lead absorption and calcium competitive dynamics. Scientific Reports. 2019;**9**: 1-38. DOI: 10.1038/s41598-019-50654-7

[49] Gulson BL, Mizon KJ, Korsch MJ, Palmer JM, Donnelly JB. Mobilization of lead from human bone tissue during pregnancy and lactation - a summary of long-term research. Science of the Total Environment. 2003;**303**:79-104. DOI: 10.1016/S0048-9697(02)00355-8

[50] Gulson B, Taylor A, Eisman J. Bone remodeling during pregnancy and post-partum assessed by metal lead levels and isotopic concentrations. Bone. 2016;**89**:40-51. DOI: 10.1016/j.

[51] Ying WY, Xu SK, Li H, Yan MH. The effects of lead exposure on placental NF-κB expression and the consequences

Molecular Teratology. 2005;**73**:409-420.

yrtph.2009.02.005

ojped.2012.21010

s10995-012-0947-5

DOI: 10.1002/bdra.20127

27.4.339

*Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

2009;**54**:105-113. DOI: 10.1016/j. yrtph.2009.02.005

*Lead Chemistry*

Reproductive Toxicology. 1989;**3**:221-233. DOI: 10.1016/0890-6238(89)90016-6

employed in a South African lead acid battery plant. American Journal of Industrial Medicine. 1997;**32**:369-376.

[39] La-Llave-León O, Salas Pacheco JM,

[40] La-Llave-Leon O, Estrada-Martinez S, Salas-Pacheco JM, Pena-Elosegui R, Duarte-Sustaita J, Rangel JLC, et al. Blood Lead levels and risk factors in pregnant women from Durango, Mexico. Archives of Environmental & Occupational Health. 2011;**66**:107-113. DOI: 10.1080/19338244.2010.511311

[41] Kaličanin B, Velimirović D. A study of the possible harmful effects of cosmetic beauty products on human health. Biological Trace Element Research. 2016;**170**:476-484. DOI: 10.1007/s12011-015-0477-2

[42] Nourmoradi H, Foroghi M, Farhadkhani M, Dastjerdi MV.

10.1155/2013/962727

[43] Al-Saleh I, Al-Enazi S, Shinwari N. Assessment of lead in cosmetic products. Regulatory Toxicology and Pharmacology.

Assessment of lead and cadmium levels in frequently used cosmetic products in Iran. Journal of Environmental and Public Health. 2013;**2013**:2-7. DOI:

DOI: 10.1002/(SICI)1097- 0274(199710)32:4<369::AID-

[38] Popovic M, McNeill FE, Chettle DR, Webber CE, Lee CV, Kaye WE. Impact of occupational exposure on lead levels in women. Environmental Health Perspectives. 2005;**113**:478-484. DOI: 10.1289/

Estrada Martínez S, Esquivel Rodríguez E, Castellanos Juárez FX, Sandoval Carrillo A, et al. The relationship

between blood lead levels and occupational exposure in a pregnant population. BMC Public Health. 2016;**16**:1231. DOI: 10.1186/

s12889-016-3902-3

AJIM8>3.0.CO;2-P

ehp.7386

[30] Hsu PC, Liu MY, Hsu CC, Chen LY,

Mehrotra PK. Environmental exposure to lead as a risk for prostate cancer. Biomedical and Environmental Sciences. 2002;**15**:298-305

[32] Verze P, Cai T, Lorenzetti S. The role of the prostate in male fertility, health and disease. Nature Reviews. Urology. 2016;**13**:379-386. DOI: 10.1038/

δ-Aminolevulinic acid dehydratase genotype and lead toxicity: A HuGE review. American Journal of Epidemiology. 2001;**154**:1-13. DOI:

[34] Vigeh M, Saito H, Sawada S. Lead exposure in female workers who are pregnant or of childbearing age. Industrial Health. 2011;**49**:255-261. DOI:

[35] Xu B, Chia SE, Tsakok M, Ong CN. Trace elements in blood and seminal plasma and their relationship to sperm quality. Reproductive Toxicology.

[37] Robins TG, Bornman MS, Ehrlich RI, Cantrell AC, Pienaar E, Vallabh J, et al. Semen quality and fertility of men

[36] El-Zohairy EA, Youssef AF, Abul-Nasr SM, Fahmy IM, Salem D, Kahil AK, et al. Reproductive hazards of lead exposure among urban Egyptian men. Reproductive Toxicology. 1996;**10**:145-151. DOI: 10.1016/0890-6238(95)02057-8

nrurol.2016.89

[33] Kelada SN, Shelton E, Kaufmann RB, Khoury MJ.

10.1126/science.3.53.32

10.2486/indhealth.MS1192

1993;**7**:613-618

Guo YL. Lead exposure causes generation of reactive oxygen species and functional impairment in rat sperm. Toxicology. 1997;**122**:133-143. DOI: 10.1016/S0300-483X(97)00090-5

[31] Siddiqui MK, Srivastava S,

**16**

[44] Phipps A, Fels H, Burns MS, Gerstenberger SL. Lead poisoning due to geophagia: The consumption of miniature pottery. Open Journal of Pediatrics. 2012;**02**:60-66. DOI: 10.4236/ ojped.2012.21010

[45] Thihalolipavan S, Candalla BM, Ehrlich J. Examining pica in NYC pregnant women with elevated blood lead levels. Maternal and Child Health Journal. 2013;**17**:49-55. DOI: 10.1007/ s10995-012-0947-5

[46] Bellinger DC. Teratogen update: Lead and pregnancy. Birth Defects Research Part A – Clinical and Molecular Teratology. 2005;**73**:409-420. DOI: 10.1002/bdra.20127

[47] Barry PS, Mossman DB. Lead concentrations in human tissues. British Journal of Industrial Medicine. 1970;**27**:339-351. DOI: 10.1136/oem. 27.4.339

[48] Rădulescu A, Lundgren S. A pharmacokinetic model of lead absorption and calcium competitive dynamics. Scientific Reports. 2019;**9**: 1-38. DOI: 10.1038/s41598-019-50654-7

[49] Gulson BL, Mizon KJ, Korsch MJ, Palmer JM, Donnelly JB. Mobilization of lead from human bone tissue during pregnancy and lactation - a summary of long-term research. Science of the Total Environment. 2003;**303**:79-104. DOI: 10.1016/S0048-9697(02)00355-8

[50] Gulson B, Taylor A, Eisman J. Bone remodeling during pregnancy and post-partum assessed by metal lead levels and isotopic concentrations. Bone. 2016;**89**:40-51. DOI: 10.1016/j. bone.2016.05.005

[51] Ying WY, Xu SK, Li H, Yan MH. The effects of lead exposure on placental NF-κB expression and the consequences for gestation. Reproductive Toxicology. 2009;**27**:190-195. DOI: 10.1016/j. reprotox.2008.12.006

[52] Gundacker C, Hengstschläger M. The role of the placenta in fetal exposure to heavy metals. Wiener Medizinische Wochenschrift. 2012;**162**:201-206. DOI: 10.1007/s10354-012-0074-3

[53] Hertz-Picciotto I. The evidence that lead increases the risk for spontaneous abortion. American Journal of Industrial Medicine. 2000;**38**:300-309. DOI: 10.1002/1097-0274(200009)38: 3<300::AID-AJIM9>3.0.CO;2-C

[54] Vigeh M, Yokoyama K, Seyedaghamiri Z, Shinohara A, Matsukawa T, Chiba M, et al. Blood lead at currently acceptable levels may cause preterm labour. Occupational and Environmental Medicine. 2011;**68**:231- 234. DOI: 10.1136/oem.2009.050419

[55] Taylor CM, Golding J, Emond AM. Adverse effects of maternal lead levels on birth outcomes in the ALSPAC study: A prospective birth cohort study. BJOG: An International Journal of Obstetrics and Gynaecology. 2015;**122**:322-328. DOI: 10.1111/1471-0528.12756

[56] Soomro MH, Baiz N, Huel G, Yazbeck C, Botton J, Heude B, et al. Exposure to heavy metals during pregnancy related to gestational diabetes mellitus in diabetes-free mothers. Science of the Total Environment. 2019;**656**:870-876. DOI: 10.1016/j.scitotenv.2018.11.422

[57] Wells EM, Navas-Acien A, Herbstman JB, Apelberg BJ, Silbergeld EK, Caldwell KL, et al. Low-level lead exposure and elevations in blood pressure during pregnancy. Environmental Health Perspectives. 2011;**119**:664-669. DOI: 10.1289/ ehp.1002666

[58] Vigeh M, Yokoyama K, Mazaheri M, Beheshti S, Ghazizadeh S, Sakai T, et al. Relationship between increased

blood lead and pregnancy hypertension in women without occupational lead exposure in Tehran, Iran. Archives of Environmental Health. 2004;**59**:70-75. DOI: 10.3200/AEOH.59.2.70-75

[59] Yoon JH, Ahn YS. The association between blood lead level and clinical mental disorders in fifty thousand lead-exposed male workers. Journal of Affective Disorders. 2016;**190**:41-46. DOI: 10.1016/j.jad.2015.09.030

[60] Bayat F, Akbari SAA, Dabirioskoei A, Nasiri M, Mellati A. The relationship between blood Lead level and preeclampsia. Electronic Physician. 2016;**8**:3450-3455. DOI: 10.19082/3450

[61] Dawson EB, Evans DR, Kelly R, Van Hook JW. Blood cell lead, calcium, and magnesium levels associated with pregnancy-induced hypertension and preeclampsia. Biological Trace Element Research. 2000;**74**:107-116. DOI: 10.1385/BTER:74:2:107

[62] Disha SS, Goyal M, Kumar PK, Ghosh R, Sharma P. Association of raised blood lead levels in pregnant women with preeclampsia: A study at tertiary centre. Taiwanese Journal of Obstetrics & Gynecology. 2019;**58**: 60-63. DOI: 10.1016/j.tjog.2018.11.011

[63] Ikechukwu IC, Ojareva OIA, Ibhagbemien AJ, Okhoaretor OF, Oluwatomi OB, Akhalufo OS, et al. Blood lead, calcium, and phosphorus in women with preeclampsia in Edo State, Nigeria. Archives of Environmental and Occupational Health. 2012;**67**:163-169. DOI: 10.1080/19338244.2011.619212

[64] Vigeh M, Yokoyama K, Ramezanzadeh F, Dahaghin M, Sakai T, Morita Y, et al. Lead and other trace metals in preeclampsia: A case-control study in Tehran, Iran. Environmental Research. 2006;**100**:268-275. DOI: 10.1016/j.envres.2005.05.005

[65] Vigeh M, Yokoyama K, Shinohara A, Afshinrokh M, Yunesian M. Early pregnancy blood lead levels and the risk of premature rupture of the membranes. Reproductive Toxicology. 2010;**30**:477-480. DOI: 10.1016/j. reprotox.2010.05.007

[66] Huang S, Xia W, Sheng X, Qiu L, Zhang B, Chen T, et al. Maternal lead exposure and premature rupture of membranes: A birth cohort study in China. BMJ Open. 2018;**8**:e021565. DOI: 10.1136/bmjopen-2018-021565

[67] Srivastava S, Mehrotra PK, Srivastava SP, Tandon I, Siddiqui MKJ. Blood lead and zinc in pregnant women and their offspring in intrauterine growth retardation cases. Journal of Analytical Toxicology. 2001;**25**:461-465. DOI: 10.1093/jat/25.6.461

[68] Zhu M, Fitzgerald EF, Gelberg KH, Lin S, Druschel CM. Maternal lowlevel lead exposure and fetal growth. Environmental Health Perspectives. 2010;**118**:1471-1475. DOI: 10.1289/ ehp.0901561

[69] Zhang B, Xia W, Li Y, Bassig BA, Zhou A, Wang Y, et al. Prenatal exposure to lead in relation to risk of preterm low birth weight: A matched case-control study in China. Reproductive Toxicology. 2015;**57**:190- 195. DOI: 10.1016/j.reprotox.2015.06.051

[70] Murphy MJ, Graziano JH, Popovac D, Kline JK, Mehmeti A, Factor-Litvak P, et al. Past pregnancy outcomes among women living in the vicinity of a lead smelter in Kosovo, Yugoslavia. American Journal of Public Health. 1990;**80**:33-35. DOI: 10.2105/ AJPH.80.1.33

[71] Tabacova S, Balabaeva L. Environmental pollutants in relation to complications of pregnancy. Environmental Health Perspectives. 1993;**101**:27-31. DOI: 10.2307/3431372

**19**

*Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

[72] Hertz-Picciotto I, Schramm M, Watt-Morse M, Chantala K, Anderson J, Osterloh J. Patterns and determinants of blood lead during pregnancy. American Journal of Epidemiology. 2000;**152**:829Environmental Health Perspectives. 1988;**78**:15-22. DOI: 10.1289/ehp.887815

[80] Navas-Acien A, Guallar E, Silbergeld EK, Rothenberg SJ. Lead exposure and cardiovascular disease a systematic review. Environmental Health Perspectives. 2007;**115**:472-482.

[81] Han L, Wang X, Han R, Xu M, Zhao Y, Gao Q, et al. Association between blood lead level and blood pressure: An occupational populationbased study in Jiangsu province, China. PLoS One. 2018;**13**:1-10. DOI: 10.1371/

[82] Rothenberg SJ, Kondrasho V, Manalo M, Jiang J, Cuellar R, Garcia M, et al. Increases in hypertension and blood pressure during pregnancy with increased bone lead levels. American Journal of Epidemiology. 2002;**156**: 1079-1087. DOI: 10.1093/aje/kwf163

DOI: 10.1289/ehp.9785

journal.pone.0200289

[83] Magri J, Sammut M,

S0020-7292(03)00212-1

Savona-Ventura C. Lead and other metals in gestational hypertension. International Journal of Gynecology & Obstetrics. 2003;**83**:29-36. DOI: 10.1016/

[84] Ugwuja E, Ejikeme B, Obuna J. Impacts of elevated prenatal blood lead on trace element status and pregnancy outcomes in occupationally nonexposed women. International Journal of Occupational Environmental Medicine. 2011;**2**:143-156

[85] Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of preeclampsia and the other hypertensive disorders of pregnancy. Best Practice & Research: Clinical Obstetrics & Gynaecology. 2011;**25**:391-403. DOI: 10.1016/j.bpobgyn.2011.01.006

[86] Vaziri ND, Khan M. Interplay of reactive oxygen species and nitric oxide in the pathogenesis of experimental lead-induced hypertension. Clinical

837. DOI: 10.1093/aje/152.9.829

[73] Silbergeld EK, Schwartz J, Mahaffey K. Lead and osteoporosis: Mobilization of lead from bone in postmenopausal women. Environmental Research. 1988;**47**:79-94. DOI: 10.1016/

[74] Potula V, Kaye W. Is lead exposure a risk factor for bone loss? Journal of Women's Health. 2005;**14**:461-464. DOI:

[75] Sanín LH, González-Cossío T, Romieu I, Peterson KE, Ruíz S, Palazuelos E, et al. Effect of maternal lead burden on infant weight and weight gain at one month of age among breastfed infants. Pediatrics. 2001;**107**:1016-1023.

DOI: 10.1542/peds.107.5.1016

10.1542/peds.100.5.856

s00420-018-1367-7

2008;**128**:426-435

[78] Vaziri ND, Gonick HC.

[79] Schwartz J. The relationship between blood lead and blood pressure in the NHANES II survey.

Cardiovascular effects of lead exposure. The Indian Journal of Medical Research.

[76] González-Cossío T, Peterson KE, Sanín LH, Fishbein E, Palazuelos E, Aro A, et al. Decrease in birth weight in relation to maternal bone-lead burden. Pediatrics. 1997;**100**:856-862. DOI:

[77] Oguri T, Ebara T, Nakayama SF, Sugiura-Ogasawara M, Kamijima M, Saito H, et al. Association between maternal blood cadmium and lead concentrations and gestational diabetes mellitus in the Japan Environment and Children's Study. International Archives of Occupational and Environmental Health. 2019;**92**:209-217. DOI: 10.1007/

S0013-9351(88)80023-9

10.1089/jwh.2005.14.461

## *Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

*Lead Chemistry*

blood lead and pregnancy hypertension in women without occupational lead exposure in Tehran, Iran. Archives of Environmental Health. 2004;**59**:70-75.

[65] Vigeh M, Yokoyama K, Shinohara A, Afshinrokh M, Yunesian M. Early pregnancy blood lead levels and the risk of premature rupture of the membranes. Reproductive Toxicology. 2010;**30**:477-480. DOI: 10.1016/j.

[66] Huang S, Xia W, Sheng X, Qiu L, Zhang B, Chen T, et al. Maternal lead exposure and premature rupture of membranes: A birth cohort study in China. BMJ Open. 2018;**8**:e021565. DOI:

10.1136/bmjopen-2018-021565

[67] Srivastava S, Mehrotra PK,

DOI: 10.1093/jat/25.6.461

[69] Zhang B, Xia W, Li Y,

Bassig BA, Zhou A, Wang Y, et al. Prenatal exposure to lead in relation to risk of preterm low birth weight: A matched case-control study in China. Reproductive Toxicology. 2015;**57**:190- 195. DOI: 10.1016/j.reprotox.2015.06.051

[70] Murphy MJ, Graziano JH, Popovac D, Kline JK, Mehmeti A, Factor-Litvak P, et al. Past pregnancy outcomes among women living in the vicinity of a lead smelter in Kosovo, Yugoslavia. American Journal of Public Health. 1990;**80**:33-35. DOI: 10.2105/

[71] Tabacova S, Balabaeva L.

Environmental pollutants in relation to complications of pregnancy. Environmental Health Perspectives. 1993;**101**:27-31. DOI: 10.2307/3431372

ehp.0901561

AJPH.80.1.33

Srivastava SP, Tandon I, Siddiqui MKJ. Blood lead and zinc in pregnant women and their offspring in intrauterine growth retardation cases. Journal of Analytical Toxicology. 2001;**25**:461-465.

[68] Zhu M, Fitzgerald EF, Gelberg KH, Lin S, Druschel CM. Maternal lowlevel lead exposure and fetal growth. Environmental Health Perspectives. 2010;**118**:1471-1475. DOI: 10.1289/

reprotox.2010.05.007

DOI: 10.3200/AEOH.59.2.70-75

[59] Yoon JH, Ahn YS. The association between blood lead level and clinical mental disorders in fifty thousand lead-exposed male workers. Journal of Affective Disorders. 2016;**190**:41-46. DOI: 10.1016/j.jad.2015.09.030

[60] Bayat F, Akbari SAA, Dabirioskoei A, Nasiri M, Mellati A. The relationship between blood Lead level and preeclampsia. Electronic Physician. 2016;**8**:3450-3455. DOI: 10.19082/3450

[61] Dawson EB, Evans DR, Kelly R, Van Hook JW. Blood cell lead, calcium, and magnesium levels associated with pregnancy-induced hypertension and preeclampsia. Biological Trace Element Research. 2000;**74**:107-116. DOI:

[62] Disha SS, Goyal M, Kumar PK, Ghosh R, Sharma P. Association of raised blood lead levels in pregnant women with preeclampsia: A study at tertiary centre. Taiwanese Journal of Obstetrics & Gynecology. 2019;**58**: 60-63. DOI: 10.1016/j.tjog.2018.11.011

[63] Ikechukwu IC, Ojareva OIA, Ibhagbemien AJ, Okhoaretor OF, Oluwatomi OB, Akhalufo OS, et al. Blood lead, calcium, and phosphorus in women with preeclampsia in Edo State, Nigeria. Archives of Environmental and Occupational Health. 2012;**67**:163-169. DOI: 10.1080/19338244.2011.619212

[64] Vigeh M, Yokoyama K,

Ramezanzadeh F, Dahaghin M, Sakai T, Morita Y, et al. Lead and other trace metals in preeclampsia: A case-control study in Tehran, Iran. Environmental Research. 2006;**100**:268-275. DOI: 10.1016/j.envres.2005.05.005

10.1385/BTER:74:2:107

**18**

[72] Hertz-Picciotto I, Schramm M, Watt-Morse M, Chantala K, Anderson J, Osterloh J. Patterns and determinants of blood lead during pregnancy. American Journal of Epidemiology. 2000;**152**:829- 837. DOI: 10.1093/aje/152.9.829

[73] Silbergeld EK, Schwartz J, Mahaffey K. Lead and osteoporosis: Mobilization of lead from bone in postmenopausal women. Environmental Research. 1988;**47**:79-94. DOI: 10.1016/ S0013-9351(88)80023-9

[74] Potula V, Kaye W. Is lead exposure a risk factor for bone loss? Journal of Women's Health. 2005;**14**:461-464. DOI: 10.1089/jwh.2005.14.461

[75] Sanín LH, González-Cossío T, Romieu I, Peterson KE, Ruíz S, Palazuelos E, et al. Effect of maternal lead burden on infant weight and weight gain at one month of age among breastfed infants. Pediatrics. 2001;**107**:1016-1023. DOI: 10.1542/peds.107.5.1016

[76] González-Cossío T, Peterson KE, Sanín LH, Fishbein E, Palazuelos E, Aro A, et al. Decrease in birth weight in relation to maternal bone-lead burden. Pediatrics. 1997;**100**:856-862. DOI: 10.1542/peds.100.5.856

[77] Oguri T, Ebara T, Nakayama SF, Sugiura-Ogasawara M, Kamijima M, Saito H, et al. Association between maternal blood cadmium and lead concentrations and gestational diabetes mellitus in the Japan Environment and Children's Study. International Archives of Occupational and Environmental Health. 2019;**92**:209-217. DOI: 10.1007/ s00420-018-1367-7

[78] Vaziri ND, Gonick HC. Cardiovascular effects of lead exposure. The Indian Journal of Medical Research. 2008;**128**:426-435

[79] Schwartz J. The relationship between blood lead and blood pressure in the NHANES II survey. Environmental Health Perspectives. 1988;**78**:15-22. DOI: 10.1289/ehp.887815

[80] Navas-Acien A, Guallar E, Silbergeld EK, Rothenberg SJ. Lead exposure and cardiovascular disease a systematic review. Environmental Health Perspectives. 2007;**115**:472-482. DOI: 10.1289/ehp.9785

[81] Han L, Wang X, Han R, Xu M, Zhao Y, Gao Q, et al. Association between blood lead level and blood pressure: An occupational populationbased study in Jiangsu province, China. PLoS One. 2018;**13**:1-10. DOI: 10.1371/ journal.pone.0200289

[82] Rothenberg SJ, Kondrasho V, Manalo M, Jiang J, Cuellar R, Garcia M, et al. Increases in hypertension and blood pressure during pregnancy with increased bone lead levels. American Journal of Epidemiology. 2002;**156**: 1079-1087. DOI: 10.1093/aje/kwf163

[83] Magri J, Sammut M, Savona-Ventura C. Lead and other metals in gestational hypertension. International Journal of Gynecology & Obstetrics. 2003;**83**:29-36. DOI: 10.1016/ S0020-7292(03)00212-1

[84] Ugwuja E, Ejikeme B, Obuna J. Impacts of elevated prenatal blood lead on trace element status and pregnancy outcomes in occupationally nonexposed women. International Journal of Occupational Environmental Medicine. 2011;**2**:143-156

[85] Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of preeclampsia and the other hypertensive disorders of pregnancy. Best Practice & Research: Clinical Obstetrics & Gynaecology. 2011;**25**:391-403. DOI: 10.1016/j.bpobgyn.2011.01.006

[86] Vaziri ND, Khan M. Interplay of reactive oxygen species and nitric oxide in the pathogenesis of experimental lead-induced hypertension. Clinical

and Experimental Pharmacology & Physiology. 2007;**34**:920-925. DOI: 10.1111/j.1440-1681.2007.04644.x

[87] Vaziri ND. Mechanisms of lead-induced hypertension and cardiovascular disease. American Journal of Physiology. Heart and Circulatory Physiology. 2008;**295**:H454-H465. DOI: 10.1152/ajpheart.00158.2008

[88] Gonick HC, Ding Y, Bondy SC, Ni Z, Vaziri ND. Lead-induced hypertension: Interplay of nitric oxide and reactive oxygen species. Hypertension. 1997;**30**:1487-1492. DOI: 10.1161/01. HYP.30.6.1487

[89] Carmignani M, Volpe AR, Boscolo P, Qiao N, Di Gioacchino M, Grilli A, et al. Catcholamine and nitric oxide systems as targets of chronic lead exposure in inducing selective functional impairment. Life Sciences. 2000;**68**:401-415. DOI: 10.1016/ S0024-3205(00)00954-1

[90] Moreau T, Hannaert P, Orssaud G, Huel G, Garay RP, Claude JR, et al. Influence of membrane sodium transport upon the relation between blood lead and blood pressure in a general male population. Environmental Health Perspectives. 1988;**78**:47-51. DOI: 10.1289/ehp.887847

[91] Joo H, Choi JH, Burm E, Park H, Hong YC, Kim Y, et al. Gender difference in the effects of lead exposure at different time windows on neurobehavioral development in 5-year-old children. Science of the Total Environment. 2018;**615**:1086-1092. DOI: 10.1016/j.scitotenv.2017.10.007

[92] Vahter M, Åkesson A, Lidén C, Ceccatelli S, Berglund M. Gender differences in the disposition and toxicity of metals. Environmental Research. 2007;**104**:85-95. DOI: 10.1016/j.envres.2006.08.003

[93] Oishi H, Nomiyama H, Nomiyama K, Tomokuni K. Comparison between

males and females with respect to the porphyrin metabolic disorders found in workers occupationally exposed to lead. International Archives of Occupational and Environmental Health. 1996;**68**:298- 304. DOI: 10.1007/BF00409414

[94] Chang SH, Cheng BH, Lee SL, Chuang HY, Yang CY, Sung FC, et al. Low blood lead concentration in association with infertility in women. Environmental Research. 2006;**101**:380-386. DOI: 10.1016/j.envres.2005.10.004

[95] Keitt SK, Fagan TF, Marts SA. Understanding sex, differences in environmental health: A thought leaders' roundtable. Environmental Health Perspectives. 2004;**112**:604-609. DOI: 10.1289/ehp.6714

[96] Llop S, Lopez-Espinosa MJ, Rebagliato M, Ballester F. Gender differences in the neurotoxicity of metals in children. Toxicology. 2013;**311**:3-12. DOI: 10.1016/j.tox.2013.04.015

[97] Kumar S. Occupational, environmental and lifestyle factors associated with spontaneous abortion. Reproductive Sciences. 2011;**18**:915-930. DOI: 10.1177/1933719111413298

[98] Main KM, Skakkebæk NE, Virtanen HE, Toppari J. Genital anomalies in boys and the environment. Best Practice & Research. Clinical Endocrinology & Metabolism. 2010;**24**:279-289. DOI: 10.1016/j. beem.2009.10.003

[99] Escobar-Morreale HF. Polycystic ovary syndrome: Definition, aetiology, diagnosis and treatment. Nature Reviews. Endocrinology. 2018;**14**:270- 284. DOI: 10.1038/nrendo.2018.24

[100] Cole TJ, Ahmed ML, Preece MA, Hindmarsh P, Dunger DB. The relationship between insulin-like growth Factor 1, sex steroids and timing of the pubertal growth spurt. Clinical

**21**

*Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

DOI: 10.1515/reveh-2016-0052

[103] Liu Y, Téllez-Rojo MM,

10.1016/j.envint.2019.02.021

intox-2015-0009

Sánchez BN, Zhang Z, Afeiche MC, Mercado-García A, et al. Early lead exposure and pubertal development in a Mexico City population. Environment International. 2019;**125**:445-451. DOI:

[104] Wani AL, Ara A, Usmani JA. Lead toxicity: A review. Interdisciplinary Toxicology. 2015;**8**:55-64. DOI: 10.1515/

[105] Markowitz M. Lead poisoning: A disease for the next millennium. Current Problems in Pediatrics. 2000;**30**:62-70.

[106] Obeng-Gyasi E. Sources of lead exposure in various countries. Reviews on Environmental Health. 2019;**34**: 25-34. DOI: 10.1515/reveh-2018-0037

Esquivel-Rodríguez E, Vázquez-Alaniz F, Sandoval-Carrillo A, et al. Association between blood lead levels and deltaaminolevulinic acid dehydratase in

DOI: 10.1067/mps.2000.104053

[107] La-Llave-León O, Méndez-Hernández EM, Castellanos-Juárez FX,

pone.0224892

[102] Yao Q, Zhou G, Xu M, Dai J, Qian Z, Cai Z, et al. Blood metal levels and serum testosterone concentrations in male and female children and adolescents: NHANES 2011-2012. PLoS One. 2019;**14**:1-14. DOI: 10.1371/journal.

10.1111/cen.12682

Endocrinology. 2015;**82**:862-869. DOI:

pregnant women. International Journal of Environmental Research and Public Health. 2017;**14**:1-10. DOI: 10.3390/

ijerph14040432

[101] Sergeyev O, Burns JS, Williams PL, Korrick SA, Lee MM, Revich B, et al. The association of peripubertal serum concentrations of organochlorine chemicals and blood lead with growth and pubertal development in a longitudinal cohort of boys: A review of published results from the Russian Children's Study. Reviews on Environmental Health. 2017;**32**:83-92.

*Effects of Lead on Reproductive Health DOI: http://dx.doi.org/10.5772/intechopen.91992*

*Lead Chemistry*

and Experimental Pharmacology & Physiology. 2007;**34**:920-925. DOI: 10.1111/j.1440-1681.2007.04644.x

males and females with respect to the porphyrin metabolic disorders found in workers occupationally exposed to lead. International Archives of Occupational and Environmental Health. 1996;**68**:298-

304. DOI: 10.1007/BF00409414

[94] Chang SH, Cheng BH, Lee SL, Chuang HY, Yang CY, Sung FC, et al. Low blood lead concentration in association with infertility in women. Environmental Research. 2006;**101**:380-386. DOI: 10.1016/j.envres.2005.10.004

[95] Keitt SK, Fagan TF, Marts SA. Understanding sex, differences in environmental health: A thought leaders' roundtable. Environmental Health Perspectives. 2004;**112**:604-609.

[96] Llop S, Lopez-Espinosa MJ, Rebagliato M, Ballester F. Gender

DOI: 10.1016/j.tox.2013.04.015

[97] Kumar S. Occupational, environmental and lifestyle factors associated with spontaneous abortion. Reproductive Sciences. 2011;**18**:915-930.

DOI: 10.1177/1933719111413298

[98] Main KM, Skakkebæk NE, Virtanen HE, Toppari J. Genital

beem.2009.10.003

anomalies in boys and the environment. Best Practice & Research. Clinical Endocrinology & Metabolism. 2010;**24**:279-289. DOI: 10.1016/j.

[99] Escobar-Morreale HF. Polycystic ovary syndrome: Definition, aetiology, diagnosis and treatment. Nature Reviews. Endocrinology. 2018;**14**:270- 284. DOI: 10.1038/nrendo.2018.24

[100] Cole TJ, Ahmed ML, Preece MA,

Hindmarsh P, Dunger DB. The relationship between insulin-like growth Factor 1, sex steroids and timing of the pubertal growth spurt. Clinical

differences in the neurotoxicity of metals in children. Toxicology. 2013;**311**:3-12.

DOI: 10.1289/ehp.6714

cardiovascular disease. American Journal of Physiology. Heart and Circulatory Physiology. 2008;**295**:H454-H465. DOI:

[88] Gonick HC, Ding Y, Bondy SC, Ni Z, Vaziri ND. Lead-induced hypertension: Interplay of nitric oxide and reactive oxygen species. Hypertension. 1997;**30**:1487-1492. DOI: 10.1161/01.

[89] Carmignani M, Volpe AR, Boscolo P, Qiao N, Di Gioacchino M, Grilli A, et al. Catcholamine and nitric oxide systems as targets of chronic lead exposure in inducing selective

functional impairment. Life Sciences. 2000;**68**:401-415. DOI: 10.1016/ S0024-3205(00)00954-1

[90] Moreau T, Hannaert P, Orssaud G, Huel G, Garay RP, Claude JR, et al. Influence of membrane sodium transport upon the relation between blood lead and blood pressure in a general male population. Environmental Health Perspectives. 1988;**78**:47-51. DOI:

[91] Joo H, Choi JH, Burm E, Park H, Hong YC, Kim Y, et al. Gender difference in the effects of lead exposure at different time windows on neurobehavioral development in 5-year-old children. Science of the Total Environment. 2018;**615**:1086-1092. DOI:

10.1016/j.scitotenv.2017.10.007

[92] Vahter M, Åkesson A, Lidén C, Ceccatelli S, Berglund M. Gender differences in the disposition and toxicity of metals. Environmental Research. 2007;**104**:85-95. DOI: 10.1016/j.envres.2006.08.003

[93] Oishi H, Nomiyama H, Nomiyama K, Tomokuni K. Comparison between

[87] Vaziri ND. Mechanisms of lead-induced hypertension and

10.1152/ajpheart.00158.2008

HYP.30.6.1487

10.1289/ehp.887847

**20**

Endocrinology. 2015;**82**:862-869. DOI: 10.1111/cen.12682

[101] Sergeyev O, Burns JS, Williams PL, Korrick SA, Lee MM, Revich B, et al. The association of peripubertal serum concentrations of organochlorine chemicals and blood lead with growth and pubertal development in a longitudinal cohort of boys: A review of published results from the Russian Children's Study. Reviews on Environmental Health. 2017;**32**:83-92. DOI: 10.1515/reveh-2016-0052

[102] Yao Q, Zhou G, Xu M, Dai J, Qian Z, Cai Z, et al. Blood metal levels and serum testosterone concentrations in male and female children and adolescents: NHANES 2011-2012. PLoS One. 2019;**14**:1-14. DOI: 10.1371/journal. pone.0224892

[103] Liu Y, Téllez-Rojo MM, Sánchez BN, Zhang Z, Afeiche MC, Mercado-García A, et al. Early lead exposure and pubertal development in a Mexico City population. Environment International. 2019;**125**:445-451. DOI: 10.1016/j.envint.2019.02.021

[104] Wani AL, Ara A, Usmani JA. Lead toxicity: A review. Interdisciplinary Toxicology. 2015;**8**:55-64. DOI: 10.1515/ intox-2015-0009

[105] Markowitz M. Lead poisoning: A disease for the next millennium. Current Problems in Pediatrics. 2000;**30**:62-70. DOI: 10.1067/mps.2000.104053

[106] Obeng-Gyasi E. Sources of lead exposure in various countries. Reviews on Environmental Health. 2019;**34**: 25-34. DOI: 10.1515/reveh-2018-0037

[107] La-Llave-León O, Méndez-Hernández EM, Castellanos-Juárez FX, Esquivel-Rodríguez E, Vázquez-Alaniz F, Sandoval-Carrillo A, et al. Association between blood lead levels and deltaaminolevulinic acid dehydratase in

pregnant women. International Journal of Environmental Research and Public Health. 2017;**14**:1-10. DOI: 10.3390/ ijerph14040432

**23**

**Chapter 2**

**Abstract**

Epigenetics and Lead

Lead exposure continues to threaten human health in a worldwide perspective. Among the multiple target organs affected by lead, central nervous system (CNS) pervades in the adverse consequences by chronic lead exposure, leading to a variety of neurotoxic manifestations and neurological disorders. The epigenetic machinery plays a vital role in the control of key neural functions, particularly neuronal development. Faulty epigenetic gene regulation can have marked deleterious effect on the developing brain that can last for an entire lifespan. Mounting evidence suggests that lead exposure can pose detrimental effect on CNS through these epigenetic mechanisms. And this chapter reviews the current understandings of concrete epigenetic forms, exemplified by DNA methylation, histone modification, and ncRNAs, responding to lead exposure and moderating the consequent neurotoxicity. In addition, Alzheimer's disease (AD) is presented as a typical instance to explain how environmental lead exposure results in the occurrence of AD in an "early exposure, late onset" fashion. A future perspective, highlighting additional forms of epigenetic elements as well as interactive actions among different molecules, was also proposed. In summary, epigenetics was substantially implicated in

**Keywords:** epigenetics, lead neurotoxicity, DNA methylation, histone modification,

Lead (Pb) is a ubiquitous and persistent neurotoxicant that continues to threaten

human health in a global perspective [1]. Although lead has been removed from paints and gasoline, it remains a serious concern as it can still be found in a variety of daily products, including toys, batteries, food, and water [2]. Although Pb poisoning is a preventable disease, thousands of new cases in the United States were reported each year, and about 500,000 children under 5 years old have blood lead levels (BLLs) greater than a threshold level of 5 g/dl, according to Centers for Disease Control and Prevention (CDC) reports [3–7]. Elevated BLLs have become the first noninfection condition to be notifiable at the national level [7]. Lead can cause a series of adverse human consequences at a very low level exposure [8]. Therefore, CDC continually decreased the safe threshold of BLLs, and the current "safe" levels of exposure to lead are 5 mg/dl for children, but still there have been studies to identify cognitive impairments below that dosage, implying that "no level

Neurotoxicity

regulating lead neurotoxicity.

ncRNA, Alzheimer's disease

of lead exposure is safe" [6, 9].

**1. Introduction**

*Yi Xu, Tian Wang and Jie Zhang*

## **Chapter 2**

## Epigenetics and Lead Neurotoxicity

*Yi Xu, Tian Wang and Jie Zhang*

## **Abstract**

Lead exposure continues to threaten human health in a worldwide perspective. Among the multiple target organs affected by lead, central nervous system (CNS) pervades in the adverse consequences by chronic lead exposure, leading to a variety of neurotoxic manifestations and neurological disorders. The epigenetic machinery plays a vital role in the control of key neural functions, particularly neuronal development. Faulty epigenetic gene regulation can have marked deleterious effect on the developing brain that can last for an entire lifespan. Mounting evidence suggests that lead exposure can pose detrimental effect on CNS through these epigenetic mechanisms. And this chapter reviews the current understandings of concrete epigenetic forms, exemplified by DNA methylation, histone modification, and ncRNAs, responding to lead exposure and moderating the consequent neurotoxicity. In addition, Alzheimer's disease (AD) is presented as a typical instance to explain how environmental lead exposure results in the occurrence of AD in an "early exposure, late onset" fashion. A future perspective, highlighting additional forms of epigenetic elements as well as interactive actions among different molecules, was also proposed. In summary, epigenetics was substantially implicated in regulating lead neurotoxicity.

**Keywords:** epigenetics, lead neurotoxicity, DNA methylation, histone modification, ncRNA, Alzheimer's disease

## **1. Introduction**

Lead (Pb) is a ubiquitous and persistent neurotoxicant that continues to threaten human health in a global perspective [1]. Although lead has been removed from paints and gasoline, it remains a serious concern as it can still be found in a variety of daily products, including toys, batteries, food, and water [2]. Although Pb poisoning is a preventable disease, thousands of new cases in the United States were reported each year, and about 500,000 children under 5 years old have blood lead levels (BLLs) greater than a threshold level of 5 g/dl, according to Centers for Disease Control and Prevention (CDC) reports [3–7]. Elevated BLLs have become the first noninfection condition to be notifiable at the national level [7]. Lead can cause a series of adverse human consequences at a very low level exposure [8]. Therefore, CDC continually decreased the safe threshold of BLLs, and the current "safe" levels of exposure to lead are 5 mg/dl for children, but still there have been studies to identify cognitive impairments below that dosage, implying that "no level of lead exposure is safe" [6, 9].

Lead pervades many organs and systems in the human body, but the prime target of lead toxicity is CNS, both in adults and in children [10], resulting in the so-called "neurotoxicity." The developing brain is particularly susceptible to lead neurotoxicity, as demonstrated by several epidemiological and experimental studies [2, 3]. Due to the fact that lead can freely cross blood brain barrier, lead neurotoxicity can also be manifested in adults, with a larger exposure dosage. Particularly, it should be noteworthy that early life exposure to lead can produce persistent alterations in the brain structure of adults, causing lasting impairment of brain function and behavior [3, 11]. Adverse neurotoxic effects caused by lead include intellectual and behavioral deficits in children; deficits in fine motor function and coordination; and deficits in lower performance on intelligence tests [10]. Higher level of lead can cause a wide spectrum of neurological disorders, such as convulsions and coma, including multiple instances of neurodegenerative disorders, such as AD and Parkinson's disease [12–15]. Thus, there is a critical need to understand the mechanisms of lead neurotoxicity.

Among the cellular and molecular mechanisms suggested to underlie lead neurotoxicity, amounting evidence underscored roles of epigenetic molecules. This fast-moving filed of epigenetics has opened a novel avenue of research for understanding how environmentally toxic signals like lead exposure could be readily sensed by organisms and then relayed to reprogram the expression of key functional genes, consequently giving rise to neurotoxic manifestations [3, 16–19]. This chapter is aimed to discuss the advances of epigenetic alterations in response to lead-induced neural deficits, focusing on the concrete epigenetic species and their responsive details. We will also present a synoptic view of epigenetic implications in etiology of AD caused by long-term lead exposure and bring out the possible future perspectives of the related research topics.

## **2. Molecular mechanism of lead-induced neurotoxicity**

Since lead was found to mediate severe neurological impairment toward both children and adults, myriad studies were appreciated to decipher the cellular and molecular alterations underlying this neurotoxic incident. Several routes of action have been most commonly proposed, such as oxidative stress, disruption of blood brain barrier, decreased cellular energy metabolism, deregulation of calcium signaling, and abnormal neural transmission [3, 20]. In terms of relevance to neuronal development and synaptic transmission, postsynaptic mechanisms represented by N-methyl-D-aspartate receptor (NMDAR), presynaptic mechanisms, and brainderived neurotrophic factor (BDNF) signaling were shown to be involved in lead neurotoxicity [8, 21].

NMDR plays an essential role in hippocampus-mediated learning and memory, and its dysfunction is associated with spatial learning abnormalities, as well as dendritic atrophies [22]. Lead regularly disrupted NMDAR function by acting as a potent antagonist. Apart from it, lead exposure also disrupts normal NMDAR ontogeny, such as reducing NR2A content, altering expression of NR1 splice variants [23, 24].

Chronic lead exposure also results in impaired neurotransmission. A previous finding showed that chronic lead exposure reduced Ca2+-dependent glutamate and γ-aminobutyric acid (GABA) release in the rat hippocampus [25, 26]. And in cultured hippocampal neurons, lead exposure was found to impair excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs) [27]. Our lab recently published a finding that chronic lead exposure can inhibit the release of neurotransmitters by interfering with its vesicle pool recycling, and the main protein impacted is synapsin 1, which expression and phosphorylation was prone to lead invasion [28].

**25**

tical interventions [43, 44].

*Epigenetics and Lead Neurotoxicity*

*DOI: http://dx.doi.org/10.5772/intechopen.92657*

lead-led neurological damages and diseases [33, 34].

**3. Epigenetic mechanisms**

An emerging theme involved in lead neurotoxicity is the disruption of brainderived neurotrophic factor (BDNF) expression. BDNF is a trans-synaptic signaling molecule that is released from both dendrites and axons [29]. In response to lead exposure, BDNF levels in cell cultures were downregulated, and the exogenous addition of BDNF can rescue the deleterious effect of Pb [30]. As a regulator of Ca2+ signaling and homeostasis, BDNF perturbation in turn led to the disrupted Ca2+ dependent pathways, which compromise severe neural representations caused by lead exposure [31]. As an alternative consequence, lead impaired the hippocampal dendritic spines, reduced their density, and changed their morphology [32]. These neuronal and molecular processes might reflect variable aspects of lead-induced neurotoxicity. Compared to it, roles of global regulators, such as the emerging epigenetic regulators, are not sufficiently understood. However, given the conformity with outstanding characteristics of lead neurotoxicity, like "early exposure, persisted effect," epigenetics was long hypothesized to be implicated in the etiology of lead-induced psychological disorders [3]. This was supported by further identification of lead exposure as a risk factor of Alzheimer's disease and schizophrenia. Our next section will focus on epigenetic determinants involved in

Epigenetics is defined as the heritable changes in gene expression that are not related to alterations in the genetic code [3]. Epigenetic regulation is found to modify the conformational state of chromatin and the accessibility of specific gene promoters to the transcriptional machinery [14]. There are three main epigenetic mechanisms broadly studied: DNA methylation, posttranslational modifications of histones, and noncoding RNA (ncRNA) [35–37]. The basic modes of action of three epigenetic forms were shown in **Figure 1**. DNA methylation is the most-studied epigenetic mechanism, which involves primarily cytosine methylation of Cytosine Guanine dinucleotides (CpG) via DNA methyltransferases (DNMTs). CpG methylation is often linked with transcriptional inhibition as it interferes with the normal binding and activity of transcription binding proteins [38]. The exception to this is CpG islands, which are CpG-rich sequences that are densely populated with unmethylated CpGs [2]. CpG islands offer the possibility of being differentially regulated by the environmental signals, which are a prime site to study the influence of lead on epigenetic determinants of ensuing neurotoxic phenotypes [39]. Gene expression is also regulated by histone modifications [36]. Histones are alkaline proteins that wrapped around DNA in nucleosomes and moderated gene transcription by modulating chromatin compaction and accessibility [40]. The terminal tails of histone can undergo covalent posttranslational modifications (PTMs), which in turn alter their interaction with DNA. Diverse modification forms were discovered and studied, as well as their influence on transcription of objective genes, including acetylation, phosphorylation, methylation, and ubiquitination [2]. The complex forms of histone modifications could coexist in regulating a common gene or genome, establishing an intricate and complex regulatory network called "histone code" [41, 42]. The proposal of this definition opens an avenue to show the potential accuracy and delicacy of gene expression regulation, via the action of histone modifications, which are operated by corresponding enzymes, such as histone acetyltransferases, histone deacetylases, histone methylases, and histone demethylases. Among them, histone deacetylases have been widely studied and identified as key molecular targets for pharmaceu-

#### *Epigenetics and Lead Neurotoxicity DOI: http://dx.doi.org/10.5772/intechopen.92657*

*Lead Chemistry*

Lead pervades many organs and systems in the human body, but the prime target of lead toxicity is CNS, both in adults and in children [10], resulting in the so-called "neurotoxicity." The developing brain is particularly susceptible to lead neurotoxicity, as demonstrated by several epidemiological and experimental studies [2, 3]. Due to the fact that lead can freely cross blood brain barrier, lead neurotoxicity can also be manifested in adults, with a larger exposure dosage. Particularly, it should be noteworthy that early life exposure to lead can produce persistent alterations in the brain structure of adults, causing lasting impairment of brain function and behavior [3, 11]. Adverse neurotoxic effects caused by lead include intellectual and behavioral deficits in children; deficits in fine motor function and coordination; and deficits in lower performance on intelligence tests [10]. Higher level of lead can cause a wide spectrum of neurological disorders, such as convulsions and coma, including multiple instances of neurodegenerative disorders, such as AD and Parkinson's disease [12–15]. Thus,

there is a critical need to understand the mechanisms of lead neurotoxicity. Among the cellular and molecular mechanisms suggested to underlie lead neurotoxicity, amounting evidence underscored roles of epigenetic molecules. This fast-moving filed of epigenetics has opened a novel avenue of research for understanding how environmentally toxic signals like lead exposure could be readily sensed by organisms and then relayed to reprogram the expression of key functional genes, consequently giving rise to neurotoxic manifestations [3, 16–19]. This chapter is aimed to discuss the advances of epigenetic alterations in response to lead-induced neural deficits, focusing on the concrete epigenetic species and their responsive details. We will also present a synoptic view of epigenetic implications in etiology of AD caused by long-term lead exposure and bring out the possible future

perspectives of the related research topics.

neurotoxicity [8, 21].

splice variants [23, 24].

**2. Molecular mechanism of lead-induced neurotoxicity**

Since lead was found to mediate severe neurological impairment toward both children and adults, myriad studies were appreciated to decipher the cellular and molecular alterations underlying this neurotoxic incident. Several routes of action have been most commonly proposed, such as oxidative stress, disruption of blood brain barrier, decreased cellular energy metabolism, deregulation of calcium signaling, and abnormal neural transmission [3, 20]. In terms of relevance to neuronal development and synaptic transmission, postsynaptic mechanisms represented by N-methyl-D-aspartate receptor (NMDAR), presynaptic mechanisms, and brainderived neurotrophic factor (BDNF) signaling were shown to be involved in lead

NMDR plays an essential role in hippocampus-mediated learning and memory, and its dysfunction is associated with spatial learning abnormalities, as well as dendritic atrophies [22]. Lead regularly disrupted NMDAR function by acting as a potent antagonist. Apart from it, lead exposure also disrupts normal NMDAR ontogeny, such as reducing NR2A content, altering expression of NR1

Chronic lead exposure also results in impaired neurotransmission. A previous finding showed that chronic lead exposure reduced Ca2+-dependent glutamate and γ-aminobutyric acid (GABA) release in the rat hippocampus [25, 26]. And in cultured hippocampal neurons, lead exposure was found to impair excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs) [27]. Our lab recently published a finding that chronic lead exposure can inhibit the release of neurotransmitters by interfering with its vesicle pool recycling, and the main protein impacted is synapsin 1, which expression and phosphorylation was prone to lead invasion [28].

**24**

An emerging theme involved in lead neurotoxicity is the disruption of brainderived neurotrophic factor (BDNF) expression. BDNF is a trans-synaptic signaling molecule that is released from both dendrites and axons [29]. In response to lead exposure, BDNF levels in cell cultures were downregulated, and the exogenous addition of BDNF can rescue the deleterious effect of Pb [30]. As a regulator of Ca2+ signaling and homeostasis, BDNF perturbation in turn led to the disrupted Ca2+ dependent pathways, which compromise severe neural representations caused by lead exposure [31]. As an alternative consequence, lead impaired the hippocampal dendritic spines, reduced their density, and changed their morphology [32].

These neuronal and molecular processes might reflect variable aspects of lead-induced neurotoxicity. Compared to it, roles of global regulators, such as the emerging epigenetic regulators, are not sufficiently understood. However, given the conformity with outstanding characteristics of lead neurotoxicity, like "early exposure, persisted effect," epigenetics was long hypothesized to be implicated in the etiology of lead-induced psychological disorders [3]. This was supported by further identification of lead exposure as a risk factor of Alzheimer's disease and schizophrenia. Our next section will focus on epigenetic determinants involved in lead-led neurological damages and diseases [33, 34].

## **3. Epigenetic mechanisms**

Epigenetics is defined as the heritable changes in gene expression that are not related to alterations in the genetic code [3]. Epigenetic regulation is found to modify the conformational state of chromatin and the accessibility of specific gene promoters to the transcriptional machinery [14]. There are three main epigenetic mechanisms broadly studied: DNA methylation, posttranslational modifications of histones, and noncoding RNA (ncRNA) [35–37]. The basic modes of action of three epigenetic forms were shown in **Figure 1**. DNA methylation is the most-studied epigenetic mechanism, which involves primarily cytosine methylation of Cytosine Guanine dinucleotides (CpG) via DNA methyltransferases (DNMTs). CpG methylation is often linked with transcriptional inhibition as it interferes with the normal binding and activity of transcription binding proteins [38]. The exception to this is CpG islands, which are CpG-rich sequences that are densely populated with unmethylated CpGs [2]. CpG islands offer the possibility of being differentially regulated by the environmental signals, which are a prime site to study the influence of lead on epigenetic determinants of ensuing neurotoxic phenotypes [39].

Gene expression is also regulated by histone modifications [36]. Histones are alkaline proteins that wrapped around DNA in nucleosomes and moderated gene transcription by modulating chromatin compaction and accessibility [40]. The terminal tails of histone can undergo covalent posttranslational modifications (PTMs), which in turn alter their interaction with DNA. Diverse modification forms were discovered and studied, as well as their influence on transcription of objective genes, including acetylation, phosphorylation, methylation, and ubiquitination [2]. The complex forms of histone modifications could coexist in regulating a common gene or genome, establishing an intricate and complex regulatory network called "histone code" [41, 42]. The proposal of this definition opens an avenue to show the potential accuracy and delicacy of gene expression regulation, via the action of histone modifications, which are operated by corresponding enzymes, such as histone acetyltransferases, histone deacetylases, histone methylases, and histone demethylases. Among them, histone deacetylases have been widely studied and identified as key molecular targets for pharmaceutical interventions [43, 44].

#### **Figure 1.**

*Types of epigenetic modifications. (A) CpG methylation; (B) histone modifications represented by acetylation and methylation; (C) biogenesis and inhibitory action of microRNA (miRNA).*

Another layer of epigenetic regulation involves noncoding RNAs (ncRNAs), defined as functional RNA molecules that are not translated into proteins [3]. The category of ncRNA with relevance with epigenetic regulation is composed of microRNA (miRNA), lncRNA, piRNA, and snoRNA, which regulate gene expression at both transcriptional and posttranscriptional levels [37]. miRNA received the most attention among them, and details of miRNA types involved in various epigenetic regulation and neuronal processes were studied comprehensively. For instance, a recent publication revealed that a series of miRNAs can respond to and mediate spinal muscular atrophy pathogenesis [45]; miR-137 participated in the modulation of neuronal maturation by targeting an ubiquitin ligase mind bomb-1 [46].

The different forms of epigenetic regulation are often functionally interlaced, showing an interactive relationship. DNA methylation was commonly accompanied by a specific form of histone methylation, establishing a so-called "hand-in-hand"

**27**

*Epigenetics and Lead Neurotoxicity*

*DOI: http://dx.doi.org/10.5772/intechopen.92657*

intermittent gene expression changes [14].

**4. Lead-induced epigenetic alterations in CNS**

development of lead neurotoxicity.

systems associated with lead neurotoxicity:

**4.1 DNA methylation**

assembly [47]. Histone deacetylase can be recruited by DNA methylation or its functional partner, and these molecules can cooperate with each other to determine (most commonly inhibit) the expressional status of the objective gene [48]. DNA methylations and histone modifications are both involved in establishing patterns of gene expression, and they may play distinct roles in inducing persistent or

Epigenetic mechanisms are implicated in neuronal development, maintenance of cell identity, and aging process [49, 50]. Meanwhile, epigenetic perturbations that lead to chromatin remodeling are in association with a number of neuropsychiatric and neurodegenerative disorders [14, 51], and they are particularly relevant in response to environmental toxicant exposure early in life [38]. The impact of epigenetic determinants can be long lasting, or even transgenerational, that is, the epigenetic traits and gene expression patterns can be sometimes inherited by next

generations, which are not previously exposed to the causative agents [52].

Considering that epigenetic factors are associated with CNS functioning and meanwhile susceptible to environmental exposure, we next discuss the epigenetic outcome brought by lead exposure and the roles of these changes in the etiology and

The relations of lead exposure with neural epigenetic alterations have long been established. Developmental lead exposure results in a variety of epigenetic changes, characterized by DNA methylation alterations, which can impact gene expression patterns and affect nervous system development [5]. Lead can promptly affect the dynamism of epigenetic determinants and promote the rapid turnover of DNA methylation [4]. Consistent with these findings and statements, lead is known to be an epigenetic modifier [53]. The following are advances of three main epigenetic

Lead exposure can result in the global changes of DNA methylation profiles in CNS, and the detailed orientation of methylome changes varied depending on the studied genetic microenvironment. Singh et al. stated that developmental lead exposure disrupted the hippocampal methylome, and the effect is dependent on the gender, timing, and level of exposure [5]. In particular, the global methylome alterations did not reflect the methylation status of the specific genes. That identified lowlevel lead exposure as a causative agent of gene-specific DNA methylation patterns in brain [54]. Senut et al. found that lead exposure disrupts global DNA methylation in human embryonic stem cells and alters their neuronal differentiation [4]. An epidemiological study investigated 105 children participants from birth to 78 months and tested peripheral blood DNA to quantify CpG methylation at Differentially Methylated Regions (DMRs) of 22 human imprinted genes. This study provided evidence that early childhood lead exposure resulted in gene-specific DNA methylation differences in the DMRs of PEG3, PLAGL1/HYMAI, and IGF2/H19 [51]. In 2009, Pilsner et al. published the first human study to reveal that maternal bone lead levels were associated with changes in DNA methylation levels in the umbilical cord blood leukocytes of the offspring [55]. In animal studies, DNA methylome-related genes, including DNA methyltransferases, methyl-cytosine-phosphate-guanine (Me-CpG) binding protein-2 (MeCP2), and methionine synthase, were recognized as the potential targets of lead exposure [56, 57]. Sanchez-Martin et al. reported

#### *Epigenetics and Lead Neurotoxicity DOI: http://dx.doi.org/10.5772/intechopen.92657*

*Lead Chemistry*

**26**

**Figure 1.**

Another layer of epigenetic regulation involves noncoding RNAs (ncRNAs), defined as functional RNA molecules that are not translated into proteins [3]. The category of ncRNA with relevance with epigenetic regulation is composed of microRNA (miRNA), lncRNA, piRNA, and snoRNA, which regulate gene expression at both transcriptional and posttranscriptional levels [37]. miRNA received the most attention among them, and details of miRNA types involved in various epigenetic regulation and neuronal processes were studied comprehensively. For instance, a recent publication revealed that a series of miRNAs can respond to and mediate spinal muscular atrophy pathogenesis [45]; miR-137 participated in the modulation

*Types of epigenetic modifications. (A) CpG methylation; (B) histone modifications represented by acetylation* 

*and methylation; (C) biogenesis and inhibitory action of microRNA (miRNA).*

of neuronal maturation by targeting an ubiquitin ligase mind bomb-1 [46].

The different forms of epigenetic regulation are often functionally interlaced, showing an interactive relationship. DNA methylation was commonly accompanied by a specific form of histone methylation, establishing a so-called "hand-in-hand"

assembly [47]. Histone deacetylase can be recruited by DNA methylation or its functional partner, and these molecules can cooperate with each other to determine (most commonly inhibit) the expressional status of the objective gene [48]. DNA methylations and histone modifications are both involved in establishing patterns of gene expression, and they may play distinct roles in inducing persistent or intermittent gene expression changes [14].

Epigenetic mechanisms are implicated in neuronal development, maintenance of cell identity, and aging process [49, 50]. Meanwhile, epigenetic perturbations that lead to chromatin remodeling are in association with a number of neuropsychiatric and neurodegenerative disorders [14, 51], and they are particularly relevant in response to environmental toxicant exposure early in life [38]. The impact of epigenetic determinants can be long lasting, or even transgenerational, that is, the epigenetic traits and gene expression patterns can be sometimes inherited by next generations, which are not previously exposed to the causative agents [52].

## **4. Lead-induced epigenetic alterations in CNS**

Considering that epigenetic factors are associated with CNS functioning and meanwhile susceptible to environmental exposure, we next discuss the epigenetic outcome brought by lead exposure and the roles of these changes in the etiology and development of lead neurotoxicity.

The relations of lead exposure with neural epigenetic alterations have long been established. Developmental lead exposure results in a variety of epigenetic changes, characterized by DNA methylation alterations, which can impact gene expression patterns and affect nervous system development [5]. Lead can promptly affect the dynamism of epigenetic determinants and promote the rapid turnover of DNA methylation [4]. Consistent with these findings and statements, lead is known to be an epigenetic modifier [53]. The following are advances of three main epigenetic systems associated with lead neurotoxicity:

## **4.1 DNA methylation**

Lead exposure can result in the global changes of DNA methylation profiles in CNS, and the detailed orientation of methylome changes varied depending on the studied genetic microenvironment. Singh et al. stated that developmental lead exposure disrupted the hippocampal methylome, and the effect is dependent on the gender, timing, and level of exposure [5]. In particular, the global methylome alterations did not reflect the methylation status of the specific genes. That identified lowlevel lead exposure as a causative agent of gene-specific DNA methylation patterns in brain [54]. Senut et al. found that lead exposure disrupts global DNA methylation in human embryonic stem cells and alters their neuronal differentiation [4]. An epidemiological study investigated 105 children participants from birth to 78 months and tested peripheral blood DNA to quantify CpG methylation at Differentially Methylated Regions (DMRs) of 22 human imprinted genes. This study provided evidence that early childhood lead exposure resulted in gene-specific DNA methylation differences in the DMRs of PEG3, PLAGL1/HYMAI, and IGF2/H19 [51]. In 2009, Pilsner et al. published the first human study to reveal that maternal bone lead levels were associated with changes in DNA methylation levels in the umbilical cord blood leukocytes of the offspring [55]. In animal studies, DNA methylome-related genes, including DNA methyltransferases, methyl-cytosine-phosphate-guanine (Me-CpG) binding protein-2 (MeCP2), and methionine synthase, were recognized as the potential targets of lead exposure [56, 57]. Sanchez-Martin et al. reported

that lead exposure resulted in hypermethylation of three differentially methylated regions in the hippocampus of females, but not males [11]. Overall, lead is a strong environmental force to globally reshape DNA methylation landscape in brain, which is a susceptible organ for epigenetic regulations.

Apart from methylome, the gene-specific alterations of methylation may reflect the detailed influence of lead exposure in CNS. Zawia et al. examined the activity of DNA methyltransferase in the tissues of 23-year-old primates exposed to lead as infants. As a consequence, they found that activity of this methylation enzyme was selective for cytosine nucleotides in a CpG sequence and specific to ones that base-paired to methylated CpG sequence on the other DNA strand [25]. Some genes triggered during memory formation and synaptic plasticity, such as BDNF, showed marked changes in promoter methylation when DNMT activity is suppressed in mice hippocampus, indicating that BDNF can be potentially modulated by specified DNA methylation status [58]. Wu et al. investigated the association between prenatal maternal lead exposure and epigenome-wide DNA methylation. Among female infants, one CpG (cg24637308) showed a strong negative association with lead levels, and this CpG site was thought to be highly expressed in human brain [59]. Our previous study also measured CpG methylation levels in specific CpGrich promoter regions of DAT1 and DRD4, two dopaminergic-related genes, in the children with higher blood lead levels. According to it, a specific CpG site located upstream of DRD4-coding region was found to be hypermethylated due to lead exposure, and this changes were negatively correlated with the expression levels of DRD4 [39]. The relevant literature pertaining to associations of lead neurotoxicity and DNA methylation was summarized and shown in **Table 1**.

A number of reports suggested that alteration in DNA methylation was largely gender- and tissue-dependent [73]. Early life lead exposure of 3 and 30 ppm led to gender-specific DNA hypermethylation at Rn45a and Sfi1 genes in the hippocampus of female mice only [11]. Another study also stated that maternal lead exposure caused gender-specific epigenetic outcomes for varying degree of vulnerability later in life [74]. These gender differences might be related to the action of sex hormone and the structural discrepancies of body structure resulting in the variance of lead metabolic routes.

CpG methylation was reprogrammed through the action of DNA methylases. Amounting evidence suggested that this pathway was utilized by lead to bring adverse neurological outcome. In a 23-year-old primate with early exposure of lead, protein levels of DNMTs and MeCP2 were significantly decreased. And this attenuation was consistent with hypomethylating effects at multiple genetic loci [14]. Another report found a decreased DNA methyltransferase activity in mouse cortical neuronal cells exposed to lead for 24 h and determined later in life [16]. In a mouse study with developmental lead exposure, DNMT3a in male mice displayed increased expression with 150 and 750 ppm of Pb, while female mice had decreased expression of DNMT3a in response to 150 and 375 ppm of Pb. Moreover, developmental lead exposure can also affect the expression of DNMT1 and MeCP2 in murine hippocampus, which gender and exposure periods were critical contributing factors [57]. Therefore, both expression levels and enzymatic activities of methylation-modifying enzymes can be modulated by lead exposure in CNS.

Except from a conventional methylation form, 5-hydroxymethylated cytosine (5hmC), a new modification and mostly implicated in promoting gene expression, was recently known to be altered by lead exposure in CNS. 5hmCs was extremely abundant in rodent brains, and they are closely associated with critical neurodevelopmental processes such as neuronal differentiation and synaptic function [75]. In light of it, Sen et al. reported that prenatal exposure to lead can alter the hydroxymethylation profile of 5hmC-riched clusters of imprinted genes, which resulted in an

**29**

*Epigenetics and Lead Neurotoxicity*

**Animal (Age) Exposure** 

Newborns From birth

Rats (PND55) 10 days prior

Human embryonic stem cell

Newborns (prenatal)

Mice (10 months)

Mice (PND 20 and 700)

Mice (PND20 and PND700)

Mice (PND1 to PND20)

Monkeys (23 years)

Mice (2 months)

*DOI: http://dx.doi.org/10.5772/intechopen.92657*

**duration**

A: day 1 B: day 5 C: days 0–19 D: days 11–19

to 78 months

2 weeks prior mating and during gestation and lactation until PND21

Gestational D13 until PND20

breeding till weaning of 55D

Gestational D13 until PND20

PND1 to PND21

Birth until 400D

2 months prior mating and during gestation and lactation until PND2

**Epigenetic mechanisms**

development

methylation

Prenatal DNA methylation

DNA methylation status of genes crucial to brain

at LINE-1 repetitive elements; UCB LINE-1

DMR methylation for PEG3 (A), IGF2/ H19 (B), and HYMA/ PLAGL1 (C)

Average brain methylation: IAP 110:80%

↓DNMT1 with postnatal

↓DNMT1 with postnatal

↑DNMT1 with postnatal

501 downregulated genes and 647 upregulated genes

↑Dlx1 methylation ↓Gene expression of Dlx1/2/5/6 ↑Gene expression of

Hypermethylation in:

loci in chromosome2 Sfi1 loci in chromosome11 (Rn45s loci inchromosome17)

Tubb3

Rn4.5s

↓DNMT1 ↑APPmRNA ↑Aβ1-40mRNA ↑Aβ1-42mRNA

150ppm Pb

375ppm Pb

750ppm Pb ↓DNMT1 will all perinatal Pb

**Pathophysiological outcomes (possible)**

Exposure to Pb subtly alters the neuronal differentiation of exposed hESCs

Epigenetic alterations have detrimental effects on the developing brain, neurological development, and

disease

old age

DNA hypermethylation Gene repression in

Sex-dependent and gene-specific DNA methylation

Neurodegeneration, narcolepsy

Defects in neuronal maturation, synaptic plasticity, learning, memory, cognition, and behavior

Affecting immune responses, metal binding, metabolism, transcription, and transduction

Hyperactivity, weight loss, abnormal behavior

DNA methylation (sex and tissue specific)

Alzheimer's disease [16]

**References**

[4]

[38]

[51]

[60]

[61]

[57]

[56]

[62]

[11]

*Lead Chemistry*

that lead exposure resulted in hypermethylation of three differentially methylated regions in the hippocampus of females, but not males [11]. Overall, lead is a strong environmental force to globally reshape DNA methylation landscape in brain, which

Apart from methylome, the gene-specific alterations of methylation may reflect the detailed influence of lead exposure in CNS. Zawia et al. examined the activity of DNA methyltransferase in the tissues of 23-year-old primates exposed to lead as infants. As a consequence, they found that activity of this methylation enzyme was selective for cytosine nucleotides in a CpG sequence and specific to ones that base-paired to methylated CpG sequence on the other DNA strand [25]. Some genes triggered during memory formation and synaptic plasticity, such as BDNF, showed marked changes in promoter methylation when DNMT activity is suppressed in mice hippocampus, indicating that BDNF can be potentially modulated by specified DNA methylation status [58]. Wu et al. investigated the association between prenatal maternal lead exposure and epigenome-wide DNA methylation. Among female infants, one CpG (cg24637308) showed a strong negative association with lead levels, and this CpG site was thought to be highly expressed in human brain [59]. Our previous study also measured CpG methylation levels in specific CpGrich promoter regions of DAT1 and DRD4, two dopaminergic-related genes, in the children with higher blood lead levels. According to it, a specific CpG site located upstream of DRD4-coding region was found to be hypermethylated due to lead exposure, and this changes were negatively correlated with the expression levels of DRD4 [39]. The relevant literature pertaining to associations of lead neurotoxicity

A number of reports suggested that alteration in DNA methylation was largely gender- and tissue-dependent [73]. Early life lead exposure of 3 and 30 ppm led to gender-specific DNA hypermethylation at Rn45a and Sfi1 genes in the hippocampus of female mice only [11]. Another study also stated that maternal lead exposure caused gender-specific epigenetic outcomes for varying degree of vulnerability later in life [74]. These gender differences might be related to the action of sex hormone and the structural discrepancies of body structure resulting in the variance of lead

CpG methylation was reprogrammed through the action of DNA methylases. Amounting evidence suggested that this pathway was utilized by lead to bring adverse neurological outcome. In a 23-year-old primate with early exposure of lead, protein levels of DNMTs and MeCP2 were significantly decreased. And this attenuation was consistent with hypomethylating effects at multiple genetic loci [14]. Another report found a decreased DNA methyltransferase activity in mouse cortical neuronal cells exposed to lead for 24 h and determined later in life [16]. In a mouse study with developmental lead exposure, DNMT3a in male mice displayed increased expression with 150 and 750 ppm of Pb, while female mice had decreased expression of DNMT3a in response to 150 and 375 ppm of Pb. Moreover, developmental lead exposure can also affect the expression of DNMT1 and MeCP2 in murine hippocampus, which gender and exposure periods were critical contributing factors [57]. Therefore, both expression levels and enzymatic activities of methylation-modifying enzymes can be modulated by lead exposure in CNS. Except from a conventional methylation form, 5-hydroxymethylated cytosine (5hmC), a new modification and mostly implicated in promoting gene expression, was recently known to be altered by lead exposure in CNS. 5hmCs was extremely abundant in rodent brains, and they are closely associated with critical neurodevelopmental processes such as neuronal differentiation and synaptic function [75]. In light of it, Sen et al. reported that prenatal exposure to lead can alter the hydroxymethylation profile of 5hmC-riched clusters of imprinted genes, which resulted in an

is a susceptible organ for epigenetic regulations.

and DNA methylation was summarized and shown in **Table 1**.

**28**

metabolic routes.



**31**

Mice (E18, PND0, PND6, and PND60)

*Epigenetics and Lead Neurotoxicity*

**Animal (Age) Exposure** 

Mice (PND20, 180 and 700)

Rats (20–22 days)

Rats (2-4 weeks and 12–14 weeks)

Mice (10 months)

*DOI: http://dx.doi.org/10.5772/intechopen.92657*

**duration**

PND1 to PND20

**Epigenetic mechanisms**

(1.5 fold)

(1.6 fold)

(4.8 fold)

(2 fold)

8 weeks ↑miR-211 with 300ppm Pb (1.75 old) ↓ miR-494 with 300ppm Pb (2.04 fold) ↑miR-449a with 300ppm Pb (2.89 fold) ↑miR-34c with 300ppm Pb (4.05 fold) ↑miR-34b with 300ppm Pb (4.48 fold) ↑miR-204 with 300ppm Pb (5.48 fold)

40D Apoptotic cells with

2 weeks prior to mating and continued throughout gestation to 3 weeks after birth

days prior to breeding to PND 21 EPN: birth through weaning (PND 21) LPN: birth through postnatal day 55

2 months prior to breeding and throughout lactation

Rat (PND55) PERI: 10

fold)

↑miR-106b at PND20

↓ miR-34c at PND180

↑ miR-132 at PND20

↓miR-124 at PND700

↑miR-448 with 300ppm Pb (30.51 fold) ↓mRNA with 300ppm Pb (Bcl2, Itpr1) ↓mRNA Map2k1 with 300ppm Pb

irregular nuclear membrane, chromatin clumping, and nuclear fragmentation

ARTN & C5aR1 methylation 32 ppm Pb exposure ) Ankdd1b methylation 2.1 ppm Pb exposure)

Quantities of methylation changes at gene promotor region and varies according to

Changes of H3K9Ac, H3K4Me3,

H3K9Me2, H3K27Me3

genders

level

↑miR-29b at PND20 (1.6

**Pathophysiological outcomes (possible)**

Alzheimer's disease, tauopathies

Neural injury, neurodegeneration, axon and synapse dysfunction, impaired neural development and regeneration, impaired performance, Alzheimer's disease, Parkinson's disease and depression

Apoptosis [69]

Death of neurons, Alzheimer's disease, migraine, and major depressive disorder

Schizophrenia, Alzheimer's disease, memory impairment,

Cognition deficits, behavioral dysfunction, neurodevelopmental

disorders

etc.

**References**

[67]

[68]

[70]

[5]

[71]


#### *Epigenetics and Lead Neurotoxicity DOI: http://dx.doi.org/10.5772/intechopen.92657*

*Lead Chemistry*

Mice (PND0 and PND6)

Monkeys (3–6,12,23 years)

Mice (Weeks 20)

Mice (PND20, 180,270, 540, and 700)

Transgenic mice (15) (PND20, 30, 40, and 60)

**Animal (Age) Exposure** 

Rats Perinatal to

60D

Birth until 400D

PND1 to PND20

PND1 to PND20

**duration**

2 months prior breeding and throughout lactation

**Epigenetic mechanisms**

& PND6 ↓H3K9/14Ac ↓H3K9Me3 ↓H3K9/14Ac: 50% at

PND0 with 100ppm Pb ↑H3K9/14Ac: 60% at

PND0 with 100ppm Pb

(22)

23years

E1 to E10 Hypomethylated Chd7 gene

Acetylated H3 in hippocampus ↑p300 (HAT) mRNA ↑HDAC1 mRNA

Altered gene expression

↓Dnmt3a and Dnmt1 at

↑Chd7 gene expression (4.7 folds) Altered histone methylation

↓MeCP2 at PND20 and

↑MAT2A at PND270, 540 and 700 ↓H3K9Ac protein at

↓H3K4Me2 protein at

Hyperphosphorylation (internal and external brain capsule) ↑ miR34c expression b/w PND20 and 50 ↑ tau mRNA at PND20 ↑CDK5 mRNA at PND40

↑ Total tau protein at PND20 and 40 ↑CDK5 protein at PND40 and 60 ↑ Phosphorylated tau Ser396 protein at PND20 and 30

↓DNMT1 protein ↑DNMT3a mRNA at

PND20

PND700

PND20

270

↑APP mRNA and protein

↓MeCP2 at 23years ↑H3K9ac, H4K8ac, H4K12ac ↑H3K4me2

↓H3K9/14Ac:b/w PND0 & PND6 (HPC) ↓ H3K9Me3:b/w PND0

**Pathophysiological outcomes (possible)**

Weight loss, abnormal brain development and cognitive function (sex, age, and brain region specific)

Hyperactivity, behavioral disorder, neurological disorder, ADHD (dose specific)

Neurodegeneration in old age, up and downregulation of

Autism-like behavior, multiple behavioral abnormalities

Alzheimer's disease, tauopathies

Alzheimer disease [15]

genes

**References**

[63]

[64]

[14]

[65]

[66]

**30**


#### **Table 1.**

*Summary of some literature concerning epigenetic changes involved in lead neurotoxicity.*

altered expression of objective genes in a gender-dependent manner. 5hmC may also serve as potential biomarkers for lead susceptibility to neurological diseases [76].

As a general rule, the changes of DNA methylation levels were often negatively correlated with the transcription levels of the objective genes. But this association was dependent on gender, the exposure periods, and their relative genetic locations. Interestingly, for females, genes regulated by DNA methylation were inclined to encode RNA- and protein-related processes; and for males, the enriched pathways included signaling pathways, stress, and neural responses to stimuli [5].

#### **4.2 Histone modification**

Compared to DNA methylation, fewer associations between histone modification and lead neurotoxicity were reported. Categorized by posttranslational forms, most studies focused on histone acetylation changes in response to lead exposure. A specific histone acetylation level results from the balanced counteraction of histone acetyltransferases (HATs) and histone deacetylases (HDACs). An acetylated form normally corresponds to a more relaxed chromatin status, leading to an enhanced expression of the target genes, and *vice versa* [77]. In 2014, our lab published a relatively novel article describing an increased acetylated form of histone H3 as exposed by 5 or 25 mg/l of lead. This alteration accompanies with the enhanced transcription of p300, a typical HAT [64]. Subsequently, the interesting point is that chronic lead exposure reduced the total level of H3K9ac, displaying an opposite tendency to total H3ac levels, which unveiled a specific alteration depending on the concrete acetylation sites, as well as the neural models and exposure conditions used [78].

Some innovative progresses were made in the primates with early life exposure. Bihaqi et al. observed that apart from DNMTs and MeCP2, lead also caused lifelong alterations of H3K9ac, H3K8ac, and H4K12ac, which levels were increased only in 23-year-old adults, not in 12-year-old primates [14]. In another instance, perinatal lead exposure downregulated H3K9ac levels in aging mice, a proof that key epigenetic regulators can be linked with development of Alzheimer's disease [15]. Murine hippocampus and frontal cortex were similar in lead-induced epigenetic changes, that is, H3K9/14ac was gradually reduced as exposure prolonged, factored by mixed actions of gender and prenatal stress [63]. The literature pertaining to histone modifications and lead neurotoxicity was shown in **Table 1**.

**33**

*Epigenetics and Lead Neurotoxicity*

neurological outcomes.

**4.3 ncRNA**

*DOI: http://dx.doi.org/10.5772/intechopen.92657*

Different from histone acetylation, histone methylation gained a stricter site specificity and more stable to maintain gene expression patterns [79]. With the developmental exposure of lead, primates of 400-day olds were subjected to epigenetic examination in brains. H3K4me2 was found to be increased significantly, indicating an activated propensity of related gene expression [14]. In another animal study, H3K9me3 displayed a relatively stable tendency with treatment of lead in mice, and those cases varied depending on the studied brain regions and genders [63]. According to general knowledge gained in this field, H3K4me basically played roles in promoting gene expression, while H3K27me and H3K9me mostly displayed negative regulatory activity. Our previous finding underpinned the importance of H3K27me3 in modulating lead-induced spatial memory deficits [80]. We found that chronic lead exposure perinatally could reduce the global H3K27me3 levels in rat hippocampus, and this alteration led to a genome-wide reprogramming of this repressive epigenetic mark on the target genes. This result gave a picture of how an epigenetic change can give rise to a global genetic response and the ensuing adverse

In contrast with acetylation and methylation, very few studies were shown to investigate the interaction of lead neurotoxicity and other forms of histone modifications. In spite of deficiency of relevant literature, this study is supposed to be promising to totally decipher histone codes involved in lead neurotoxicity. H2A ubiquitination was recently found to be associated with DNA damage response, which suggested that site-specific histone ubiquitination organizes the spatiotemporal recruitment of DNA repair factors, and these recruitments facilitated DNA repair pathway choice between

ncRNAs are epigenetic regulators susceptible to environmental signals. Among diverse forms of ncRNAs, microRNA (miRNA) was most extensively studied concerning their relations with lead neurotoxicity. In rats chronically exposed to lead, at least seven miRNAs were altered considering their expression levels. In details, miR-204, miR-211, miR-448, miR-449a, miR-34b, and miR34c were dramatically upregulated, while miR-494 was downregulated. These miRNAs were implicated in regulating genes involved in neurodegeneration, synaptogenesis, and neuronal injury [68]. Masoud et al. observed that early life lead exposure yielded a transient increase in the expression of AD-related miRNAs, such as miR-106b, miR-29b, and miR-132 [67]. Another rat exposure model with 100 ppm Pb also gave some evidence that some miRNAs, mainly targeting to a histone methyltransferase EZH2, were divergently regulated by lead in pup hippocampus. In response to lead, abundance of miR-137 and miR-101 was elevated, and miR-144d was decreased. The aberrant stimulation miR-137 may have important physiological relevance, as it formed a negative regulatory loop with EZH2, which drove the downregulation of H3K27me3 [80]. Some examples

of miRNA changes during lead-induced neurotoxicity were shown in **Table 1**. It is insufficient for other forms of ncRNAs remodeled by lead exposure in CNS. In 2018, Nan published an interesting article with relevance to this research field [82]. The authors identified a novel lincRNA (long noncoding RNA), namely lncRNAL20992, as a key responsor toward lead neurotoxicity. lncRNAL20992 was significantly upregulated in a lead-induced neuronal injury model. Four proteins were found to physically interact with lncRNAL20992 to mediate the lead-induced neuronal injury. To date, few associations of piRNAs or circRNAs were discovered with lead-induced neurotoxicity. Interestingly, a 98-nucleotide nuclear RNA with unknown function called Rn4.5s, as well as a RNA precursor Rn45s, showed changes

in methylation in the hippocampus of females exposed to 3 ppm of lead [11].

homologous recombination and nonhomologous end joining [81].

#### *Epigenetics and Lead Neurotoxicity DOI: http://dx.doi.org/10.5772/intechopen.92657*

*Lead Chemistry*

Mice (PND0 and PND6)

Mice (PND20 and PND50)

**Table 1.**

**Animal (Age) Exposure** 

**duration**

Pb acetate for 2 months prior to breeding until sacrifice

PND 1 to PND 20

**4.2 Histone modification**

altered expression of objective genes in a gender-dependent manner. 5hmC may also serve as potential biomarkers for lead susceptibility to neurological diseases [76]. As a general rule, the changes of DNA methylation levels were often negatively correlated with the transcription levels of the objective genes. But this association was dependent on gender, the exposure periods, and their relative genetic locations. Interestingly, for females, genes regulated by DNA methylation were inclined to encode RNA- and protein-related processes; and for males, the enriched pathways

Compared to DNA methylation, fewer associations between histone modification and lead neurotoxicity were reported. Categorized by posttranslational forms, most studies focused on histone acetylation changes in response to lead exposure. A specific histone acetylation level results from the balanced counteraction of histone acetyltransferases (HATs) and histone deacetylases (HDACs). An acetylated form normally corresponds to a more relaxed chromatin status, leading to an enhanced expression of the target genes, and *vice versa* [77]. In 2014, our lab published a relatively novel article describing an increased acetylated form of histone H3 as exposed by 5 or 25 mg/l of lead. This alteration accompanies with the enhanced transcription of p300, a typical HAT [64]. Subsequently, the interesting point is that chronic lead exposure reduced the total level of H3K9ac, displaying an opposite tendency to total H3ac levels, which unveiled a specific alteration depending on the concrete acetyla-

included signaling pathways, stress, and neural responses to stimuli [5].

*Summary of some literature concerning epigenetic changes involved in lead neurotoxicity.*

**Epigenetic mechanisms**

↓MECP2

Changes of H3K9/14Ac and H3K9Me3 level

↑Dnmt3a mRNA & miR-29b (PND50) ↓DNMT1 mRNA (PND50)

↑miR-148a(PND50) ↑SP1 mRNA(PND20) ↑miR-124(PND50) ↓APP mRNA(PND20) ↑miR-106b(PND50)

**Pathophysiological outcomes (possible)**

Cognitive/behavioral problems during childhood

Tau-induced cell apoptosis in AD; neurodegeneration **References**

[63]

[72]

tion sites, as well as the neural models and exposure conditions used [78].

modifications and lead neurotoxicity was shown in **Table 1**.

Some innovative progresses were made in the primates with early life exposure. Bihaqi et al. observed that apart from DNMTs and MeCP2, lead also caused lifelong alterations of H3K9ac, H3K8ac, and H4K12ac, which levels were increased only in 23-year-old adults, not in 12-year-old primates [14]. In another instance, perinatal lead exposure downregulated H3K9ac levels in aging mice, a proof that key epigenetic regulators can be linked with development of Alzheimer's disease [15]. Murine hippocampus and frontal cortex were similar in lead-induced epigenetic changes, that is, H3K9/14ac was gradually reduced as exposure prolonged, factored by mixed actions of gender and prenatal stress [63]. The literature pertaining to histone

**32**

Different from histone acetylation, histone methylation gained a stricter site specificity and more stable to maintain gene expression patterns [79]. With the developmental exposure of lead, primates of 400-day olds were subjected to epigenetic examination in brains. H3K4me2 was found to be increased significantly, indicating an activated propensity of related gene expression [14]. In another animal study, H3K9me3 displayed a relatively stable tendency with treatment of lead in mice, and those cases varied depending on the studied brain regions and genders [63]. According to general knowledge gained in this field, H3K4me basically played roles in promoting gene expression, while H3K27me and H3K9me mostly displayed negative regulatory activity. Our previous finding underpinned the importance of H3K27me3 in modulating lead-induced spatial memory deficits [80]. We found that chronic lead exposure perinatally could reduce the global H3K27me3 levels in rat hippocampus, and this alteration led to a genome-wide reprogramming of this repressive epigenetic mark on the target genes. This result gave a picture of how an epigenetic change can give rise to a global genetic response and the ensuing adverse neurological outcomes.

In contrast with acetylation and methylation, very few studies were shown to investigate the interaction of lead neurotoxicity and other forms of histone modifications. In spite of deficiency of relevant literature, this study is supposed to be promising to totally decipher histone codes involved in lead neurotoxicity. H2A ubiquitination was recently found to be associated with DNA damage response, which suggested that site-specific histone ubiquitination organizes the spatiotemporal recruitment of DNA repair factors, and these recruitments facilitated DNA repair pathway choice between homologous recombination and nonhomologous end joining [81].

## **4.3 ncRNA**

ncRNAs are epigenetic regulators susceptible to environmental signals. Among diverse forms of ncRNAs, microRNA (miRNA) was most extensively studied concerning their relations with lead neurotoxicity. In rats chronically exposed to lead, at least seven miRNAs were altered considering their expression levels. In details, miR-204, miR-211, miR-448, miR-449a, miR-34b, and miR34c were dramatically upregulated, while miR-494 was downregulated. These miRNAs were implicated in regulating genes involved in neurodegeneration, synaptogenesis, and neuronal injury [68]. Masoud et al. observed that early life lead exposure yielded a transient increase in the expression of AD-related miRNAs, such as miR-106b, miR-29b, and miR-132 [67]. Another rat exposure model with 100 ppm Pb also gave some evidence that some miRNAs, mainly targeting to a histone methyltransferase EZH2, were divergently regulated by lead in pup hippocampus. In response to lead, abundance of miR-137 and miR-101 was elevated, and miR-144d was decreased. The aberrant stimulation miR-137 may have important physiological relevance, as it formed a negative regulatory loop with EZH2, which drove the downregulation of H3K27me3 [80]. Some examples of miRNA changes during lead-induced neurotoxicity were shown in **Table 1**.

It is insufficient for other forms of ncRNAs remodeled by lead exposure in CNS. In 2018, Nan published an interesting article with relevance to this research field [82]. The authors identified a novel lincRNA (long noncoding RNA), namely lncRNAL20992, as a key responsor toward lead neurotoxicity. lncRNAL20992 was significantly upregulated in a lead-induced neuronal injury model. Four proteins were found to physically interact with lncRNAL20992 to mediate the lead-induced neuronal injury. To date, few associations of piRNAs or circRNAs were discovered with lead-induced neurotoxicity. Interestingly, a 98-nucleotide nuclear RNA with unknown function called Rn4.5s, as well as a RNA precursor Rn45s, showed changes in methylation in the hippocampus of females exposed to 3 ppm of lead [11].

## **5. Epigenetic mechanisms of lead-induced Alzheimer's disease**

By modifying the global epigenetic landscape, early life lead exposure had not only immediate adverse consequences for brain development but also persistent effects till the later life. This toxic property may increase the susceptibility of organisms to diseases, especially CNS-related diseases [3]. It has been long established that chronic lead contact is an important risk factor for the pathogenesis of Alzheimer's disease [83]. This finding is significant because AD is the most common form of dementia, which affects aging individual. There were at least 25 million people worldwide affected by this disease in 2003, including at least 4.5 million people in the United States [84]. Similar to other neurodegenerative diseases, AD is a complex and heterogeneous disorder with both environmental and genetic etiology.

There are a variety of molecular mechanisms proposed to mediate the leadinduced pathogenesis of AD. In monkeys, Wu et al. discovered that with lead exposure in infants, the aging monkeys exhibited abnormal expression alterations of AD-related genes and a key transcriptional regulator specificity protein 1 (Sp1). This was manifested by increasing AβPP, b-site AβPP cleaving enzyme (BACE), and Aβ and by decreasing DNA methyltransferase activity [16]. In an epidemiological review toward the Mexican population, it was summarized that early-life lead exposure was a potential risk factor for AD in the Mexican population [85]. While these mechanisms partly explained the key cellular and molecular changes brought by lead exposure, it is still pivotal to figure out the "fetal programming" phenomenon involved in the studied pathogenesis.

Roles of epigenetics are much appreciated due to their similar modes of action with "fetal origin of adult disease," which characterizes the basic regularities underlying lead-induced pathogenesis of AD [3, 11]. One anticipated way to achieve long-lasting or permanent changes in gene expression is to alter the structural makeup of the DNA bases that led to hypermethylation or hypomethylation consequences. The changes of DNA methylation in promoters or other gene regulatory components are found to be extremely stable and can even transmitted to the next generation. This style of action is consistent with the neurotoxic course of Pb to induce AD and is anticipated to fetal program the key AD-related genes, enabling their long abnormal transcriptions. Compared to CpG methylation, histone modifications are normally unable to elicit permanent regulatory effect till aging period, as evidenced by previous findings that H3K9ac and H3K4me2 followed lifespan-dependent changing curves, whereas variable time points showed different altering orientations [15]. Therefore, CpG methylation might be a competent epigenetic mechanism of choice to be used to explain the long development of AD. In another aspect, susceptible response from specific histone modification may be used to early predict the risk of AD, on the basis of their potential genetic associations.

Given these observations, White et al. proposed the possible pathways by which epigenetic factors mediate Pb-led pathogenesis of AD (**Figure 2**) [25]. They regarded epigenetics, mainly represented by CpG methylation, as potential key mechanisms that manifested delay consequences of lead exposure and consequent Alzheimer's disease. According to this hypothesis, early-life lead exposure caused a cascade of molecular changes exemplified by reducing CpG methylations at promoters of key AD-related genes, such as APP and BACE. Assisted by the actions of MeCP2 or SP1, these methylation reductions promoted the gene expression toward the corresponding proteins. Subsequently, Aβ was synthesized and started to accumulate in the later life. When the accumulation reached to a threshold value,

**35**

life lead exposure.

**Figure 2.**

**6. Conclusion and future directions**

*Epigenetics and Lead Neurotoxicity*

*DOI: http://dx.doi.org/10.5772/intechopen.92657*

AD symptoms started to emerge and progress. This hypothesis gives an intriguing example to implicate epigenetic factors with Alzheimer's disease induced by early-

*Possible epigenetic mechanism of Alzheimer's disease induced by early life lead exposure.*

In conclusion, epigenetic factors played essential roles in mediating leadinduced neurotoxicity. Comprehensive investigations unveiled the importance of CpG methylations in multiple genetic loci in rodents and primates. CpG methylation on a specific gene promoter might give rise to a long-term suppression of gene expression, in which case formed a phenomenon of "fetal programming" of neurological disease. In addition, changes of histone modifications might reflect a relatively dynamic signal to moderate the ensuing molecular relay and neurotoxic manifestations. As a newly emerging research field, it is anticipated to have several future directions about relevant of epigenetic factors to lead neurotoxicity: (1) new epigenetic mechanisms, such as 5hmC, RNA methylation, and scarcely mentioned ncRNA forms, need to be thoroughly investigated regarding their associations with lead neurotoxicity; (2) most previous studies observed the huge impact of gender on the neurotoxic performances, but very few explanations were provided. Epigenetic differences and causing agents between the genders should be investigated with insight; (3) there are currently some medicine developed to target epigenetic sites, like HDAC inhibitors. However, the sole histone deacetylase is

*Epigenetics and Lead Neurotoxicity DOI: http://dx.doi.org/10.5772/intechopen.92657*

*Lead Chemistry*

and genetic etiology.

involved in the studied pathogenesis.

their potential genetic associations.

**5. Epigenetic mechanisms of lead-induced Alzheimer's disease**

By modifying the global epigenetic landscape, early life lead exposure had not only immediate adverse consequences for brain development but also persistent effects till the later life. This toxic property may increase the susceptibility of organisms to diseases, especially CNS-related diseases [3]. It has been long established that chronic lead contact is an important risk factor for the pathogenesis of Alzheimer's disease [83]. This finding is significant because AD is the most common form of dementia, which affects aging individual. There were at least 25 million people worldwide affected by this disease in 2003, including at least 4.5 million people in the United States [84]. Similar to other neurodegenerative diseases, AD is a complex and heterogeneous disorder with both environmental

There are a variety of molecular mechanisms proposed to mediate the leadinduced pathogenesis of AD. In monkeys, Wu et al. discovered that with lead exposure in infants, the aging monkeys exhibited abnormal expression alterations of AD-related genes and a key transcriptional regulator specificity protein 1 (Sp1). This was manifested by increasing AβPP, b-site AβPP cleaving enzyme (BACE), and Aβ and by decreasing DNA methyltransferase activity [16]. In an epidemiological review toward the Mexican population, it was summarized that early-life lead exposure was a potential risk factor for AD in the Mexican population [85]. While these mechanisms partly explained the key cellular and molecular changes brought by lead exposure, it is still pivotal to figure out the "fetal programming" phenomenon

Roles of epigenetics are much appreciated due to their similar modes of action with "fetal origin of adult disease," which characterizes the basic regularities underlying lead-induced pathogenesis of AD [3, 11]. One anticipated way to achieve long-lasting or permanent changes in gene expression is to alter the structural makeup of the DNA bases that led to hypermethylation or hypomethylation consequences. The changes of DNA methylation in promoters or other gene regulatory components are found to be extremely stable and can even transmitted to the next generation. This style of action is consistent with the neurotoxic course of Pb to induce AD and is anticipated to fetal program the key AD-related genes, enabling their long abnormal transcriptions. Compared to CpG methylation, histone modifications are normally unable to elicit permanent regulatory effect till aging period, as evidenced by previous findings that H3K9ac and H3K4me2 followed lifespan-dependent changing curves, whereas variable time points showed different altering orientations [15]. Therefore, CpG methylation might be a competent epigenetic mechanism of choice to be used to explain the long development of AD. In another aspect, susceptible response from specific histone modification may be used to early predict the risk of AD, on the basis of

Given these observations, White et al. proposed the possible pathways by which epigenetic factors mediate Pb-led pathogenesis of AD (**Figure 2**) [25]. They regarded epigenetics, mainly represented by CpG methylation, as potential key mechanisms that manifested delay consequences of lead exposure and consequent Alzheimer's disease. According to this hypothesis, early-life lead exposure caused a cascade of molecular changes exemplified by reducing CpG methylations at promoters of key AD-related genes, such as APP and BACE. Assisted by the actions of MeCP2 or SP1, these methylation reductions promoted the gene expression toward the corresponding proteins. Subsequently, Aβ was synthesized and started to accumulate in the later life. When the accumulation reached to a threshold value,

**34**

**Figure 2.** *Possible epigenetic mechanism of Alzheimer's disease induced by early life lead exposure.*

AD symptoms started to emerge and progress. This hypothesis gives an intriguing example to implicate epigenetic factors with Alzheimer's disease induced by earlylife lead exposure.

## **6. Conclusion and future directions**

In conclusion, epigenetic factors played essential roles in mediating leadinduced neurotoxicity. Comprehensive investigations unveiled the importance of CpG methylations in multiple genetic loci in rodents and primates. CpG methylation on a specific gene promoter might give rise to a long-term suppression of gene expression, in which case formed a phenomenon of "fetal programming" of neurological disease. In addition, changes of histone modifications might reflect a relatively dynamic signal to moderate the ensuing molecular relay and neurotoxic manifestations. As a newly emerging research field, it is anticipated to have several future directions about relevant of epigenetic factors to lead neurotoxicity: (1) new epigenetic mechanisms, such as 5hmC, RNA methylation, and scarcely mentioned ncRNA forms, need to be thoroughly investigated regarding their associations with lead neurotoxicity; (2) most previous studies observed the huge impact of gender on the neurotoxic performances, but very few explanations were provided. Epigenetic differences and causing agents between the genders should be investigated with insight; (3) there are currently some medicine developed to target epigenetic sites, like HDAC inhibitors. However, the sole histone deacetylase is

## *Lead Chemistry*

unable to reflect the global epigenetic aspects and to use for intervention with full efficacy. Other specific reversing pharmaceuticals targeting epigenetic factors are warranted to be developed to interfere with development of neurological disease induced by lead exposure.

## **Acknowledgements**

The work of this chapter was supported by the Fundamental Research Funds for the Central Universities (JZ2020HGTB0053) and the Key Research and Development Project in Anhui (201904e01020001).

## **Conflict of interest**

The authors declare no conflict of interest.

## **Abbreviations**


**37**

**Author details**

China

Yi Xu\*, Tian Wang and Jie Zhang

provided the original work is properly cited.

\*Address all correspondence to: xuyixuyi3734@163.com

School of Food Science and Bioengineering, Hefei University of Technology, Hefei,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Epigenetics and Lead Neurotoxicity*

*DOI: http://dx.doi.org/10.5772/intechopen.92657*

*Epigenetics and Lead Neurotoxicity DOI: http://dx.doi.org/10.5772/intechopen.92657*

*Lead Chemistry*

induced by lead exposure.

**Acknowledgements**

**Conflict of interest**

**Abbreviations**

unable to reflect the global epigenetic aspects and to use for intervention with full efficacy. Other specific reversing pharmaceuticals targeting epigenetic factors are warranted to be developed to interfere with development of neurological disease

The work of this chapter was supported by the Fundamental Research Funds

for the Central Universities (JZ2020HGTB0053) and the Key Research and

Development Project in Anhui (201904e01020001).

The authors declare no conflict of interest.

5hmC 5-hydroxymethylated cytosine

BACE b-site AβPP cleaving enzyme BDNF brain-derived neurotrophic factor

CpG Cytosine Guanine dinucleotides

DMR Differentially Methylated Region

EPSC excitatory postsynaptic currents

H3K8ac lysine acetylation at histone H3K8 H3K9ac lysine acetylation at histone H3K9 H4K12ac lysine acetylation at histone H4K12 H3K4me lysine methylation at histone H3K4 H3K9me lysine methylation at histone H3K9 H3K27me lysine methylation at histone H3K27

CDC Centers for Disease Control and Prevention

AD Alzheimer's disease

CNS central nervous system

DAT1 dopamine transporter 1

DNMT DNA methyltransferases DRD4 dopamine receptor 4

HAT histone acetyltransferases HDAC histone deacetylase lncRNA long noncoding RNA

IPSC inhibitory postsynaptic currents

NMDAR N-methyl-D-aspartate receptor

PTM posttranslational modifications

SP1 regulator specificity protein 1

ncRNA noncoding RNA

piRNA piwi-interacting RNA

snoRNA small nucleolar RNA

Pb lead

MeCP2 methyl-cytosine-phosphate-guanine (Me-CpG) binding protein-2

GABA γ-aminobutyric acid

BLL blood lead level

**36**

## **Author details**

Yi Xu\*, Tian Wang and Jie Zhang School of Food Science and Bioengineering, Hefei University of Technology, Hefei, China

\*Address all correspondence to: xuyixuyi3734@163.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Neal AP, Guilarte TR. Molecular neurobiology of lead (Pb2+): Effects on synaptic function. Molecular Neurobiology. 2010;**42**(3):151-160

[2] Raciti M, Ceccatelli S. Epigenetic mechanisms in developmental neurotoxicity. Neurotoxicology and Teratology. 2018;**66**:94-101

[3] Senut MC, Cingolani P, Sen A, Kruger A, Shaik A, Hirsch H, et al. Epigenetics of early-life lead exposure and effects on brain development. Epigenomics. 2012;**4**(6):665-674

[4] Senut MC, Sen A, Cingolani P, Shaik A, Land SJ, Ruden DM. Lead exposure disrupts global DNA methylation in human embryonic stem cells and alters their neuronal differentiation. Toxicological Sciences. 2014;**139**(1):142-161

[5] Singh G, Singh V, Wang ZX, Voisin G, Lefebvre F, Navenot JM, et al. Effects of developmental lead exposure on the hippocampal methylome: Influences of sex and timing and level of exposure. Toxicology Letters. 2018;**290**:63-72

[6] Eid A, Zawia N. Consequences of lead exposure, and it's emerging role as an epigenetic modifier in the aging brain. Neurotoxicology. 2016;**56**:254-261

[7] https://www.cdc.gov/nceh/lead/ data/index.htm [Internet]. 2020

[8] Neal AP. Mechanisms of heavy metal neurotoxicity: Lead and manganese. Journal of Drug Metabolism & Toxicology. 2015;**06**(03). DOI: 10.4172/2157-7609.S5-002

[9] Bellinger DC. Very low lead exposures and children's neurodevelopment. Current Opinion in Pediatrics. 2008; **20**(2):172-177

[10] Sanders T, Liu Y, Buchner V, Tchounwou PB. Neurotoxic effects and biomarkers of lead exposure: A review. Reviews on Environmental Health. 2009;**24**(1):15-45

[11] Sanchez-Martin FJ, Lindquist DM, Landero-Figueroa J, Zhang X, Chen J, Cecil KM, et al. Sex- and tissue-specific methylome changes in brains of mice perinatally exposed to lead. Neurotoxicology. 2015;**46**:92-100

[12] Weuve J, Press DZ, Grodstein F, Wright RO, Hu H, Weisskopf MG. Cumulative exposure to lead and cognition in persons with Parkinson's disease. Movement Disorders. 2013;**28**(2):176-182

[13] Wu S, Liu H, Zhao H, Wang X, Chen J, Xia D, et al. Environmental lead exposure aggravates the progression of Alzheimer's disease in mice by targeting on blood brain barrier. Toxicology Letters. 2020;**319**:138-147

[14] Bihaqi SW, Huang H, Wu J, Zawia NH. Infant exposure to lead (Pb) and epigenetic modifications in the aging primate brain: Implications for Alzheimer's disease. Journal of Alzheimer's Disease. 2011;**27**(4):819-833

[15] Eid A, Bihaqi SW, Renehan WE, Zawia NH. Developmental lead exposure and lifespan alterations in epigenetic regulators and their correspondence to biomarkers of Alzheimer's disease. Alzheimer's & Dementia. 2016;**2**:123-131

[16] Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, et al. Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): Evidence for a developmental origin and environmental link for AD. The Journal of Neuroscience. 2008;**28**(1):3-9

**39**

*Epigenetics and Lead Neurotoxicity*

*DOI: http://dx.doi.org/10.5772/intechopen.92657*

[17] Mazumdar M, Xia W, Hofmann O, Gregas M, Ho Sui S, Hide W, et al. Prenatal lead levels, plasma amyloid beta levels, and gene expression in young adulthood. Environmental Health Perspectives. 2012;**120**(5):702-707

mRNAs in the hippocampus of neonatal rats by digoxigenin-labeled in situ hybridization histochemistry. Neurotoxicology and Teratology.

[25] White LD, Cory-Slechta DA, Gilbert ME, Tiffany-Castiglioni E, Zawia NH, Virgolini M, et al. New and evolving concepts in the neurotoxicology of lead. Toxicology

and Applied Pharmacology.

[26] Lasley SM, Gilbert ME. Rat hippocampal glutamate and GABA release exhibit biphasic effects as a function of chronic lead exposure level. Toxicological Sciences.

2002;**24**(2):149-160

2007;**225**(1):1-27

2002;**66**(1):139-147

[27] Braga MF, Pereira EF, Albuquerque EX. Nanomolar concentrations of lead inhibit glutamatergic and GABAergic

[28] Ding JJ, Zou RX, He HM, Lou ZY, Xu Y, Wang HL. Pb inhibits hippocampal synaptic transmission via cyclin-dependent kinase-5 dependent Synapsin 1 phosphorylation. Toxicology

Letters. 2018;**296**:125-131

[29] Matsuda N, Lu H, Fukata Y, Noritake J, Gao H, Mukherjee S, et al. Differential activity-dependent

factor from axon and dendrite. The Journal of Neuroscience. 2009;**29**(45):14185-14198

2010;**116**(1):249-263

secretion of brain-derived neurotrophic

[30] Neal AP, Stansfield KH, Worley PF, Thompson RE, Guilarte TR. Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: Potential role of NMDA receptor-dependent BDNF signaling. Toxicological Sciences.

[31] Walz C, Jungling K, Lessmann V, Gottmann K. Presynaptic plasticity

transmission in hippocampal neurons. Brain Research. 1999;**826**(1):22-34

[18] Park SS, Skaar DA, Jirtle RL, Hoyo C. Epigenetics, obesity and early-life cadmium or lead exposure.

Epigenomics. 2017;**9**(1):57-75

[19] Goodrich JM, Sanchez BN,

[20] Lidsky TI, Schneider JS. Lead neurotoxicity in children: Basic mechanisms and clinical correlates.

Brain. 2003;**126**(Pt 1):5-19

2000;**97**(10):5540-5545

[21] Wilson MA, Johnston MV, Goldstein GW, Blue ME. Neonatal lead exposure impairs development of rodent barrel field cortex. Proceedings of the National Academy of Sciences of the United States of America.

[22] Chen C, Tonegawa S. Molecular genetic analysis of synaptic plasticity, activity-dependent neural development,

mammalian brain. Annual Review of Neuroscience. 1997;**20**:157-184

learning, and memory in the

[23] Nihei MK, Desmond NL, McGlothan JL, Kuhlmann AC, Guilarte TR. N-methyl-D-aspartate receptor subunit changes are associated with lead-induced deficits of longterm potentiation and spatial learning. Neuroscience. 2000;**99**(2):233-242

[24] Zhang XY, Liu AP, Ruan DY, Liu J. Effect of developmental lead exposure on the expression of specific NMDA receptor subunit

Hernandez-Avila M, Hu H, et al. Quality control and statistical modeling for environmental epigenetics: A study on in utero lead exposure and DNA methylation at birth. Epigenetics.

Dolinoy DC, Zhang Z,

2015;**10**(1):19-30

## *Epigenetics and Lead Neurotoxicity DOI: http://dx.doi.org/10.5772/intechopen.92657*

[17] Mazumdar M, Xia W, Hofmann O, Gregas M, Ho Sui S, Hide W, et al. Prenatal lead levels, plasma amyloid beta levels, and gene expression in young adulthood. Environmental Health Perspectives. 2012;**120**(5):702-707

[18] Park SS, Skaar DA, Jirtle RL, Hoyo C. Epigenetics, obesity and early-life cadmium or lead exposure. Epigenomics. 2017;**9**(1):57-75

[19] Goodrich JM, Sanchez BN, Dolinoy DC, Zhang Z, Hernandez-Avila M, Hu H, et al. Quality control and statistical modeling for environmental epigenetics: A study on in utero lead exposure and DNA methylation at birth. Epigenetics. 2015;**10**(1):19-30

[20] Lidsky TI, Schneider JS. Lead neurotoxicity in children: Basic mechanisms and clinical correlates. Brain. 2003;**126**(Pt 1):5-19

[21] Wilson MA, Johnston MV, Goldstein GW, Blue ME. Neonatal lead exposure impairs development of rodent barrel field cortex. Proceedings of the National Academy of Sciences of the United States of America. 2000;**97**(10):5540-5545

[22] Chen C, Tonegawa S. Molecular genetic analysis of synaptic plasticity, activity-dependent neural development, learning, and memory in the mammalian brain. Annual Review of Neuroscience. 1997;**20**:157-184

[23] Nihei MK, Desmond NL, McGlothan JL, Kuhlmann AC, Guilarte TR. N-methyl-D-aspartate receptor subunit changes are associated with lead-induced deficits of longterm potentiation and spatial learning. Neuroscience. 2000;**99**(2):233-242

[24] Zhang XY, Liu AP, Ruan DY, Liu J. Effect of developmental lead exposure on the expression of specific NMDA receptor subunit

mRNAs in the hippocampus of neonatal rats by digoxigenin-labeled in situ hybridization histochemistry. Neurotoxicology and Teratology. 2002;**24**(2):149-160

[25] White LD, Cory-Slechta DA, Gilbert ME, Tiffany-Castiglioni E, Zawia NH, Virgolini M, et al. New and evolving concepts in the neurotoxicology of lead. Toxicology and Applied Pharmacology. 2007;**225**(1):1-27

[26] Lasley SM, Gilbert ME. Rat hippocampal glutamate and GABA release exhibit biphasic effects as a function of chronic lead exposure level. Toxicological Sciences. 2002;**66**(1):139-147

[27] Braga MF, Pereira EF, Albuquerque EX. Nanomolar concentrations of lead inhibit glutamatergic and GABAergic transmission in hippocampal neurons. Brain Research. 1999;**826**(1):22-34

[28] Ding JJ, Zou RX, He HM, Lou ZY, Xu Y, Wang HL. Pb inhibits hippocampal synaptic transmission via cyclin-dependent kinase-5 dependent Synapsin 1 phosphorylation. Toxicology Letters. 2018;**296**:125-131

[29] Matsuda N, Lu H, Fukata Y, Noritake J, Gao H, Mukherjee S, et al. Differential activity-dependent secretion of brain-derived neurotrophic factor from axon and dendrite. The Journal of Neuroscience. 2009;**29**(45):14185-14198

[30] Neal AP, Stansfield KH, Worley PF, Thompson RE, Guilarte TR. Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: Potential role of NMDA receptor-dependent BDNF signaling. Toxicological Sciences. 2010;**116**(1):249-263

[31] Walz C, Jungling K, Lessmann V, Gottmann K. Presynaptic plasticity

**38**

**20**(2):172-177

*Lead Chemistry*

**References**

[1] Neal AP, Guilarte TR. Molecular neurobiology of lead (Pb2+): Effects on synaptic function. Molecular Neurobiology. 2010;**42**(3):151-160

[10] Sanders T, Liu Y, Buchner V, Tchounwou PB. Neurotoxic effects and biomarkers of lead exposure: A review. Reviews on Environmental Health.

[11] Sanchez-Martin FJ, Lindquist DM, Landero-Figueroa J, Zhang X, Chen J, Cecil KM, et al. Sex- and tissue-specific

methylome changes in brains of mice perinatally exposed to lead. Neurotoxicology. 2015;**46**:92-100

[12] Weuve J, Press DZ, Grodstein F, Wright RO, Hu H, Weisskopf MG. Cumulative exposure to lead and cognition in persons with Parkinson's disease. Movement Disorders.

[13] Wu S, Liu H, Zhao H, Wang X, Chen J, Xia D, et al. Environmental lead exposure aggravates the progression of Alzheimer's disease in mice by targeting on blood brain barrier. Toxicology

2009;**24**(1):15-45

2013;**28**(2):176-182

Letters. 2020;**319**:138-147

Dementia. 2016;**2**:123-131

[16] Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, et al. Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): Evidence for a developmental origin and environmental link for AD. The Journal

of Neuroscience. 2008;**28**(1):3-9

[14] Bihaqi SW, Huang H, Wu J,

Zawia NH. Infant exposure to lead (Pb) and epigenetic modifications in the aging primate brain: Implications for Alzheimer's disease. Journal of Alzheimer's Disease. 2011;**27**(4):819-833

[15] Eid A, Bihaqi SW, Renehan WE, Zawia NH. Developmental lead exposure and lifespan alterations in epigenetic regulators and their correspondence to biomarkers of Alzheimer's disease. Alzheimer's &

[2] Raciti M, Ceccatelli S. Epigenetic mechanisms in developmental neurotoxicity. Neurotoxicology and

[3] Senut MC, Cingolani P, Sen A, Kruger A, Shaik A, Hirsch H, et al. Epigenetics of early-life lead exposure and effects on brain development. Epigenomics. 2012;**4**(6):665-674

[4] Senut MC, Sen A, Cingolani P, Shaik A, Land SJ, Ruden DM. Lead exposure disrupts global DNA methylation in human embryonic stem cells and alters their neuronal differentiation. Toxicological Sciences.

[5] Singh G, Singh V, Wang ZX,

Voisin G, Lefebvre F, Navenot JM, et al. Effects of developmental lead exposure on the hippocampal methylome: Influences of sex and timing and level of exposure. Toxicology Letters.

[6] Eid A, Zawia N. Consequences of lead exposure, and it's emerging role as an epigenetic modifier in the aging brain. Neurotoxicology. 2016;**56**:254-261

[7] https://www.cdc.gov/nceh/lead/ data/index.htm [Internet]. 2020

[8] Neal AP. Mechanisms of heavy metal neurotoxicity: Lead and

10.4172/2157-7609.S5-002

manganese. Journal of Drug Metabolism & Toxicology. 2015;**06**(03). DOI:

[9] Bellinger DC. Very low lead exposures and children's neurodevelopment. Current Opinion in Pediatrics. 2008;

2014;**139**(1):142-161

2018;**290**:63-72

Teratology. 2018;**66**:94-101

in an immature neocortical network requires NMDA receptor activation and BDNF release. Journal of Neurophysiology. 2006;**96**(6):3512-3516

[32] Du Y, Ge MM, Xue W, Yang QQ, Wang S, Xu Y, et al. Chronic Lead exposure and mixed factors of GenderxAgexBrain regions interactions on dendrite growth, spine maturity and NDR kinase. PLoS One. 2015;**10**(9):e0138112

[33] Bihaqi SW. Early life exposure to lead (Pb) and changes in DNA methylation: Relevance to Alzheimer's disease. Reviews on Environmental Health. 2019;**34**(2):187-195

[34] Sallmen M, Suvisaari J, Lindbohm ML, Malaspina D, Opler MG. Paternal occupational lead exposure and offspring risks for schizophrenia. Schizophrenia Research. 2016;**176**(2-3): 560-565

[35] Perera F, Herbstman J. Prenatal environmental exposures, epigenetics, and disease. Reproductive Toxicology. 2011;**31**(3):363-373

[36] Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Research. 2011;**21**(3):381-395

[37] Esteller M. Non-coding RNAs in human disease. Nature Reviews. Genetics. 2011;**12**(12):861-874

[38] Nye MD, Fry RC, Hoyo C, Murphy SK. Investigating epigenetic effects of prenatal exposure to toxic metals in newborns: Challenges and benefits. Medical Epigenetics. 2014;**2**(1):53-59

[39] Xu Y, Chen XT, Luo M, Tang Y, Zhang G, Wu D, et al. Multiple epigenetic factors predict the attention deficit/hyperactivity disorder among the Chinese Han children. Journal of Psychiatric Research. 2015;**64**:40-50

[40] Campos EI, Reinberg D. Histones: Annotating chromatin. Annual Review of Genetics. 2009;**43**:559-599

[41] Farrelly LA, Maze I. An emerging perspective on 'histone code' mediated regulation of neural plasticity and disease. Current Opinion in Neurobiology. 2019;**59**:157-163

[42] Bhanu NV, Sidoli S, Yuan ZF, Molden RC, Garcia BA. Regulation of proline-directed kinases and the trans-histone code H3K9me3/ H4K20me3 during human myogenesis. The Journal of Biological Chemistry. 2019;**294**(20):8296-8308

[43] Kao AC-C, Chan KW, Anthony DC, Lennox BR, Burnet PW. Prebiotic reduction of brain histone deacetylase (HDAC) activity and olanzapinemediated weight gain in rats, are acetate independent. Neuropharmacology. 2019;**150**:184-191

[44] Bagheri A, Habibzadeh P, Razavipour SF, Volmar C-H, Chee NT, Brothers SP, et al. HDAC inhibitors induce expression and promote neurite outgrowth in human neural progenitor cells-derived neurons. International Journal of Molecular Sciences. 2019;**20**(5):1109-1124

[45] Magri F, Vanoli F, Corti S. miRNA in spinal muscular atrophy pathogenesis and therapy. Journal of Cellular and Molecular Medicine. 2018;**22**(2):755-767

[46] Smrt RD, Szulwach KE, Pfeiffer RL, Li X, Guo W, Pathania M, et al. MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells. 2010;**28**(6):1060-1070

[47] Fuks F. DNA methylation and histone modifications: Teaming up to silence genes. Current Opinion in Genetics & Development. 2005;**15**(5):490-495

[48] Honda S, Bicocca VT, Gessaman JD, Rountree MR, Yokoyama A, Yu EY,

**41**

*Epigenetics and Lead Neurotoxicity*

[49] Shahbazian MD, Zoghbi HY. Rett syndrome and MeCP2: Linking epigenetics and neuronal function. American Journal of Human Genetics.

[50] Azpurua J, Eaton BA. Neuronal epigenetics and the aging synapse. Frontiers in Cellular Neuroscience.

[51] Li Y, Xie C, Murphy SK, Skaar D, Nye M, Vidal AC, et al. Lead exposure during early human development and DNA methylation of imprinted gene regulatory elements in adulthood. Environmental Health Perspectives.

[52] Vandegehuchte MB, Janssen CR. Epigenetics and its implications for ecotoxicology. Ecotoxicology.

Joshi MB, Dsouza HS. Ecogenetics of lead toxicity and its influence on risk assessment. Human & Experimental Toxicology. 2019;**38**(9):1031-1059

2002;**71**(6):1259-1272

2016;**124**(5):666-673

2011;**20**(3):607-624

2017;**9**(2):149-160

[53] Mani MS, Kabekkodu SP,

[54] Sanchez OF, Lee J, Yu King Hing N, Kim SE, Freeman JL, Yuan C. Lead (Pb) exposure reduces global DNA methylation level by noncompetitive inhibition and alteration of DNMT expression. Metallomics.

[55] Pilsner JR, Hu H, Ettinger A,

on genomic methylation of cord blood DNA. Environmental Health Perspectives. 2009;**117**(9):1466-1471

Sanchez BN, Wright RO, Cantonwine D, et al. Influence of prenatal lead exposure

2015;**9**:208

*DOI: http://dx.doi.org/10.5772/intechopen.92657*

et al. Dual chromatin recognition by the histone deacetylase complex HCHC is required for proper DNA methylation in *Neurospora crassa*. Proceedings of the National Academy of Sciences of the United States of America. 2016;**113**(41):E6135-E6E44

[56] Dosunmu R, Alashwal H, Zawia NH. Genome-wide expression and methylation profiling in the aged rodent brain due to early-life Pb exposure and its relevance to aging. Mechanisms of Ageing and Development. 2012;**133**(6):435-443

2013;**217**(1):75-81

2017;**125**(8):087019

[57] Schneider JS, Kidd SK, Anderson DW. Influence of developmental lead exposure on expression of DNA methyltransferases and methyl cytosine-binding proteins in hippocampus. Toxicology Letters.

[58] Levenson JM, Roth TL, Lubin FD, Miller CA, Huang IC, Desai P, et al. Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. The Journal of Biological Chemistry. 2006;**281**(23):15763-15773

[59] Wu S, Hivert MF, Cardenas A, Zhong J, Rifas-Shiman SL, Agha G, et al. Exposure to low levels of Lead in utero and umbilical cord blood DNA methylation in project viva: An epigenome-wide association study. Environmental Health Perspectives.

[60] Montrose L, Faulk C, Francis J, Dolinoy DC. Perinatal lead (Pb) exposure results in sex and tissuedependent adult DNA methylation alterations in murine IAP transposons.

Environmental and Molecular Mutagenesis. 2017;**58**(8):540-550

[61] Alashwal H, Dosunmu R, Zawia NH. Integration of genomewide expression and methylation data: Relevance to aging and

2012;**33**(6):1450-1453

2017;**33**(11):867-875

[62] Duan Y, Peng L, Shi H, Jiang Y. The effects of lead on GABAergic interneurons in rodents. Toxicology and Industrial Health.

Alzheimer's disease. Neurotoxicology.

*Epigenetics and Lead Neurotoxicity DOI: http://dx.doi.org/10.5772/intechopen.92657*

*Lead Chemistry*

in an immature neocortical network requires NMDA receptor activation and BDNF release. Journal of

[32] Du Y, Ge MM, Xue W, Yang QQ, Wang S, Xu Y, et al. Chronic Lead exposure and mixed factors of GenderxAgexBrain regions interactions on dendrite growth, spine maturity and NDR kinase. PLoS One.

2015;**10**(9):e0138112

[33] Bihaqi SW. Early life exposure to lead (Pb) and changes in DNA methylation: Relevance to Alzheimer's disease. Reviews on Environmental

Lindbohm ML, Malaspina D, Opler MG. Paternal occupational lead exposure and offspring risks for schizophrenia. Schizophrenia Research. 2016;**176**(2-3):

[35] Perera F, Herbstman J. Prenatal environmental exposures, epigenetics, and disease. Reproductive Toxicology.

[36] Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Research.

[37] Esteller M. Non-coding RNAs in human disease. Nature Reviews. Genetics. 2011;**12**(12):861-874

[38] Nye MD, Fry RC, Hoyo C, Murphy SK. Investigating epigenetic effects of prenatal exposure to toxic metals in newborns: Challenges and benefits. Medical Epigenetics.

[39] Xu Y, Chen XT, Luo M, Tang Y, Zhang G, Wu D, et al. Multiple

epigenetic factors predict the attention deficit/hyperactivity disorder among the Chinese Han children. Journal of Psychiatric Research. 2015;**64**:40-50

Health. 2019;**34**(2):187-195

[34] Sallmen M, Suvisaari J,

560-565

2011;**31**(3):363-373

2011;**21**(3):381-395

2014;**2**(1):53-59

Neurophysiology. 2006;**96**(6):3512-3516

[40] Campos EI, Reinberg D. Histones: Annotating chromatin. Annual Review

[41] Farrelly LA, Maze I. An emerging perspective on 'histone code' mediated

of Genetics. 2009;**43**:559-599

regulation of neural plasticity and disease. Current Opinion in Neurobiology. 2019;**59**:157-163

[42] Bhanu NV, Sidoli S, Yuan ZF, Molden RC, Garcia BA. Regulation of proline-directed kinases and the trans-histone code H3K9me3/ H4K20me3 during human myogenesis. The Journal of Biological Chemistry.

[43] Kao AC-C, Chan KW, Anthony DC, Lennox BR, Burnet PW. Prebiotic reduction of brain histone deacetylase (HDAC) activity and olanzapinemediated weight gain in rats, are acetate independent. Neuropharmacology.

2019;**294**(20):8296-8308

2019;**150**:184-191

2019;**20**(5):1109-1124

2010;**28**(6):1060-1070

[44] Bagheri A, Habibzadeh P,

Razavipour SF, Volmar C-H, Chee NT, Brothers SP, et al. HDAC inhibitors induce expression and promote neurite outgrowth in human neural progenitor cells-derived neurons. International Journal of Molecular Sciences.

[45] Magri F, Vanoli F, Corti S. miRNA in spinal muscular atrophy pathogenesis and therapy. Journal of Cellular and Molecular Medicine. 2018;**22**(2):755-767

[46] Smrt RD, Szulwach KE, Pfeiffer RL,

MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells.

[47] Fuks F. DNA methylation and histone modifications: Teaming up to silence genes. Current Opinion in Genetics & Development. 2005;**15**(5):490-495

[48] Honda S, Bicocca VT, Gessaman JD, Rountree MR, Yokoyama A, Yu EY,

Li X, Guo W, Pathania M, et al.

**40**

et al. Dual chromatin recognition by the histone deacetylase complex HCHC is required for proper DNA methylation in *Neurospora crassa*. Proceedings of the National Academy of Sciences of the United States of America. 2016;**113**(41):E6135-E6E44

[49] Shahbazian MD, Zoghbi HY. Rett syndrome and MeCP2: Linking epigenetics and neuronal function. American Journal of Human Genetics. 2002;**71**(6):1259-1272

[50] Azpurua J, Eaton BA. Neuronal epigenetics and the aging synapse. Frontiers in Cellular Neuroscience. 2015;**9**:208

[51] Li Y, Xie C, Murphy SK, Skaar D, Nye M, Vidal AC, et al. Lead exposure during early human development and DNA methylation of imprinted gene regulatory elements in adulthood. Environmental Health Perspectives. 2016;**124**(5):666-673

[52] Vandegehuchte MB, Janssen CR. Epigenetics and its implications for ecotoxicology. Ecotoxicology. 2011;**20**(3):607-624

[53] Mani MS, Kabekkodu SP, Joshi MB, Dsouza HS. Ecogenetics of lead toxicity and its influence on risk assessment. Human & Experimental Toxicology. 2019;**38**(9):1031-1059

[54] Sanchez OF, Lee J, Yu King Hing N, Kim SE, Freeman JL, Yuan C. Lead (Pb) exposure reduces global DNA methylation level by noncompetitive inhibition and alteration of DNMT expression. Metallomics. 2017;**9**(2):149-160

[55] Pilsner JR, Hu H, Ettinger A, Sanchez BN, Wright RO, Cantonwine D, et al. Influence of prenatal lead exposure on genomic methylation of cord blood DNA. Environmental Health Perspectives. 2009;**117**(9):1466-1471

[56] Dosunmu R, Alashwal H, Zawia NH. Genome-wide expression and methylation profiling in the aged rodent brain due to early-life Pb exposure and its relevance to aging. Mechanisms of Ageing and Development. 2012;**133**(6):435-443

[57] Schneider JS, Kidd SK, Anderson DW. Influence of developmental lead exposure on expression of DNA methyltransferases and methyl cytosine-binding proteins in hippocampus. Toxicology Letters. 2013;**217**(1):75-81

[58] Levenson JM, Roth TL, Lubin FD, Miller CA, Huang IC, Desai P, et al. Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. The Journal of Biological Chemistry. 2006;**281**(23):15763-15773

[59] Wu S, Hivert MF, Cardenas A, Zhong J, Rifas-Shiman SL, Agha G, et al. Exposure to low levels of Lead in utero and umbilical cord blood DNA methylation in project viva: An epigenome-wide association study. Environmental Health Perspectives. 2017;**125**(8):087019

[60] Montrose L, Faulk C, Francis J, Dolinoy DC. Perinatal lead (Pb) exposure results in sex and tissuedependent adult DNA methylation alterations in murine IAP transposons. Environmental and Molecular Mutagenesis. 2017;**58**(8):540-550

[61] Alashwal H, Dosunmu R, Zawia NH. Integration of genomewide expression and methylation data: Relevance to aging and Alzheimer's disease. Neurotoxicology. 2012;**33**(6):1450-1453

[62] Duan Y, Peng L, Shi H, Jiang Y. The effects of lead on GABAergic interneurons in rodents. Toxicology and Industrial Health. 2017;**33**(11):867-875

[63] Schneider JS, Anderson DW, Kidd SK, Sobolewski M, Cory-Slechta DA. Sex-dependent effects of lead and prenatal stress on posttranslational histone modifications in frontal cortex and hippocampus in the early postnatal brain. Neurotoxicology. 2016;**54**:65-71

[64] Luo M, Xu Y, Cai R, Tang Y, Ge MM, Liu ZH, et al. Epigenetic histone modification regulates developmental lead exposure induced hyperactivity in rats. Toxicology Letters. 2014;**225**(1):78-85

[65] Hill DS, Cabrera R, Wallis Schultz D, Zhu H, Lu W, Finnell RH, et al. Autism-like behavior and epigenetic changes associated with autism as consequences of in utero exposure to environmental pollutants in a mouse model. Behavioural Neurology. 2015;**2015**:426263

[66] Dash M, Eid A, Subaiea G, Chang J, Deeb R, Masoud A, et al. Developmental exposure to lead (Pb) alters the expression of the human tau gene and its products in a transgenic animal model. Neurotoxicology. 2016;**55**:154-159

[67] Masoud AM, Bihaqi SW, Machan JT, Zawia NH, Renehan WE. Early-life exposure to lead (Pb) alters the expression of microRNA that target proteins associated with Alzheimer's disease. Journal of Alzheimer's Disease. 2016;**51**(4):1257-1264

[68] An J, Cai T, Che H, Yu T, Cao Z, Liu X, et al. The changes of miRNA expression in rat hippocampus following chronic lead exposure. Toxicology Letters. 2014;**229**(1):158-166

[69] Sharifi AM, Mousavi SH, Jorjani M. Effect of chronic lead exposure on proapoptotic Bax and anti-apoptotic Bcl-2 protein expression in rat hippocampus in vivo. Cellular and Molecular Neurobiology. 2010;**30**(5):769-774

[70] Dou JF, Farooqui Z, Faulk CD, Barks AK, Jones T, Dolinoy DC, et al. Perinatal lead (Pb) exposure and cortical neuron-specific DNA methylation in male mice. Genes (Basel). 2019;**10**(4):274-288

[71] Varma G, Sobolewski M, Cory-Slechta DA, Schneider JS. Sex- and brain region-specific effects of prenatal stress and lead exposure on permissive and repressive post-translational histone modifications from embryonic development through adulthood. Neurotoxicology. 2017;**62**:207-217

[72] Masoud AM, Bihaqi SW, Alansi B, Dash M, Subaiea GM, Renehan WE, et al. Altered microRNA, mRNA, and protein expression of neurodegeneration-related biomarkers and their transcriptional and epigenetic modifiers in a human tau transgenic mouse model in response to developmental lead exposure. Journal of Alzheimer's Disease. 2018;**63**(1):273-282

[73] Khalid M, Abdollahi M. Epigenetic modifications associated with pathophysiological effects of lead exposure. Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews. 2019;**37**(4): 235-287

[74] Kundakovic M, Lim S, Gudsnuk K, Champagne FA. Sexspecific and strain-dependent effects of early life adversity on behavioral and epigenetic outcomes. Frontiers in Psychiatry. 2013;**4**:78

[75] Szulwach KE, Li X, Li Y, Song CX, Wu H, Dai Q, et al. 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nature Neuroscience. 2011;**14**(12):1607-1616

[76] Sen A, Cingolani P, Senut MC, Land S, Mercado-Garcia A, Tellez-Rojo MM, et al. Lead exposure induces changes in 5-hydroxymethylcytosine

**43**

*Epigenetics and Lead Neurotoxicity*

clusters in CpG islands in human

2019;**11**(487):2064-2076

[78] Wu Y, Xu Y, Huang X, Ye D, Han M, Wang HL. Regulatory roles of histone deacetylases 1 and 2 in Pb-induced neurotoxicity. Toxicological

Sciences. 2018;**162**(2):688-701

[79] Shafabakhsh R, Aghadavod E, Ghayour-Mobarhan M, Ferns G, Asemi Z. Role of histone modification and DNA methylation in signaling pathways involved in diabetic retinopathy. Journal of Cellular Physiology. 2019;**234**(6):7839-7846

[80] Gu X, Xu Y, Xue WZ, Wu Y, Ye Z, Xiao G, et al. Interplay of miR-137 and EZH2 contributes to the genome-wide redistribution of H3K27me3 underlying the Pb-induced memory impairment. Cell Death & Disease. 2019;**10**(9):671

[81] Uckelmann M, Sixma TK. Histone ubiquitination in the DNA damage response. DNA Repair. 2017;**56**:92-101

Zhang N, Chen L, et al. Editor's highlight: lncRNAL20992 regulates apoptotic proteins to promote lead-induced neuronal apoptosis. Toxicological Sciences. 2018;**161**(1):115-124

[83] Basha MR, Wei W, Bakheet SA, Benitez N, Siddiqi HK, Ge YW, et al. The fetal basis of amyloidogenesis:

overexpression of amyloid precursor protein and beta-amyloid in the aging brain. The Journal of Neuroscience.

Exposure to lead and latent

2005;**25**(4):823-829

[82] Nan A, Jia Y, Li X, Liu M,

*DOI: http://dx.doi.org/10.5772/intechopen.92657*

embryonic stem cells and umbilical cord blood. Epigenetics. 2015;**10**(7):607-621

[84] Hebert LE, Scherr PA,

2003;**60**(8):1119-1122

2019;**24**(8):1285-1303

Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: Prevalence estimates using the 2000 census. Archives of Neurology.

[85] Chin-Chan M, Cobos-Puc L, Alvarado-Cruz I, Bayar M,

Ermolaeva M. Early-life Pb exposure as a potential risk factor for Alzheimer's disease: Are there hazards for the Mexican population? Journal of Biological Inorganic Chemistry.

[77] Hutson TH, Kathe C, Palmisano I, Bartholdi K, Hervera A, De Virgiliis F, et al. Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models. Science Translational Medicine.

### *Epigenetics and Lead Neurotoxicity DOI: http://dx.doi.org/10.5772/intechopen.92657*

*Lead Chemistry*

2016;**54**:65-71

2014;**225**(1):78-85

2015;**2015**:426263

2016;**55**:154-159

2016;**51**(4):1257-1264

[65] Hill DS, Cabrera R,

Wallis Schultz D, Zhu H, Lu W, Finnell RH, et al. Autism-like behavior and epigenetic changes associated with autism as consequences of in utero exposure to environmental pollutants in a mouse model. Behavioural Neurology.

[66] Dash M, Eid A, Subaiea G, Chang J, Deeb R, Masoud A, et al. Developmental exposure to lead (Pb) alters the expression of the human tau gene and its products in a transgenic animal model. Neurotoxicology.

[67] Masoud AM, Bihaqi SW,

Machan JT, Zawia NH, Renehan WE. Early-life exposure to lead (Pb) alters the expression of microRNA that target proteins associated with Alzheimer's disease. Journal of Alzheimer's Disease.

[68] An J, Cai T, Che H, Yu T, Cao Z, Liu X, et al. The changes of miRNA expression in rat hippocampus following chronic lead exposure. Toxicology Letters. 2014;**229**(1):158-166

[69] Sharifi AM, Mousavi SH, Jorjani M. Effect of chronic lead exposure on proapoptotic Bax and anti-apoptotic Bcl-2 protein expression in rat hippocampus

in vivo. Cellular and Molecular Neurobiology. 2010;**30**(5):769-774

[63] Schneider JS, Anderson DW,

[64] Luo M, Xu Y, Cai R, Tang Y, Ge MM, Liu ZH, et al. Epigenetic histone modification regulates developmental lead exposure induced hyperactivity in rats. Toxicology Letters.

Cory-Slechta DA. Sex-dependent effects of lead and prenatal stress on posttranslational histone modifications in frontal cortex and hippocampus in the early postnatal brain. Neurotoxicology.

[70] Dou JF, Farooqui Z, Faulk CD, Barks AK, Jones T, Dolinoy DC, et al. Perinatal lead (Pb) exposure and cortical neuron-specific DNA methylation in male mice. Genes (Basel). 2019;**10**(4):274-288

[71] Varma G, Sobolewski M,

[72] Masoud AM, Bihaqi SW, Alansi B, Dash M, Subaiea GM,

and their transcriptional and epigenetic modifiers in a human tau transgenic mouse model in response to developmental lead exposure. Journal of Alzheimer's Disease. 2018;**63**(1):273-282

[73] Khalid M, Abdollahi M.

[74] Kundakovic M, Lim S, Gudsnuk K, Champagne FA. Sexspecific and strain-dependent effects of early life adversity on behavioral and epigenetic outcomes. Frontiers in

Psychiatry. 2013;**4**:78

235-287

Epigenetic modifications associated with pathophysiological effects of lead exposure. Journal of

Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews. 2019;**37**(4):

[75] Szulwach KE, Li X, Li Y, Song CX, Wu H, Dai Q, et al. 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nature Neuroscience. 2011;**14**(12):1607-1616

[76] Sen A, Cingolani P, Senut MC, Land S, Mercado-Garcia A, Tellez-Rojo MM, et al. Lead exposure induces changes in 5-hydroxymethylcytosine

Cory-Slechta DA, Schneider JS. Sex- and brain region-specific effects of prenatal stress and lead exposure on permissive and repressive post-translational histone modifications from embryonic development through adulthood. Neurotoxicology. 2017;**62**:207-217

Renehan WE, et al. Altered microRNA, mRNA, and protein expression of neurodegeneration-related biomarkers

Kidd SK, Sobolewski M,

**42**

clusters in CpG islands in human embryonic stem cells and umbilical cord blood. Epigenetics. 2015;**10**(7):607-621

[77] Hutson TH, Kathe C, Palmisano I, Bartholdi K, Hervera A, De Virgiliis F, et al. Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models. Science Translational Medicine. 2019;**11**(487):2064-2076

[78] Wu Y, Xu Y, Huang X, Ye D, Han M, Wang HL. Regulatory roles of histone deacetylases 1 and 2 in Pb-induced neurotoxicity. Toxicological Sciences. 2018;**162**(2):688-701

[79] Shafabakhsh R, Aghadavod E, Ghayour-Mobarhan M, Ferns G, Asemi Z. Role of histone modification and DNA methylation in signaling pathways involved in diabetic retinopathy. Journal of Cellular Physiology. 2019;**234**(6):7839-7846

[80] Gu X, Xu Y, Xue WZ, Wu Y, Ye Z, Xiao G, et al. Interplay of miR-137 and EZH2 contributes to the genome-wide redistribution of H3K27me3 underlying the Pb-induced memory impairment. Cell Death & Disease. 2019;**10**(9):671

[81] Uckelmann M, Sixma TK. Histone ubiquitination in the DNA damage response. DNA Repair. 2017;**56**:92-101

[82] Nan A, Jia Y, Li X, Liu M, Zhang N, Chen L, et al. Editor's highlight: lncRNAL20992 regulates apoptotic proteins to promote lead-induced neuronal apoptosis. Toxicological Sciences. 2018;**161**(1):115-124

[83] Basha MR, Wei W, Bakheet SA, Benitez N, Siddiqi HK, Ge YW, et al. The fetal basis of amyloidogenesis: Exposure to lead and latent overexpression of amyloid precursor protein and beta-amyloid in the aging brain. The Journal of Neuroscience. 2005;**25**(4):823-829

[84] Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: Prevalence estimates using the 2000 census. Archives of Neurology. 2003;**60**(8):1119-1122

[85] Chin-Chan M, Cobos-Puc L, Alvarado-Cruz I, Bayar M, Ermolaeva M. Early-life Pb exposure as a potential risk factor for Alzheimer's disease: Are there hazards for the Mexican population? Journal of Biological Inorganic Chemistry. 2019;**24**(8):1285-1303

**45**

**Chapter 3**

**Abstract**

Solutions

able metal ions such as Na<sup>+</sup>

parameter, batch/column modes

**1. Introduction**

*Rajendra Sukhadeorao Dongre*

Lead: Toxicological Profile,

Pollution Aspects and Remedial

Water quality is the keen concern all over the world. As water resources get contaminated naturally or artificially, at last they affect our health as well as economic and social development of the nations. Among the prominent chemical pollutants, lead alone has threatened health of billions due to deterioration in water quality. Thus, safe water for drinking becomes a major worried issue of UNICEF as a major stakeholder in sustaining water quality with responsibility to improve and sustain quality of water through its programs around the world. The mitigation of contaminations through effective techniques is the common global effort toward remediation of pollutions. This chapter has investigated viability of ordinary organic waste and natural polymeric material like chitin, chitosan, and doped bio-composite adsorbents for the mitigation of Pb2+ ions from water. The relatively higher adsorption potential of synthesized composites is studied for removing excessive lead concentration from water as tested in batch and column mode. Certain exchange-

effective in Pb2+ retention and facilitate its adsorption. Certain pilot domestic units provide simple, efficient, and fesasible options for removal of Pb2+ ions from water.

**Keywords:** lead(II), chitosan, biocomposite, adsorption, diffusion, thermodynamic

The need of pure and safe water to the society is a precondition for health and development along with a basic human right as very well cited in the slogan below:

Yet, millions of people throughout developing world denied this fundamental fact/right. Water borne diseases may arise through insufficient safe water supplies coupled with poor sanitation, and hygiene causes about 4 million death/year including children [1]. International communities are doing lots of attempts in this sense. Billion people do not have access to improve water sources and are not able to get pure and safe water for drinking as well as for other purposes. In fact, the magnitude of water quality problem is even larger than being projected. The existing

*Water is abundant, besides inexpensive, Yet pure Water is fewer, While good health, needs to drink it in safe, pure and upmost care!*

, Ca2+, and Mg2+ aid to form solid precipitate, which is

## **Chapter 3**

## Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions

*Rajendra Sukhadeorao Dongre*

## **Abstract**

Water quality is the keen concern all over the world. As water resources get contaminated naturally or artificially, at last they affect our health as well as economic and social development of the nations. Among the prominent chemical pollutants, lead alone has threatened health of billions due to deterioration in water quality. Thus, safe water for drinking becomes a major worried issue of UNICEF as a major stakeholder in sustaining water quality with responsibility to improve and sustain quality of water through its programs around the world. The mitigation of contaminations through effective techniques is the common global effort toward remediation of pollutions. This chapter has investigated viability of ordinary organic waste and natural polymeric material like chitin, chitosan, and doped bio-composite adsorbents for the mitigation of Pb2+ ions from water. The relatively higher adsorption potential of synthesized composites is studied for removing excessive lead concentration from water as tested in batch and column mode. Certain exchangeable metal ions such as Na<sup>+</sup> , Ca2+, and Mg2+ aid to form solid precipitate, which is effective in Pb2+ retention and facilitate its adsorption. Certain pilot domestic units provide simple, efficient, and fesasible options for removal of Pb2+ ions from water.

**Keywords:** lead(II), chitosan, biocomposite, adsorption, diffusion, thermodynamic parameter, batch/column modes

## **1. Introduction**

The need of pure and safe water to the society is a precondition for health and development along with a basic human right as very well cited in the slogan below:

*Water is abundant, besides inexpensive, Yet pure Water is fewer, While good health, needs to drink it in safe, pure and upmost care!*

Yet, millions of people throughout developing world denied this fundamental fact/right. Water borne diseases may arise through insufficient safe water supplies coupled with poor sanitation, and hygiene causes about 4 million death/year including children [1]. International communities are doing lots of attempts in this sense. Billion people do not have access to improve water sources and are not able to get pure and safe water for drinking as well as for other purposes. In fact, the magnitude of water quality problem is even larger than being projected. The existing

improved sources in developing countries do not provide water of adequate quality for drinking and other purposes.

In 2006, UNICEF has drawn global strategy to distinguish growing importance of ensuring safe drinking water, sanitation, and hygiene strategies for the decade 2006–2015 in its special programs [1–3]. In many Asian countries, the tube well water is viable for extensive toxic and hazardous contaminations such as arsenic, fluoride, and lead [1, 2]. Even today more than half of the world population depends on ground water being a vital source for drinking as it contributes 97% of global freshwater. In a number of geographical regions, ground water is a vital source for drinking due to the fact that it contributes single largest supply for serving drinking water. Especially in India, almost 80% ground water is needed for rural domestic need and 50% needed for urban population. Thus, clean ground water supply is most essential to serve the basic and critical necessities for various utility purposes. Over the years, the availability of pure and safe waters for drinking and other functions has been great concern for better environment [3, 4].

Efficient synthetic purification/treatment processes are used to remove detrimental chemical/biological pollutants along with suspended solids from water and to provide pure and safe water for multiple consumptions such as drinking, therapeutics, pharmaceuticals, chemical, and industrial uses. Throughout the world many, water treatments are almost remains same as mention below:


Ground water is purer and safer than surface water due to earth covering that works as a natural filter, which is the major source for domestic purposes in the developing country like India [2, 5]. In fact, few decades back, water seems to be odorless, free from turbidity, and good from the esthetic point of view and considered to be pure and unpolluted. The concept of water pollution has now changed as even clear water may be latently polluted. As well, surface water is also contaminated by effluents from industries, municipalities, and other places. The contamination of hazardous anions like fluoride in particular and other anions such as nitrate, sulfate, and phosphate in ground water is a wide spread phenomenon causing health problem. The available domestic water purification processes are seldom suitable for rural people due to high cost and maintenance. This creates a great gap between developed water purification technology and its anticipated application [1–4, 6, 7].

Heavy metals such as Zn, Cu, As, Hg, Cr, Ni, Cd, and Pb cause severe problem for humans and aquatic ecosystems if discharged in water through industries and other sources due to particular toxic, hazardous, and carcinogenic nature as well as accumulations in the body based on relative chemical and physiological characteristics [1–4, 6, 8]. The removal of heavy metals from water is seriously needed because of the imposed environmental pollution and ecological degradation. The adsorption process is widely used for the removal of heavy metals from wastewater because of its low cost, availability, and eco-friendly nature. Both commercial adsorbents and bio-adsorbents are used for the removal of heavy metals from wastewater, with high removal capacity. This chapter compiles information on different adsorbents used for Pb2+ removal and provides information on the commercially available. Innovative processes and technologies are involved for lessening toxicity so as to cater demands of environmental standards being developed for the treatment of heavy metal polluted wastewater.

**47**

*Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions*

hazardous to man-health and environment conditions [1–4, 6].

results in enduring health risks to all the elements of ecosystem.

are recognized by the USEPA as mentioned in **Table 1**.

**1.1 Precedence pollutants in water**

As recommended by the WHO, the maximum tolerable limit of lead metal in drinking water is 0.05 mg/L, while Environmental Protection Agency allows the permissible limit for Pb2+ in wastewater as 50 ppb (part per billion). However, industrial wastewaters own Pb2+ ion with the amount ranging between 200 and 500 mg/L, which is a lot more than that of water quality standards. Maximum contamination/limiting level concentration and types of heavy metals as discharged

The introduction of contaminants into the environment causes pollution, which

is the unfavorable alterations of our surroundings. This pollution can be in the form of chemical substances or energy such as noise, heat, and light [6]. Thus, the pollutants can be naturally occurring substances or energies; however, things are considered contaminants if they exist excess of natural levels. All such pollutants that enter the atmosphere by any known or unknown sources surely create harms or discomfort to humans and other living organisms of the planet.Many water

Toxic heavy metal removal from domestic wastes, sewage, and industrial outlets is a challenging task, especially in waste effluents. Various methodologies are being investigated as and when for the mitigation of such heavy metal pollution in water [1–4, 6, 8]. The heavy metals including lead, cadmium, and mercury are removed from industrial wastewater by means of assorted techniques namely physicochemical precipitation, electrochemical reduction, ion exchangers, reverse osmosis, cementation, electrodialysis, electrowinning, electrocoagulation, membrane separation, and adsorption. However, technical applications, plant easiness, and cost are vital parameters to choose utmost appropriate treatments for the mitigation of heavy metal pollution from water [4]. Physicochemical adsorption is quite a cheap and capable method for retention of heavy metals from industrial effluents due to its easy, successful, and profitable features. Heavy metal pollution subsists in wastes of a number of industries, such as metal plating, mining, tanneries, chloralkali, radiator built-up, smelting, alloy-making printed circuit board making, and storage batteries. Assorted metals such as tin, lead, and nickel metal-based solder plates shown familiar resistant over plated if applied for solderable applications as metal plating are recommended, as deposited inter-metallic formations ensuing diffusion barrier viable as good solder base for soldering applications. Most of the aforesaid industries discharged huge wastewater contaminated with lead and deemed utmost

Lead gets absorbed or accumulated in living species and subsequently penetrates in human systems through food chains/cycles. Ingested lead beyond its stringent/ permitted level results in serious health disorders. Thus, it is compulsory to treat Pb2+ contaminations prior to its discharge into the environment [6, 8]. In fact, heavy metal lead is soft, malleable, bluish gray color being picky interested due to innate toxicity and extensive existence in the atmosphere. Lead is the most toxic metal considered as a priority pollutant as an industrial pollutant, which enters in an environment via soil, air, and water/wastewater. Lead is a systemic poison very toxic in nature because it causes anemia, kidney malfunction, brain tissue damage, and death in severe poisoning [9]. Lead pollution dispersed over the soil and ground water through natural sources and industrial effluents. Certain processing industries, such as acid-battery making, metal plating and finishing, ammunition, anti-knocking agent-tetraethyl-lead synthesis, ceramic/glass industries, and environmental clearout practices, dispersed lead polluted water, which is the foremost lead pollution sources. Alternatively, high lead concentration in the atmosphere also

*DOI: http://dx.doi.org/10.5772/intechopen.93095*

#### *Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions DOI: http://dx.doi.org/10.5772/intechopen.93095*

*Lead Chemistry*

for drinking and other purposes.

radiations.

improved sources in developing countries do not provide water of adequate quality

and other functions has been great concern for better environment [3, 4].

i.physical processes like filtration, sedimentation, and distillation;

ii.biological methods such as slow sand filter/bioactive carbon; and

iii. chemical techniques, viz. coagulation flocculation, chlorination, and UV

Ground water is purer and safer than surface water due to earth covering that works as a natural filter, which is the major source for domestic purposes in the developing country like India [2, 5]. In fact, few decades back, water seems to be odorless, free from turbidity, and good from the esthetic point of view and considered to be pure and unpolluted. The concept of water pollution has now changed as even clear water may be latently polluted. As well, surface water is also contaminated by effluents from industries, municipalities, and other places. The contamination of hazardous anions like fluoride in particular and other anions such as nitrate, sulfate, and phosphate in ground water is a wide spread phenomenon causing health problem. The available domestic water purification processes are seldom suitable for rural people due to high cost and maintenance. This creates a great gap between developed water purification technology and its anticipated application [1–4, 6, 7]. Heavy metals such as Zn, Cu, As, Hg, Cr, Ni, Cd, and Pb cause severe problem for humans and aquatic ecosystems if discharged in water through industries and other sources due to particular toxic, hazardous, and carcinogenic nature as well as accumulations in the body based on relative chemical and physiological characteristics [1–4, 6, 8]. The removal of heavy metals from water is seriously needed because of the imposed environmental pollution and ecological degradation. The adsorption process is widely used for the removal of heavy metals from wastewater because of its low cost, availability, and eco-friendly nature. Both commercial adsorbents and bio-adsorbents are used for the removal of heavy metals from wastewater, with high removal capacity. This chapter compiles information on different adsorbents used for Pb2+ removal and provides information on the commercially available. Innovative processes and technologies are involved for lessening toxicity so as to cater demands of environmental standards being developed for the treatment of heavy metal polluted wastewater.

many, water treatments are almost remains same as mention below:

Efficient synthetic purification/treatment processes are used to remove detrimental chemical/biological pollutants along with suspended solids from water and to provide pure and safe water for multiple consumptions such as drinking, therapeutics, pharmaceuticals, chemical, and industrial uses. Throughout the world

In 2006, UNICEF has drawn global strategy to distinguish growing importance of ensuring safe drinking water, sanitation, and hygiene strategies for the decade 2006–2015 in its special programs [1–3]. In many Asian countries, the tube well water is viable for extensive toxic and hazardous contaminations such as arsenic, fluoride, and lead [1, 2]. Even today more than half of the world population depends on ground water being a vital source for drinking as it contributes 97% of global freshwater. In a number of geographical regions, ground water is a vital source for drinking due to the fact that it contributes single largest supply for serving drinking water. Especially in India, almost 80% ground water is needed for rural domestic need and 50% needed for urban population. Thus, clean ground water supply is most essential to serve the basic and critical necessities for various utility purposes. Over the years, the availability of pure and safe waters for drinking

**46**

Toxic heavy metal removal from domestic wastes, sewage, and industrial outlets is a challenging task, especially in waste effluents. Various methodologies are being investigated as and when for the mitigation of such heavy metal pollution in water [1–4, 6, 8]. The heavy metals including lead, cadmium, and mercury are removed from industrial wastewater by means of assorted techniques namely physicochemical precipitation, electrochemical reduction, ion exchangers, reverse osmosis, cementation, electrodialysis, electrowinning, electrocoagulation, membrane separation, and adsorption. However, technical applications, plant easiness, and cost are vital parameters to choose utmost appropriate treatments for the mitigation of heavy metal pollution from water [4]. Physicochemical adsorption is quite a cheap and capable method for retention of heavy metals from industrial effluents due to its easy, successful, and profitable features. Heavy metal pollution subsists in wastes of a number of industries, such as metal plating, mining, tanneries, chloralkali, radiator built-up, smelting, alloy-making printed circuit board making, and storage batteries. Assorted metals such as tin, lead, and nickel metal-based solder plates shown familiar resistant over plated if applied for solderable applications as metal plating are recommended, as deposited inter-metallic formations ensuing diffusion barrier viable as good solder base for soldering applications. Most of the aforesaid industries discharged huge wastewater contaminated with lead and deemed utmost hazardous to man-health and environment conditions [1–4, 6].

Lead gets absorbed or accumulated in living species and subsequently penetrates in human systems through food chains/cycles. Ingested lead beyond its stringent/ permitted level results in serious health disorders. Thus, it is compulsory to treat Pb2+ contaminations prior to its discharge into the environment [6, 8]. In fact, heavy metal lead is soft, malleable, bluish gray color being picky interested due to innate toxicity and extensive existence in the atmosphere. Lead is the most toxic metal considered as a priority pollutant as an industrial pollutant, which enters in an environment via soil, air, and water/wastewater. Lead is a systemic poison very toxic in nature because it causes anemia, kidney malfunction, brain tissue damage, and death in severe poisoning [9]. Lead pollution dispersed over the soil and ground water through natural sources and industrial effluents. Certain processing industries, such as acid-battery making, metal plating and finishing, ammunition, anti-knocking agent-tetraethyl-lead synthesis, ceramic/glass industries, and environmental clearout practices, dispersed lead polluted water, which is the foremost lead pollution sources. Alternatively, high lead concentration in the atmosphere also results in enduring health risks to all the elements of ecosystem.

As recommended by the WHO, the maximum tolerable limit of lead metal in drinking water is 0.05 mg/L, while Environmental Protection Agency allows the permissible limit for Pb2+ in wastewater as 50 ppb (part per billion). However, industrial wastewaters own Pb2+ ion with the amount ranging between 200 and 500 mg/L, which is a lot more than that of water quality standards. Maximum contamination/limiting level concentration and types of heavy metals as discharged are recognized by the USEPA as mentioned in **Table 1**.

#### **1.1 Precedence pollutants in water**

The introduction of contaminants into the environment causes pollution, which is the unfavorable alterations of our surroundings. This pollution can be in the form of chemical substances or energy such as noise, heat, and light [6]. Thus, the pollutants can be naturally occurring substances or energies; however, things are considered contaminants if they exist excess of natural levels. All such pollutants that enter the atmosphere by any known or unknown sources surely create harms or discomfort to humans and other living organisms of the planet.Many water


#### **Table 1.**

*Maximum contamination/limiting level (MCL) concentration and types of heavy metals being discharged as recognized by the USEPA standards [1–4, 6].*

pollutants may get discharged through domestic, industrial, and agricultural wastes due to human activities or domestic sources. In past years, water with odorless, colorless, and free from turbidity was considered as good, pure, and unpolluted from the esthetic point of view [1–4, 6]. But this entire concept of water pollution was changed. Now even if water is colorless and odorless, it can be polluted and may contain microbes as well as dissolved impurities such as toxic metals, organic pollutants, and radioactive materials. Thus, water pollution can be defined as any change in physical, chemical, or biological properties of matter. It is not possible to analysis water quality for all of chemical pollutants that could cause health problems, nor is it indispensable. However, most of these contaminants occur rarely, and many result from human contagion and affect a few water sources. The chemicals that potentially cause serious health problems by over widespread areas include arsenic, fluoride, phosphate, and nitrate (from swage and fertilizers) [1, 8].

Some of these anionic chemical pollutants are more often found in ground water, though surface water can also be impacted. In order to plan new water supply projects, especially to ground water resources, contamination from lead, arsenic, fluoride, phosphate, and nitrate should be given priority [5, 7, 8, 10]. Subsequently, second priority is to be given to metals (principally iron and manganese). The inorganic chemicals are common cause for water to be rejected from the esthetic view and also enhance salinity of water (saltiness or dissolved salt content of water body). The fresh or naturally occurring water has salinity <0.05% as characterized by low concentrations of dissolved salts [6].

#### **1.2 Significant studies of lead removal**

The advancement of today was seeded by research years ago, and progress of tomorrow will be the result of today's planned research. Comprehension of allied literature of past studies is very much indispensable for any investigation work to formulate sound methodology that acts as a guiding source during advancement of research. Chitin and chitosan are the frequently used biomaterials in mitigation of water pollutants [1, 8]. But, low mechanical resistance and high solubility in acid

**49**

**2.1 Air**

*Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions*

crisis, and this research is a small attempt for a big problem.

medium limit their applications in applied conditions, as observed in water treatment. However, such disadvantages can be overcome by preparation of chitin- and chitosanbased biocomposite matrix by doping techniques. The biopolymer-based adsorbent media can be chemically and mechanically stabilized by doping chitosan matrix to alter its solubility and brittleness. Herein, a novel de-fluoridation procedure has been developed, which successfully removed fluoride from water and exhibits greater competitive adsorption capacities than those of commercial activated alumina (even at broad range of pH). The novel aspects of research work were inferred from review of literature and found that this developed Pb2+ removal technique of water works by the sorption of fluoride onto bioadsorbents in efficient way in terms of magnitude of

Lead is a soft, malleable heavy metal that belongs to the carbon group with symbol Pb (Latin: Plumbum) [1–4, 6]. It is also found in the earth's crust, and the proportion gets increased with time due to radioactive uranium disintegration. Atomic number of lead metal is 82, atomic weight 207.2, melting point 327.5°C,

, and electronic configuration [Xe] 4f14 5d10 6s2

lead has a bluish-white color after being freshly cut, but it soon tarnishes to a dull grayish color when exposed to air. Lead metal exists as the natural abundance in four stable isotopic forms namely Pb204, Pb206, Pb207, and Pb208. Metallic lead PbO rarely occurs in nature; nevertheless, the metal exists in two main oxidation states Pb2+ and Pb4+ with more stable divalent form in the aquatic environment [2]. Three lead oxides are known, that is, lead monoxide (PbO), lead dioxide (PbO2), and lead tetroxide (Pb3O4) also called minium. Lead is found in ore with other heavy metals such as zinc, silver, and copper and is extracted together with these metals. The main lead mineral is galena (PbS) that contains 86.6% lead by weight. However, as a result of human activity in the atmosphere, lead metal exists mainly as cerussite

The presence of lead in water, air, and soil environment even in traces has detrimental effects on plants and animals. The natural sources of lead are soil erosion, volcanic eruptions, sea sprays, and bush fires. The anthropogenic activities dispersed lead compounds throughout the environment. Lead is transferred continuously through air, water, and soil by natural chemical and physical processes such as weathering, runoff, precipitation, dry deposition of dust, and stream/river flow [1–4, 6].

The ingestion of lead through food and water is much greater than that of urban

air. Inhaled lead of about 20–40%, which is derived from the air, is much more readily absorbed [6]. The air released from the combustion of fossil fuels, especially leaded gasoline, and several industrial processes dealing with storage batteries, mining, and ore smelting operations are of major concern regarding lead pollution in the atmosphere. Children are more susceptible to airborne lead poisoning, and lead absorbed in the guts of infants and young children is estimated to be 5–10 times greater than in adults [2, 11]. Faulty removal of lead-based paint, street dirt, and household dust absorbed through the lungs, skin, and intestinal tract is also responsible to airborne lead contamination. Cigarette smoke is also a significant

6p2

. Metallic

*DOI: http://dx.doi.org/10.5772/intechopen.93095*

**1.3 Lead properties**

density 11.34 g/cm3

(PbCO3) and anglesite (PbSO4) [5, 7, 10].

**2. Environmental sources of lead**

*Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions DOI: http://dx.doi.org/10.5772/intechopen.93095*

medium limit their applications in applied conditions, as observed in water treatment. However, such disadvantages can be overcome by preparation of chitin- and chitosanbased biocomposite matrix by doping techniques. The biopolymer-based adsorbent media can be chemically and mechanically stabilized by doping chitosan matrix to alter its solubility and brittleness. Herein, a novel de-fluoridation procedure has been developed, which successfully removed fluoride from water and exhibits greater competitive adsorption capacities than those of commercial activated alumina (even at broad range of pH). The novel aspects of research work were inferred from review of literature and found that this developed Pb2+ removal technique of water works by the sorption of fluoride onto bioadsorbents in efficient way in terms of magnitude of crisis, and this research is a small attempt for a big problem.

#### **1.3 Lead properties**

*Lead Chemistry*

**Table 1.**

*recognized by the USEPA standards [1–4, 6].*

**Entry Heavy metal Maximum** 

**contamination level (ppm)**

1 Lead 0.005 Damage/fatal to brain, kidney diseases, circulatory

2 Arsenic 0.050 Skin manifestations, visceral cancers, vascular disease 3 Cadmium 0.01 Kidney damage, renal disorder, human carcinogen 4 Chromium (VI) 0.05 Headache, diarrhea, nausea, vomiting, carcinogenic,

5 Copper 0.25 Wilson disease, insomnia, vomiting, hematemesis,

6 Nickel 0.20 Dermatitis, nausea, chronic asthma, coughing,

7 Mercury 0.00003 Rheumatoid arthritis, diseases of the kidneys,

**Potential toxicity profiles**

and nervous system disorders, death in severe contamination

respiratory tract problems

hypotension, melena, coma, jaundice, pigmentation of skin, gastrointestinal distress, damage liver kidney

human carcinogen

circulatory system, and nervous system

pollutants may get discharged through domestic, industrial, and agricultural wastes due to human activities or domestic sources. In past years, water with odorless, colorless, and free from turbidity was considered as good, pure, and unpolluted from the esthetic point of view [1–4, 6]. But this entire concept of water pollution was changed. Now even if water is colorless and odorless, it can be polluted and may contain microbes as well as dissolved impurities such as toxic metals, organic pollutants, and radioactive materials. Thus, water pollution can be defined as any change in physical, chemical, or biological properties of matter. It is not possible to analysis water quality for all of chemical pollutants that could cause health problems, nor is it indispensable. However, most of these contaminants occur rarely, and many result from human contagion and affect a few water sources. The chemicals that potentially cause serious health problems by over widespread areas include arsenic,

*Maximum contamination/limiting level (MCL) concentration and types of heavy metals being discharged as* 

fluoride, phosphate, and nitrate (from swage and fertilizers) [1, 8].

by low concentrations of dissolved salts [6].

**1.2 Significant studies of lead removal**

Some of these anionic chemical pollutants are more often found in ground water, though surface water can also be impacted. In order to plan new water supply projects, especially to ground water resources, contamination from lead, arsenic, fluoride, phosphate, and nitrate should be given priority [5, 7, 8, 10]. Subsequently, second priority is to be given to metals (principally iron and manganese). The inorganic chemicals are common cause for water to be rejected from the esthetic view and also enhance salinity of water (saltiness or dissolved salt content of water body). The fresh or naturally occurring water has salinity <0.05% as characterized

The advancement of today was seeded by research years ago, and progress of tomorrow will be the result of today's planned research. Comprehension of allied literature of past studies is very much indispensable for any investigation work to formulate sound methodology that acts as a guiding source during advancement of research. Chitin and chitosan are the frequently used biomaterials in mitigation of water pollutants [1, 8]. But, low mechanical resistance and high solubility in acid

**48**

Lead is a soft, malleable heavy metal that belongs to the carbon group with symbol Pb (Latin: Plumbum) [1–4, 6]. It is also found in the earth's crust, and the proportion gets increased with time due to radioactive uranium disintegration. Atomic number of lead metal is 82, atomic weight 207.2, melting point 327.5°C, density 11.34 g/cm3 , and electronic configuration [Xe] 4f14 5d10 6s2 6p2 . Metallic lead has a bluish-white color after being freshly cut, but it soon tarnishes to a dull grayish color when exposed to air. Lead metal exists as the natural abundance in four stable isotopic forms namely Pb204, Pb206, Pb207, and Pb208. Metallic lead PbO rarely occurs in nature; nevertheless, the metal exists in two main oxidation states Pb2+ and Pb4+ with more stable divalent form in the aquatic environment [2]. Three lead oxides are known, that is, lead monoxide (PbO), lead dioxide (PbO2), and lead tetroxide (Pb3O4) also called minium. Lead is found in ore with other heavy metals such as zinc, silver, and copper and is extracted together with these metals. The main lead mineral is galena (PbS) that contains 86.6% lead by weight. However, as a result of human activity in the atmosphere, lead metal exists mainly as cerussite (PbCO3) and anglesite (PbSO4) [5, 7, 10].

## **2. Environmental sources of lead**

The presence of lead in water, air, and soil environment even in traces has detrimental effects on plants and animals. The natural sources of lead are soil erosion, volcanic eruptions, sea sprays, and bush fires. The anthropogenic activities dispersed lead compounds throughout the environment. Lead is transferred continuously through air, water, and soil by natural chemical and physical processes such as weathering, runoff, precipitation, dry deposition of dust, and stream/river flow [1–4, 6].

#### **2.1 Air**

The ingestion of lead through food and water is much greater than that of urban air. Inhaled lead of about 20–40%, which is derived from the air, is much more readily absorbed [6]. The air released from the combustion of fossil fuels, especially leaded gasoline, and several industrial processes dealing with storage batteries, mining, and ore smelting operations are of major concern regarding lead pollution in the atmosphere. Children are more susceptible to airborne lead poisoning, and lead absorbed in the guts of infants and young children is estimated to be 5–10 times greater than in adults [2, 11]. Faulty removal of lead-based paint, street dirt, and household dust absorbed through the lungs, skin, and intestinal tract is also responsible to airborne lead contamination. Cigarette smoke is also a significant

source of lead exposure due to lead arsenate insecticides sprayed on tobacco. Most of lead ions reside in smoke-ash; however, studies have estimated 20 nanogram of lead per cigarette smoke, leading toxic effects on lungs of smoker.

## **2.2 Food**

Food sources can be contaminated with lead due to spraying of lead arsenate insecticides or lead accumulations during food processing. Exclusively imported pottery such as ceramic cookware possess lead-containing glaze is a common source of lead toxicity. Lead solder used for sealing of food cans, especially the acidic foods such as tomato, okra and orange, grapefruit, or cranberry juices are also key sources of lead intake. Canned juices and canned baby foods such as evaporated milk may contain up to 100 and 200 μg of lead per liter, respectively [12], as high as 300 μg/ day total lead uptake through food. Ingestion of peeled lead-based paint pica in children causes poisoning [2, 8, 13].

#### **2.3 Soil**

The toxic lead compounds are strongly adsorbed onto the upper layers of soil and do not leach into the subsoil. The average residence time of lead in the atmosphere is about 10 days. The presence of high concentration of lead in the soils results in lead contaminated fruits and vegetables. Particulate pollutants are emitted through leaded paints, leaded gasoline, and lead in pipes that can also contaminate the soil with heavy metal lead/Pb2+ [14].

#### **2.4 Water**

The solubility of lead compounds is the highest in soft and acidic water, and it is a function of pH, hardness, and salinity of water sample. Several industries engaged in releasing of industrial wastewater effluents, lead acid batteries, fertilizers, pesticides, and mining waste; metallurgical, chemical, and petrochemical industries are prominent sources of releasing toxic lead in the water stream. Lead rarely occurs in natural water bodies, but the major source of lead in drinking water is from leadbased plumbing materials. The corrosion of such leaded pipes/fixtures enhances lead amount in community water. Old homes constructed before 1986 owing lead pipes, fixtures, and solder are the main contributor to lead in tap water. Other water delivery systems such as lead solder used to join copper pipes, brass in faucets, coolers, and valves are liable for lead content in water. Older submerged pumps used in well water can also contain leaded-brass works. Seawater and river water contain 2–30 ppt and 3–30 ppb of lead content, respectively. Phytoplankton contains 5–10 ppm, freshwater fish 0.5–1000 ppb, and oyster 500 ppb of lead/Pb2+ concentration [15].

### **3. Control of lead contamination**

In India, the Central Pollution Control Board (CPCB) has carried out a major ground water quality survey, and the report recognized about 20 critical sites of ground water pollution in various states of India. CPCB found that industrial effluents are the primary and major cause for ground water pollution [1–4, 6, 11]. The major heavy metal contamination sites including lead metal in Indian scenario have been reported in **Figure 1**. The chemical quality of ground water as monitored by CPCB India showed that the states such as Haryana, UP, Punjab, West Bengal, Tamilnadu, and Telangana own heavy contaminations of lead metals [12, 13].

**51**

*Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions*

*DOI: http://dx.doi.org/10.5772/intechopen.93095*

**3.1 Regulatory aspects of lead in water**

**Figure 1.**

national primary drinking water standard [17].

**4. Symptoms and health effects of lead**

**4.1 Effects of lead on children**

According to the Indian Standard Institution (ISI), the tolerance limit for discharge of lead into drinking water is 0.05 mg/L and land surface water 0.1 mg/L [16]. The World Health Organization (WHO 1995) had proposed safe total lead limit of 50 ppb in drinking water, which was further decreased to 10 ppb [1–4, 6]. The permissible limit of lead ions in drinking water as set by the European Union (EU), the United States Environmental Protection Agency (USEPA), and Guidelines for Canadian Drinking Water Quality in 2012 is 10, 15, and 10 ppb, respectively. However, more recently, an EPA document recommends a zero lead/Pb2+ value in

*Heavy metal contaminations in various Indian states. Sources: Timesofindia.indiatimes.com/ articleshow/65204273.cms?utm\_source=contentofinterest&utm\_medium=text&utm\_campaign=cppst.*

The human body contains around 120 mg of lead, and 10–20% of lead is absorbed by the intestines. The doorway of poisonous lead in human system mainly through contaminated air, food, and water sources manifests overt and detrimental health problems. Lead is a cumulative poison, and it elucidates destructive effects on almost every physiological systems namely musculoskeletal, nervous, cardiovascular, digestive, reproductive, excretory, endocrine, and metabolic system. Lead is highly toxic and carcinogenic even at low concentration [2, 6]. International Agency for Research on Cancer (IARC) classifies inorganic lead compounds as probably carcinogenic to humans (Group-2A). The National Toxicology Program (NTP-2005) of the US Department of Health and Human Services concluded that "Lead and lead compounds are reasonably anticipated to be human carcinogens" [16, 17].

Children are usually more vulnerable for toxicity of lead due to immature blood-brain barrier and the fact that lead can easily cross blood brain and placental barrier, and thus they readily absorb a larger amount of lead per unit body weight than adults. The serious effects of Pb2+ on health of children include encephalopathy, peripheral neuropathy, cognitive impairment, and personality disorders (USEPA, 1986a). If the neuropathy is severe, the lesion gets permanent. Lead

*Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions DOI: http://dx.doi.org/10.5772/intechopen.93095*

#### **Figure 1.**

*Lead Chemistry*

**2.2 Food**

**2.3 Soil**

**2.4 Water**

children causes poisoning [2, 8, 13].

the soil with heavy metal lead/Pb2+ [14].

**3. Control of lead contamination**

source of lead exposure due to lead arsenate insecticides sprayed on tobacco. Most of lead ions reside in smoke-ash; however, studies have estimated 20 nanogram of

Food sources can be contaminated with lead due to spraying of lead arsenate insecticides or lead accumulations during food processing. Exclusively imported pottery such as ceramic cookware possess lead-containing glaze is a common source of lead toxicity. Lead solder used for sealing of food cans, especially the acidic foods such as tomato, okra and orange, grapefruit, or cranberry juices are also key sources of lead intake. Canned juices and canned baby foods such as evaporated milk may contain up to 100 and 200 μg of lead per liter, respectively [12], as high as 300 μg/ day total lead uptake through food. Ingestion of peeled lead-based paint pica in

The toxic lead compounds are strongly adsorbed onto the upper layers of soil and do not leach into the subsoil. The average residence time of lead in the atmosphere is about 10 days. The presence of high concentration of lead in the soils results in lead contaminated fruits and vegetables. Particulate pollutants are emitted through leaded paints, leaded gasoline, and lead in pipes that can also contaminate

The solubility of lead compounds is the highest in soft and acidic water, and it is a function of pH, hardness, and salinity of water sample. Several industries engaged in releasing of industrial wastewater effluents, lead acid batteries, fertilizers, pesticides, and mining waste; metallurgical, chemical, and petrochemical industries are prominent sources of releasing toxic lead in the water stream. Lead rarely occurs in natural water bodies, but the major source of lead in drinking water is from leadbased plumbing materials. The corrosion of such leaded pipes/fixtures enhances lead amount in community water. Old homes constructed before 1986 owing lead pipes, fixtures, and solder are the main contributor to lead in tap water. Other water delivery systems such as lead solder used to join copper pipes, brass in faucets, coolers, and valves are liable for lead content in water. Older submerged pumps used in well water can also contain leaded-brass works. Seawater and river water contain 2–30 ppt and 3–30 ppb of lead content, respectively. Phytoplankton contains 5–10 ppm, freshwater fish 0.5–1000 ppb, and oyster 500 ppb of lead/Pb2+ concentration [15].

In India, the Central Pollution Control Board (CPCB) has carried out a major ground water quality survey, and the report recognized about 20 critical sites of ground water pollution in various states of India. CPCB found that industrial effluents are the primary and major cause for ground water pollution [1–4, 6, 11]. The major heavy metal contamination sites including lead metal in Indian scenario have been reported in **Figure 1**. The chemical quality of ground water as monitored by CPCB India showed that the states such as Haryana, UP, Punjab, West Bengal, Tamilnadu, and Telangana own heavy contaminations of lead metals [12, 13].

lead per cigarette smoke, leading toxic effects on lungs of smoker.

**50**

*Heavy metal contaminations in various Indian states. Sources: Timesofindia.indiatimes.com/ articleshow/65204273.cms?utm\_source=contentofinterest&utm\_medium=text&utm\_campaign=cppst.*

#### **3.1 Regulatory aspects of lead in water**

According to the Indian Standard Institution (ISI), the tolerance limit for discharge of lead into drinking water is 0.05 mg/L and land surface water 0.1 mg/L [16]. The World Health Organization (WHO 1995) had proposed safe total lead limit of 50 ppb in drinking water, which was further decreased to 10 ppb [1–4, 6]. The permissible limit of lead ions in drinking water as set by the European Union (EU), the United States Environmental Protection Agency (USEPA), and Guidelines for Canadian Drinking Water Quality in 2012 is 10, 15, and 10 ppb, respectively. However, more recently, an EPA document recommends a zero lead/Pb2+ value in national primary drinking water standard [17].

## **4. Symptoms and health effects of lead**

The human body contains around 120 mg of lead, and 10–20% of lead is absorbed by the intestines. The doorway of poisonous lead in human system mainly through contaminated air, food, and water sources manifests overt and detrimental health problems. Lead is a cumulative poison, and it elucidates destructive effects on almost every physiological systems namely musculoskeletal, nervous, cardiovascular, digestive, reproductive, excretory, endocrine, and metabolic system. Lead is highly toxic and carcinogenic even at low concentration [2, 6]. International Agency for Research on Cancer (IARC) classifies inorganic lead compounds as probably carcinogenic to humans (Group-2A). The National Toxicology Program (NTP-2005) of the US Department of Health and Human Services concluded that "Lead and lead compounds are reasonably anticipated to be human carcinogens" [16, 17].

#### **4.1 Effects of lead on children**

Children are usually more vulnerable for toxicity of lead due to immature blood-brain barrier and the fact that lead can easily cross blood brain and placental barrier, and thus they readily absorb a larger amount of lead per unit body weight than adults. The serious effects of Pb2+ on health of children include encephalopathy, peripheral neuropathy, cognitive impairment, and personality disorders (USEPA, 1986a). If the neuropathy is severe, the lesion gets permanent. Lead

toxicity showed dark blue lead sulfide line at the gingival margin of the person. It is found that the fatal effects of lead (II) are marked by seizure, coma, and death if not treated immediately according to the USEPA studies [2, 8, 18]. Evidence suggests that lead may cause fatigue, irritability, information processing difficulties, memory problems, a reduction in sensory and motor reaction times, decisionmaking impairment, and lapses in concentration [12]. Lead interferes with heme biosynthesis by changing the activity of three enzymes δ-aminolevulinic acid synthetase (δ-ALAS), δ-aminolevulinic acid dehydratase (δ-ALAD), and ferrochelatase and thus affects the hematological system. The presence of Pb2+ ions above 70 mcg/dL in human blood exhibited microcytic and hypochromic anemia being characterized by hemoglobin reduction and basophilic stippling of erythrocytes along with a shortened life span of red blood cells (erythropoiesis) [6, 11, 12]. Increase blood lead level shows decreased intellectual capacity and IQ level of children by four to seven points for every 10 μg/dL [11]. Attention deficit hyperactivity disorder (ADHD) hearing impairment in child may disrupt peripheral nerve function (ATSDR 2007).

## **4.2 Effects of lead on adults**

Lead toxicity affects renal system as it causes many effects such as aminoaciduria, glycosuria, and hyperphosphaturia, that is, Fanconi-like syndrome [2, 19]. Kidney disease, both acute and chronic nephropathy, is a characteristic of lead toxicity [12]. Lead poisoning inhibits excretion of the waste product urate that causes a tendency for gout, that is, saturnine gout. Occupationally, lead exposed individual tends to have more hypertension than normal people and augmented risk for cardiovascular diseases, myocardial infarction, and strokes [20]. Lead toxicity includes gastrointestinal disturbances – abdominal pain, cramps, constipation, anorexia, and weight loss – immune suppression, and slight liver impairment. In adults, high levels of lead can cause headaches and disorders of mood, thinking, memory, irritability, lethargy, malaise, and paresthesia. There is also some evidence that lead exposure may affect adult's postural balance and peripheral nerve function, which can cause tremors or weakness in fingers, wrists, or ankles [2, 21]. Lead poisoning affects the human male reproductive system by decreasing the sperm count and increasing the abnormal sperm frequencies. Women are more susceptible to lead poisoning than men, and lead toxicity causes menstrual disorder, infertility miscarriages, and stillbirths. Lead inhibits several enzymes required for the synthesis of heme, causing a decrease in blood hemoglobin. Lead interferes with a hormonal form of vitamin D, which affects multiple processes in the body, including cell maturation and skeletal growth. Lead poisoning is also known to cause psychotic behavior such as hyperactivity or schizophrenia.

## **5. Assorted treatment processes for lead removal**

Detrimental heavy metals must be removed from the environment in particular water so as to protect the human beings and the environment [2–4, 6, 22]. To accomplish the increased stringent environmental regulations and maximum permissible limit of contaminant in water, a wide range of treatment technologies such as chemical precipitation, coagulation flocculation, flotation, ion exchange, membrane filtration, electrochemical treatment technologies, adsorption [5, 21], and bio-adsorption are most frequently examined for the mitigation of heavy metals from wastewater [2, 8]. Certain merits and demerits of various physicochemical methods used for the mitigation of Pb2+ from wastewater are mentioned in **Table 2**.

**53**

*Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions*

2 Adsorption Cheap, simple conditions for

3 Membrane filtration Small space requirement, low

4 Electrodialysis Elevated separation selectivity,

5 Photo-catalysis Remove metals, organics, green

The reduction of Pb2+ in wastewater to 0.05–0.10 mg/L level is required before its discharge to outlet. Certain frequently used methods for remediation of Pb2+

**Merits Demerits**

Huge sludge/waste formations, addition burden of solid-waste disposal

fouling

time

Less selective, create large wastes/secondary pollutants

Highly expensive, membrane

Costly, membrane fetid, needs more energy/power

Limited utilities, prolong

Low-cost, easy operation, high

operation, wide pH workability, high binding capacity/efficiency

pressure, high separation selectivity

efficiency

great efficiency

*The merits and demerits of various physicochemical methods used for the mitigation of Pb+2 from* 

process, less byproducts

a.**Precipitation:** It is usual practice use for remediation of Pb2+ of ppm level contamination from water. Pb2+ salts are insoluble in water and yet get entrapped as precipitates via treatment with certain chemicals such as soda lime, bisulphite, or ion exchangers in a practicable manner. This method uses many chemicals and ultimately generates huge solid wastes and thus poses a burden of sludge disposal. Besides the precipitation, techniques are nonspecific

b.**Ion exchange:** Ion exchange is another methodology use for the mitigation of Pb2+ ions from water. This is quite cheaper than the other known methods; besides ppb levels, Pb2+ ion removal can be achieved at large-scale workups. In fact, ion exchangers are natural materials namely certain clays, functionalized porous, gel polymer, zeolite, montmorillonite, and soil humus or some synthesized resins that hold positive/cation as well negative/anion exchanging parts with the other ions in solution owing to a better affinity from the surroundings [5, 7, 8, 10, 18, 23]. Certain artificial matrixes like organic resins are usual for ion exchangers used for the removal of Pb2+ ions from water/wastewater. However, such man-made ion exchangers are disadvantageous as nontolerant high level of metal due to matrix fouls [1, 5, 7, 8, 10, 18, 23]. Furthermore, synthetic/natural ion exchangers are nonselective and extremely susceptible to altered pH conditions. Ion-exchange methods have been widely used to remove heavy metals from water due to their many advantages, such as high treatment capacity, high removal efficiency, and fast kinetics [24]. The synthetic resins are most commonly preferred in ion exchange process as they effectively remove the heavy metals from the solution. The uptake of heavy metal ions by ion-exchange resins is rather affected by certain variables such as pH, temperature, initial metal concentration, and contact time. Charges present of ionic pollutant also controls ion-exchange phenomenon as reveled in purolite C-100 cation exchange resin carried abatement of Ce4+, Fe3+, and Pb2+ ions from aqueous solutions. Moreover, natural zeolites have also been widely used due to its low cost to remove heavy metal from aqueous solutions. Many researchers

and noneffective for low concentration of Pb2+ ions [2].

*DOI: http://dx.doi.org/10.5772/intechopen.93095*

**Entry Treatment** 

1 Physicochemical precipitation

**techniques**

from water are as follows:

**Table 2.**

*wastewater [2, 22].*


*Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions DOI: http://dx.doi.org/10.5772/intechopen.93095*

#### **Table 2.**

*Lead Chemistry*

function (ATSDR 2007).

**4.2 Effects of lead on adults**

toxicity showed dark blue lead sulfide line at the gingival margin of the person. It is found that the fatal effects of lead (II) are marked by seizure, coma, and death if not treated immediately according to the USEPA studies [2, 8, 18]. Evidence suggests that lead may cause fatigue, irritability, information processing difficulties, memory problems, a reduction in sensory and motor reaction times, decisionmaking impairment, and lapses in concentration [12]. Lead interferes with heme biosynthesis by changing the activity of three enzymes δ-aminolevulinic acid synthetase (δ-ALAS), δ-aminolevulinic acid dehydratase (δ-ALAD), and ferrochelatase and thus affects the hematological system. The presence of Pb2+ ions above 70 mcg/dL in human blood exhibited microcytic and hypochromic anemia being characterized by hemoglobin reduction and basophilic stippling of erythrocytes along with a shortened life span of red blood cells (erythropoiesis) [6, 11, 12]. Increase blood lead level shows decreased intellectual capacity and IQ level of children by four to seven points for every 10 μg/dL [11]. Attention deficit hyperactivity disorder (ADHD) hearing impairment in child may disrupt peripheral nerve

Lead toxicity affects renal system as it causes many effects such as aminoaciduria, glycosuria, and hyperphosphaturia, that is, Fanconi-like syndrome [2, 19]. Kidney disease, both acute and chronic nephropathy, is a characteristic of lead toxicity [12]. Lead poisoning inhibits excretion of the waste product urate that causes a tendency for gout, that is, saturnine gout. Occupationally, lead exposed individual tends to have more hypertension than normal people and augmented risk for cardiovascular diseases, myocardial infarction, and strokes [20]. Lead toxicity includes gastrointestinal disturbances – abdominal pain, cramps, constipation, anorexia, and weight loss – immune suppression, and slight liver impairment. In adults, high levels of lead can cause headaches and disorders of mood, thinking, memory, irritability, lethargy, malaise, and paresthesia. There is also some evidence that lead exposure may affect adult's postural balance and peripheral nerve function, which can cause tremors or weakness in fingers, wrists, or ankles [2, 21]. Lead poisoning affects the human male reproductive system by decreasing the sperm count and increasing the abnormal sperm frequencies. Women are more susceptible to lead poisoning than men, and lead toxicity causes menstrual disorder, infertility miscarriages, and stillbirths. Lead inhibits several enzymes required for the synthesis of heme, causing a decrease in blood hemoglobin. Lead interferes with a hormonal form of vitamin D, which affects multiple processes in the body, including cell maturation and skeletal growth. Lead poisoning is also known to cause

psychotic behavior such as hyperactivity or schizophrenia.

**5. Assorted treatment processes for lead removal**

Detrimental heavy metals must be removed from the environment in particular water so as to protect the human beings and the environment [2–4, 6, 22]. To accomplish the increased stringent environmental regulations and maximum permissible limit of contaminant in water, a wide range of treatment technologies such as chemical precipitation, coagulation flocculation, flotation, ion exchange, membrane filtration, electrochemical treatment technologies, adsorption [5, 21], and bio-adsorption are most frequently examined for the mitigation of heavy metals from wastewater [2, 8]. Certain merits and demerits of various physicochemical methods used for the mitigation of Pb2+ from wastewater are mentioned in **Table 2**.

**52**

*The merits and demerits of various physicochemical methods used for the mitigation of Pb+2 from wastewater [2, 22].*

The reduction of Pb2+ in wastewater to 0.05–0.10 mg/L level is required before its discharge to outlet. Certain frequently used methods for remediation of Pb2+ from water are as follows:


have demonstrated that zeolites exhibit good cation-exchange capacities for heavy metal ions under different experimental conditions [2–8, 10–12, 23, 25]. Clinoptilolite, natural zeolite, was extensively used to remove Pb2+ with an initial concentration of 2072 mg/L, at optimum pH 4, with an adsorption capacity of 0.21–1 meq/g in fixed bed and batch mode operation style. Clinoptilolite was studied for the removal of Pb2+ with an initial metal ion concentration of 1036 mg/L, at optimum pH 4, with a removal efficiency of 55% in batch mode experiments [26]. Inadequacies in use of this process are that ion exchange resins must be regenerated once exhausted, which in turn the regeneration eventually causes serious secondary pollution. Ion exchange process is not economical and cannot be used on large scale [5, 7, 8, 10, 18, 23–31].


**55**

pollutant [34].

and electrodialysis [1–8, 10, 23].

*Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions*

range of 8–11 exhibits the decreased solubility of various metal hydroxides. The coagulants such as alum, iron salts, and organic polymers are used to enhance the removal of heavy metals from wastewater. Lime is the preferred choice of the base used in hydroxide precipitation at industrial settings. To increase lime precipitation, fly ash was used as a seed material. By using fly ash-lime carbonation treatment, the initial concentrations of 100 mg/L of Cd2+, Cu2+, Ni2+, Zn2+, and Pb2+ from synthetic effluents can be reduced to 0.08, 0.14, 0.03, and 0.45 mg/L, respectively, at optimum pH 7 with a removal efficiency of 99.37– 99.6% [22, 32, 33]. Hydroxide precipitation has some limitations despite of its wide usage. First, it generates large volumes of relatively low-density sludge and consequently poses dewatering and disposal problems. Second, the metal hydroxide precipitation will be inhibited due to the presence of complexing agents in the wastewater, and third, as some metal hydroxides are amphoteric, accordingly in case of mixed metal pollution in water, ideal pH for one metal

h.**Sulfide precipitation:** Abatement of toxic heavy metal ions using sulfide precipitation is also an effective process. One of major advantages of sulfide precipitation over hydroxide precipitation is that sulfide precipitates are nonamphoteric and of lower solubility than hydroxide precipitates. Similarly, sulfide sludge demonstrated better thickening and dewatering characteristics than the corresponding sludge of metal hydroxide. The sulfide precipitation process can attain a higher extent of heavy metal removal over a broader pH range than hydroxide precipitation [1–3]. The technique of heavy metal removal by sulfide precipitation involves initial generation of H2S gas at low pH < 3 (Eq. (1)) and subsequent adsorption at higher pH 3–6 (Eq. (2)) as

M2+ (aq) + H2S(g) → MS(S) + 2H<sup>+</sup>

The sulfide precipitation studies revealed that Cu2+, Zn2+, and Pb2+ with the initial concentration of 0.018, 1.34, and 2.3 mM get easily precipitated out at optimum pH 3 with a removal efficiency of 100, >94, and >92%, respectively [1–4, 6]. Investigation showed that pyrite and synthetic iron sulfide are used to remove/precipitate out Cu2+, Cd2+, and Pb2+ from water/wastewater [3, 4, 6]. The major drawback of use of sulphide precipitation is the evolution of toxic H2S fumes in acidic conditions. Therefore, this precipitation needs to be carried out in neutral or basic medium. Furthermore, metal sulphide precipitation is likely to form colloidal precipitates that cause troubles in separation either by settling or by filtration processes. Chemical precipitation is appropriate to treat wastewater containing high concentration of heavy metal, and it is ineffective for low metal concentration. It is not economical and can produce large amount of sludge as a secondary

i.**Membrane filtration:** Membrane filtration technologies used in heavy metal removal are easy in operation and highly efficient and space saving, but its tribulations such as high cost, complex operation, membrane pollution, and low permeate flux have restricted their use in heavy metal removal. The membrane filtration technique includes ultra-filtration, reverse osmosis, nanofiltration,

(aq) → H2S(g) + Fe2+(aq) (1)

(aq) (2)

*DOI: http://dx.doi.org/10.5772/intechopen.93095*

may put other metals back in solution.

FeS(s) + 2H<sup>+</sup>

shown below:

*Lead Chemistry*

scale [5, 7, 8, 10, 18, 23–31].

electroplate/cathode [2, 25].

UV ray, and advanced oxidation processes.

and restore lower oxidation potential metals.

of hydroxide precipitation and sulfide precipitation.

have demonstrated that zeolites exhibit good cation-exchange capacities for heavy metal ions under different experimental conditions [2–8, 10–12, 23, 25]. Clinoptilolite, natural zeolite, was extensively used to remove Pb2+ with an initial concentration of 2072 mg/L, at optimum pH 4, with an adsorption capacity of 0.21–1 meq/g in fixed bed and batch mode operation style. Clinoptilolite was studied for the removal of Pb2+ with an initial metal ion concentration of 1036 mg/L, at optimum pH 4, with a removal efficiency of 55% in batch mode experiments [26]. Inadequacies in use of this process are that ion exchange resins must be regenerated once exhausted, which in turn the regeneration eventually causes serious secondary pollution. Ion exchange process is not economical and cannot be used on large

c.**Electrowinning:** Electrowinning is also called as electroextraction being frequently used by mining and metallurgical operations for leaching and acid draining. Metal transformation industries employed electrowinning and electrodeposition for amputation and recovery of metal lead ions at insoluble anodes. In electrowinning, metals are electrodeposited from its ores via a leaching route. Electrorefining uses a similar process to remove impurities from a metal as similar to electrorefining used for eliminating impurities from metal. In-bulk conditions, electroplating occurs economically in straightforward purification of metals. In this process, a current is passed through an inert anode via a liquid leach containing lead metal and subsequently deposited at

d.**Electrocoagulation:** Electrocoagulation is an electrochemical process, which uses electrical charges to remove Pb2+ from water in an efficient manner, while contaminants are maintained in solution. In this technique after neutralization of Pb2+ ions in the solution, the residual coagulant aids destabilization and precipitation of other reverse charges/counter ions. Electrocoagulation is also performed in number of ways such as radio-frequency diathermy or short wave electrolysis. This electrocoagulation is capable to remove Pb2+ ions due to the fact that it is hard to take out by filtration or chemical treatments. Various electrocoagulation devices are known with complexity from plain anode and cathode to the larger and more complex device using manageable electrode potentials, passivation, anode consumption, cell redox potentials, ultrasonic,

e.**Cementation:** Cementation is a heterogeneous process similar to precipitation technique wherein metal ions like Pb2+ are reduced into zero valence at a solid metallic interfaces. This is more commonly used for refining leach solutions. In its solution, Pb2+ ions are precipitated in the presence of other solid via electrochemical system as metal with higher oxidation potential bypasses in solution

f.**Chemical precipitation:** Chemical precipitation is an effective and most widely used process in the industry due to its relative simplicity and inexpensive operation [1–4, 6]. In precipitation processes, chemicals react with heavy metal ions to form insoluble precipitates that can be separated from the water by sedimentation or filtration. Conventional precipitation technique consists

g.**Hydroxide precipitation:** The most widely used hydroxide precipitation technique is relatively simple and low cost with the ease of pH control. The pH

**54**

range of 8–11 exhibits the decreased solubility of various metal hydroxides. The coagulants such as alum, iron salts, and organic polymers are used to enhance the removal of heavy metals from wastewater. Lime is the preferred choice of the base used in hydroxide precipitation at industrial settings. To increase lime precipitation, fly ash was used as a seed material. By using fly ash-lime carbonation treatment, the initial concentrations of 100 mg/L of Cd2+, Cu2+, Ni2+, Zn2+, and Pb2+ from synthetic effluents can be reduced to 0.08, 0.14, 0.03, and 0.45 mg/L, respectively, at optimum pH 7 with a removal efficiency of 99.37– 99.6% [22, 32, 33]. Hydroxide precipitation has some limitations despite of its wide usage. First, it generates large volumes of relatively low-density sludge and consequently poses dewatering and disposal problems. Second, the metal hydroxide precipitation will be inhibited due to the presence of complexing agents in the wastewater, and third, as some metal hydroxides are amphoteric, accordingly in case of mixed metal pollution in water, ideal pH for one metal may put other metals back in solution.

h.**Sulfide precipitation:** Abatement of toxic heavy metal ions using sulfide precipitation is also an effective process. One of major advantages of sulfide precipitation over hydroxide precipitation is that sulfide precipitates are nonamphoteric and of lower solubility than hydroxide precipitates. Similarly, sulfide sludge demonstrated better thickening and dewatering characteristics than the corresponding sludge of metal hydroxide. The sulfide precipitation process can attain a higher extent of heavy metal removal over a broader pH range than hydroxide precipitation [1–3]. The technique of heavy metal removal by sulfide precipitation involves initial generation of H2S gas at low pH < 3 (Eq. (1)) and subsequent adsorption at higher pH 3–6 (Eq. (2)) as shown below:

$$\text{FeS(s)} + 2\text{H}^+\text{(aq)} \rightarrow \text{H}\_2\text{S(g)} + \text{Fe}^{2+}\text{(aq)}\tag{1}$$

$$\text{M}^{2+} \text{ (aq)} + \text{H}\_2\text{S} \text{(g)} \rightarrow \text{MS(S)} + 2\text{H}^\* \text{(aq)}\tag{2}$$

The sulfide precipitation studies revealed that Cu2+, Zn2+, and Pb2+ with the initial concentration of 0.018, 1.34, and 2.3 mM get easily precipitated out at optimum pH 3 with a removal efficiency of 100, >94, and >92%, respectively [1–4, 6]. Investigation showed that pyrite and synthetic iron sulfide are used to remove/precipitate out Cu2+, Cd2+, and Pb2+ from water/wastewater [3, 4, 6]. The major drawback of use of sulphide precipitation is the evolution of toxic H2S fumes in acidic conditions. Therefore, this precipitation needs to be carried out in neutral or basic medium. Furthermore, metal sulphide precipitation is likely to form colloidal precipitates that cause troubles in separation either by settling or by filtration processes. Chemical precipitation is appropriate to treat wastewater containing high concentration of heavy metal, and it is ineffective for low metal concentration. It is not economical and can produce large amount of sludge as a secondary pollutant [34].

i.**Membrane filtration:** Membrane filtration technologies used in heavy metal removal are easy in operation and highly efficient and space saving, but its tribulations such as high cost, complex operation, membrane pollution, and low permeate flux have restricted their use in heavy metal removal. The membrane filtration technique includes ultra-filtration, reverse osmosis, nanofiltration, and electrodialysis [1–8, 10, 23].


**57**

*Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions*

flocculants in wastewater treatment, but practically, they are ineffective in heavy metal removal. The flocculation by humic acid (HA) is also studied. It is also studied to reveal better removal of Pb2+ and Zn2+ from solution by binding such ions to HA and then coagulating-flocculating with cationic polyelectrolyte polydiallyl dimethyl ammonium chloride (poly-DADMAC). Generally, coagulation-flocculation cannot treat the heavy metal wastewater completely [24]. So, it must be combined with other treatment techniques. Besides, coagulation-flocculation involves chemical utilization and sludge formation as

n.**Floatation:** Recently, flotation has found widespread use in heavy metal

removal from wastewater due to its several advantages such as high metal selectivity, high removal efficiency, high overflow rates, low operating cost, and more concentrated sludge production [27]. Flotation has been implemented to remove heavy metal from a liquid phase using small air bubble attachment. The main flotation processes are dissolved air flotation (DAF), ion flotation, and precipitation flotation used for metal ion abatement from water. Among these techniques, ion flotation has been proved to be a promising method for the wastewater treatment. The ion flotation is an adsorptive bubble separation techniques based on imparting the ionic metal species hydrophobic by the use of surfactants and removal of these hydrophobic species from wastewater by the passage of air bubbles reported the 100% removal of copper (II) and Pb2+ from water at pH 6 and 7, respectively, using ion floatation technique. Despite of several advantages, the shortcoming in use of flotation techniques involves high initial capital cost, high maintenance, and expensive operation [12, 27].

o.**Electrochemical treatment:** Electrochemical wastewater treatment technologies are rapid, well controlled, and capable of producing less sludge. It requires few chemicals and possesses better metal reduction capacity. Electrochemical technologies include electrocoagulation, electroflotation, and electrodeposition. Studies of electroflotation technique revealed more stress on separation of heavy metal ions such as iron, nickel, copper, zinc, lead, and cadmium with maximum removal [1–4, 6, 11]. The quantitative electrodeposition of copper and lead ions onto specially designed palm shell AC electrodes has been reported in the recent investigation studies [1–4, 6]. Nevertheless, the requirement of high initial capital cost and the expensive electricity supply restricts wide usage and application of electrochemical techniques in wastewater

p.**Adsorption:** Adsorption is defined as the process where a solute is removed from the liquid phase through contact with a solid adsorbent, which has a particular affinity for that particular solute [1–4, 6, 10– 12]. All adsorption processes mainly depend on the equilibrium and mass transfer rates, which involve the accretion of substances at the interface of liquid-liquid, gas-liquid, gas-solid, or liquidsolid interface. The substance being adsorbed is adsorbate, and adsorbing material is adsorbent. The reverse phenomenon of adsorption is termed as desorption where a solute/pollutant gets released from/through an adsorbent. The process of adsorption can be classified as physical adsorption/physisorption and chemical adsorption/chemisorption, which depends on the forces involved in adsorbateadsorbent interactions. Adsorption is now recognized as an effective and economic method for the mitigation of wide variety of water pollutant by sorption. Among the aforementioned technologies, adsorption has been preferred due to

*DOI: http://dx.doi.org/10.5772/intechopen.93095*

a secondary pollution.

treatment [6, 23].

*Lead Chemistry*

to remove Pb2+ and AsO4

j.**Ultra-filtration:** To obtain high removal efficiency of metal ions, the micellar enhanced ultrafiltration (MEUF) and polymer enhanced ultrafiltration (PEUF) were suggested. MEUF was first introduced by Scamehorn et al. in the 1980s for the removal of dissolved organic compounds, and multivalent metal ions from aqueous solutions used MEUF to remove Cd2+, Cu2+, Ni2+, Zn2+, and Pb2+ from synthetic water using anionic surfactants [5, 7, 8, 10]. Ferella et al. studied MEUF

at optimum pH 7.5 with a removal efficiency of 99 and 19% for Pb2+ and AsO4

respectively [5, 7, 8, 10, 23]. The recovery and reuse of exhausted surfactant is necessary; otherwise, it enhances treatment cost and in addition causes secondary pollution due to solid waste/sludge disposal problem. Hence ultra-filtration

technique has not attained wide applicability at industrial scale [12].

k.**Reverse osmosis:** Reverse osmosis (RO) is progressively more popular wastewater treatment alternative in chemical and environmental engineering. In reverse osmosis process, the water is to be purified and allowed to pass through the semi-permeable membrane and at the same time rejecting the contaminants. RO systems are yet to be broadly applied for wastewater treatment. Reverse osmosis alone is not applicable for complete recovery and reuse of fluids. Pretreatment methods namely media filtration, pH adjustment, and use of anti-precipitants are required prior to the reverse osmosis. The main disadvantage of RO is the high power utilization owing to the pumping pressures and the reinstallation of the semi-permeable membranes. Reverse osmosis and electrodialysis use semi-permeable membranes for the removal and revival of Pb2+ from water. In this technique, cation and anion membranes from water, which are tied to the electrodes in electrolytic cells under constant electrical supply and subsequent allied ions, get drifted. Treatment characteristics are optimized with respect to Pb2+ concentration in the effluents, pH, temperature, and flow volume. Reverse osmosis and electrodialysis (mentioned below) techniques use semi-permeable anionic/anionic membranes which possess certain drawbacks like high cost, generates huge sludge, low retention capacity, and less selectivity and large power usage. Thus, both these techniques are neglected while adsorption method is preferred for the remediation of heavy metal contaminants from water/wastewater [1–8, 10–12, 23].

l.**Electrodialysis:** Electrodialysis (ED) is another membrane technique used for the separation of ions through membranes from one solution to another under the influence of electric field. This process has been widely used for the treatment of brackish water, industrial effluents, recovery of useful materials from effluents, and salt production [3]. ED is also used as a potential method for wastewater treatment containing heavy metals. The effects of operating parameters on Pb2+ mitigation from water have been investigated by ED, and the results revealed that

Pb2+ separation improved with increasing voltage and temperature [12].

m. **Coagulation and flocculation:** Coagulation followed by sedimentation and filtration is one of the most significant methods for wastewater treatment, but coagulation method is restricted only to the hydrophobic colloids and suspended particles. Many coagulants such as aluminum, ferrous sulfate, and ferric chloride are widely used for the effective removal of wastewater pollutants. Flocculation is the process by which fine particulates are caused to clump or agglomerate together into flocs. In general, PAC (polyaluminum chloride), polyferric sulfate (PFS) and polyacrylamide (PAM) are widely used

<sup>−</sup>, with an initial concentration of 4.4 ppm to 7.6 mg/L

−,

**56**

flocculants in wastewater treatment, but practically, they are ineffective in heavy metal removal. The flocculation by humic acid (HA) is also studied. It is also studied to reveal better removal of Pb2+ and Zn2+ from solution by binding such ions to HA and then coagulating-flocculating with cationic polyelectrolyte polydiallyl dimethyl ammonium chloride (poly-DADMAC). Generally, coagulation-flocculation cannot treat the heavy metal wastewater completely [24]. So, it must be combined with other treatment techniques. Besides, coagulation-flocculation involves chemical utilization and sludge formation as a secondary pollution.


its flexible operation and capabilities to generate high quality treated effluent as well as adsorbent by desorption. Several adsorbents such as agricultural wastes, carbon nanotubes, biosorbents, industrial byproducts, natural substances, and activated carbon have been studied for the heavy metal wastewater treatment. Numerous studies for the removal of heavy metal ions from water onto activated carbon are well known due to its high surface area and large micropore/mesopore volumes [1–4, 6, 11, 12, 24, 27–29, 34]. The production of activated carbons from abundantly available agricultural wastes converts unwanted, additional agricultural waste to useful valuable adsorbents. Adsorption capacity of natural materials for metal Pb2+ removal from water is shown in **Table 3**.

The activated carbon of agricultural wastes such as coconut coir pith, nutshells, oil palm waste, rice husk, and peanuts is used for the removal of lead metal from water [1–4, 6, 11, 12]. *Eucalyptus camaldulensis* Dehn. bark agricultural waste bagasse was studied for the removal of contaminants from water. Carbon nanotubes are relatively new adsorbents, which show great potential for the removal of heavy metal like lead ions from water. The adsorption of Pb2+ ions onto acidified multiwalled carbon nanotubes (MWCNTs) showed the removal capacity of 85 mg/g of adsorbent at NTP conditions [1–4, 6, 11, 12]. The carbon nanotubes (CNTs) that are used as effective adsorbents for Pb2+ adsorption at pH 5, contact time 80 min, and agitation speed 50 rpm were found to have maximum adsorption capacity of 102.04 mg/g. Agricultural waste materials that act as a potential adsorbent for sequestering heavy metal ions from aqueous solution were also investigated [5, 7, 8, 10, 23]. In addition, chemically modified plant wastes that act as low cost adsorbents for heavy metal uptake from contaminated water were also reported [25]. Finally, industrial byproducts such as lignin, diatomite, clino-pyrrhotite, aragonite shells, clay, and peat were used to remove Pb2+ from water [1, 25, 34]. However, the adsorption efficiency of such industrial wastes is pH dependent and better works only in the pH range from 2 to 6 (mostly acidic), while competitive sorption capacity falls relatively in multicomponent/metal systems.


**59**

Pb2+ removal from water [1–4, 6, 10].

**7. Case studies for Pb2+ removal**

*Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions*

Chitosan has an excellent adsorption capacity due to its low chemical and mechanical strength [1–4, 6, 11, 12]; its fullest adsorptive capacities are not met [5, 7, 8, 10]. Thus, several attempts of chitosan modification were carried out in previous research studies. In present research work, the materials namely graphite, iodate, and activated carbon of *Luffa cylindrica* are used for the modification of chitosan by blending/doping or impregnation method. The resultant adsorbents obtained are called graphite-doped chitosan composite (GDCC), iodate-doped chitosan composite (IDCC), and activated carbon of *Luffa cylindrica*-doped chitosan biocomposite (ACLFCS) [5, 7, 10]. The graphite has been selected for the study so as to check the adsorptive potential of chitosan-graphite composite and its prospective applications in wastewater treatment. The deacetylated amino groups in chitosan can be chemically modified easily [5, 7, 8, 10, 23]. Iodine molecule has a characteristic property of donating a new function to the host material. The iodate salt has been selected for modification of chitosan so that to find out whether the new surface chemistry of iodate-doped chitosan composite has an impact on Pb2+ removal from water or not. *Luffa cylindrica* is mainly a lignocellulosic material composed of cellulose, hemicelluloses, and lignin (60, 30, and 10% by weight,

Agricultural residues are abundant in a number of developing countries such as India, Korea, China, Central America, and Japan. Consequently, these disposed, unconventional, and widely available *Luffa cylindrica* fibers can be transformed into an activated carbon, which is a carbonaceous material that possesses highly developed porosity, a large surface area, relatively high mechanical strength, and a variety of functional groups on its surface [10, 34]. The transformation of agricultural residue into an activated carbon ultimately provides a way to reduce its environmental burden or hazards. The cationic nature of chitosan and the anionic nature of activated carbon of *Luffa cylindrica* can produce a stable, granular biocomposite due to two oppositely charged interactions. The purpose of doping of chitosan with *Luffa cylindrica* activated carbon is to explore the expected synergistic effects achieved through the incorporation of certain functionalities in the resultant biocomposite that could be responsible for the adsorption of Pb2+. The choice of adsorbents for Pb2+ removal from water is concerned with its high adsorption efficiency, safety and simplicity for use, ease for maintaining, minimal production of residual mass, low capital cost, and nontoxicity. The synthesized adsorbents such as GDCC, IDCC, and ACLFCS satisfy all such requirements [24, 34]. To the best of our knowledge, there were no published reports on the removal of Pb2+ ions from water using GDCC, IDCC, and ACLFCS. In fact, the ability of above synthesized adsorbents to adsorb other heavy metal ions was also not reported. This provided a way for more adsorption studies for Pb2+ ions to be conducted by using these synthesized adsorbents. Batch adsorption of Pb2+ is studied as a function of various parameters, namely pH, agitation time, adsorbent doses, and initial Pb2+ concentration onto specially developed adsorbents like GDCC, IDCC, ACLFCS, raw chitosan, and activated carbon of *Luffa cylindrical* plant [1–4, 6]. Adsorption kinetics and isothermal studies are conducted to know the mechanism of batch adsorption of

Chitosan is a natural nitrogenous amino polysaccharide found to be highly selective for the uptake of toxic heavy metal ions from contaminated water resources

**6. Selective adsorbents for lead remediation**

respectively) belonging to the Cucurbitaceae family.

*DOI: http://dx.doi.org/10.5772/intechopen.93095*

**Table 3.** *Adsorption capacity of natural material for Pb2+removal from water [24].*

## **6. Selective adsorbents for lead remediation**

*Lead Chemistry*

its flexible operation and capabilities to generate high quality treated effluent as well as adsorbent by desorption. Several adsorbents such as agricultural wastes, carbon nanotubes, biosorbents, industrial byproducts, natural substances, and activated carbon have been studied for the heavy metal wastewater treatment. Numerous studies for the removal of heavy metal ions from water onto activated carbon are well known due to its high surface area and large micropore/mesopore volumes [1–4, 6, 11, 12, 24, 27–29, 34]. The production of activated carbons from abundantly available agricultural wastes converts unwanted, additional agricultural waste to useful valuable adsorbents. Adsorption capacity of natural

The activated carbon of agricultural wastes such as coconut coir pith, nutshells, oil palm waste, rice husk, and peanuts is used for the removal of lead metal from water [1–4, 6, 11, 12]. *Eucalyptus camaldulensis* Dehn. bark agricultural waste bagasse was studied for the removal of contaminants from water. Carbon nanotubes are relatively new adsorbents, which show great potential for the removal of heavy metal like lead ions from water. The adsorption of Pb2+ ions onto acidified multiwalled carbon nanotubes (MWCNTs) showed the removal capacity of 85 mg/g of adsorbent at NTP conditions [1–4, 6, 11, 12]. The carbon nanotubes (CNTs) that are used as effective adsorbents for Pb2+ adsorption at pH 5, contact time 80 min, and agitation speed 50 rpm were found to have maximum adsorption capacity of 102.04 mg/g. Agricultural waste materials that act as a potential adsorbent for sequestering heavy metal ions from aqueous solution were also investigated [5, 7, 8, 10, 23]. In addition, chemically modified plant wastes that act as low cost adsorbents for heavy metal uptake from contaminated water were also reported [25]. Finally, industrial byproducts such as lignin, diatomite, clino-pyrrhotite, aragonite shells, clay, and peat were used to remove Pb2+ from water [1, 25, 34]. However, the adsorption efficiency of such industrial wastes is pH dependent and better works only in the pH range from 2 to 6 (mostly acidic), while competitive sorption capac-

**Entry Assorted adsorbents Pb2+ adsorption capacity (mg/g)**

 Zeolite, clinoptilolite 1.6 Modified zeolite/MMZ 123 Clay (HCl-treated) 81.02 Poly(methoxyethyl)acrylamide-doped Clay 85.6 Calcinated phosphates 155 Activated phosphate 4.0 Zirconium phosphate 398 Almond shells 8.0 Palm shell oil 3.4 Maize cope and husk 456 Ecklonia maxima – marine alga 235 *Oedogonium* species 145 *Nostoc* species 93.5 *Bacillus* – bacterial biomass 467

materials for metal Pb2+ removal from water is shown in **Table 3**.

ity falls relatively in multicomponent/metal systems.

*Adsorption capacity of natural material for Pb2+removal from water [24].*

**58**

**Table 3.**

Chitosan has an excellent adsorption capacity due to its low chemical and mechanical strength [1–4, 6, 11, 12]; its fullest adsorptive capacities are not met [5, 7, 8, 10]. Thus, several attempts of chitosan modification were carried out in previous research studies. In present research work, the materials namely graphite, iodate, and activated carbon of *Luffa cylindrica* are used for the modification of chitosan by blending/doping or impregnation method. The resultant adsorbents obtained are called graphite-doped chitosan composite (GDCC), iodate-doped chitosan composite (IDCC), and activated carbon of *Luffa cylindrica*-doped chitosan biocomposite (ACLFCS) [5, 7, 10]. The graphite has been selected for the study so as to check the adsorptive potential of chitosan-graphite composite and its prospective applications in wastewater treatment. The deacetylated amino groups in chitosan can be chemically modified easily [5, 7, 8, 10, 23]. Iodine molecule has a characteristic property of donating a new function to the host material. The iodate salt has been selected for modification of chitosan so that to find out whether the new surface chemistry of iodate-doped chitosan composite has an impact on Pb2+ removal from water or not. *Luffa cylindrica* is mainly a lignocellulosic material composed of cellulose, hemicelluloses, and lignin (60, 30, and 10% by weight, respectively) belonging to the Cucurbitaceae family.

Agricultural residues are abundant in a number of developing countries such as India, Korea, China, Central America, and Japan. Consequently, these disposed, unconventional, and widely available *Luffa cylindrica* fibers can be transformed into an activated carbon, which is a carbonaceous material that possesses highly developed porosity, a large surface area, relatively high mechanical strength, and a variety of functional groups on its surface [10, 34]. The transformation of agricultural residue into an activated carbon ultimately provides a way to reduce its environmental burden or hazards. The cationic nature of chitosan and the anionic nature of activated carbon of *Luffa cylindrica* can produce a stable, granular biocomposite due to two oppositely charged interactions. The purpose of doping of chitosan with *Luffa cylindrica* activated carbon is to explore the expected synergistic effects achieved through the incorporation of certain functionalities in the resultant biocomposite that could be responsible for the adsorption of Pb2+. The choice of adsorbents for Pb2+ removal from water is concerned with its high adsorption efficiency, safety and simplicity for use, ease for maintaining, minimal production of residual mass, low capital cost, and nontoxicity. The synthesized adsorbents such as GDCC, IDCC, and ACLFCS satisfy all such requirements [24, 34]. To the best of our knowledge, there were no published reports on the removal of Pb2+ ions from water using GDCC, IDCC, and ACLFCS. In fact, the ability of above synthesized adsorbents to adsorb other heavy metal ions was also not reported. This provided a way for more adsorption studies for Pb2+ ions to be conducted by using these synthesized adsorbents. Batch adsorption of Pb2+ is studied as a function of various parameters, namely pH, agitation time, adsorbent doses, and initial Pb2+ concentration onto specially developed adsorbents like GDCC, IDCC, ACLFCS, raw chitosan, and activated carbon of *Luffa cylindrical* plant [1–4, 6]. Adsorption kinetics and isothermal studies are conducted to know the mechanism of batch adsorption of Pb2+ removal from water [1–4, 6, 10].

## **7. Case studies for Pb2+ removal**

Chitosan is a natural nitrogenous amino polysaccharide found to be highly selective for the uptake of toxic heavy metal ions from contaminated water resources

[5, 7, 8, 10, 23, 24, 34]. Due to its adsorptive potentiality, it has been popularly used for environmental cleanup or for the mitigation of toxic heavy metal ions from water/wastewater. Despite of its variety of advantages, it possesses some major inadequacies that impose an urge for its modification so as to allow its better fit for the wastewater treatment applications. The present research work dealt with the modification of chitosan by various techniques such as blending, impregnating, and doping it with inorganic/organic materials, and the resultant biocomposites can be effectively utilized for the mitigation of toxic Pb2+ from water. This case study used synthesized chitosan-doped composites which were characterizations through advanced techniques like X-ray diffraction (XRD), scanning electron microscopy (SEM), thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infra-red spectroscopy (FTIR), elemental analysis, BET, and BJH pore size distribution for better understanding of adsorption mechanism.

The batch mode Pb2+ adsorption was studied as function of different operating parameters such as pH, adsorbent doses, initial Pb2+ concentration, and agitation/ contact time. The adsorption isothermal studies were conducted by means of Langmuir and Freundlich models.

Adsorption kinetic studies conducted so as to know the time-dependent adsorption behavior of doped bioadsorbents toward the removal of Pb2+ from water. The adsorption kinetics revealed the existence of both heterogeneous surface and monolayer coverage of adsorbed Pb2+ ions via the pseudo-second-order kinetic process. Amid all biocomposites, iodate-doped composite bioadsorbent has been proved to be an effective adsorbent for the sorption of Pb2+ from water [5, 7, 8, 10, 33, 35]. An effective adsorbent dose of iodate-doped bioadsorbent was found to be 0.5 g/L with 99% efficiency achieved in 4 h [18].

The regeneration/desorption studies were done by desorption of exhausted adsorbents by means of several acid/alkali treatments, which provide the information about the respective utility of adsorbents in multifold cycles for batch mode adsorption of Pb2+ from water. Various studies demonstrated that the batch adsorption mode is used for the mitigation of Pb2+ from water using synthetically modified bioadsorbents namely raw chitosan (CS), GDCC, IDCC, ACLF, and ACLFCS [1–3, 7, 8, 18, 23, 29–31]. Chitosan-modified composites/biocomposites namely GDCC, IDCC, and ACLFCS were synthesized by means of impregnating/doping methodology [1–3, 7, 8, 18, 23, 24, 35]. Characterization studies of all synthesized chitosan composites/biocomposites were carried out by various instrumental techniques such as FTIR, TGA/DSC, XRD, BET surface area, BJH pore size distribution, SEM, and CHNS analysis. FTIR analysis of raw chitosan revealed that the absorption peaks are related to various functionalities namely ▬OH group, ▬NH2 bending in amide, and C═O stretch in amide, and these functional groups were also responsible for Pb2+ ion adsorption onto the raw chitosan. Functional groups ▬OH, C═O, and ▬NH2 were concerned with adsorption performance of Pb2+ onto GDCC [18, 24, 34].

Similarly, the functional groups ▬OH, C═O, C▬N, iodate, and ▬NH2 were responsible for Pb2+ adsorption onto IDCC. FTIR analysis of ACLF revealed that the absorption peaks are related to various functional groups namely ▬OH group, aromatic C▬H stretch, aromatic C═C stretch, and phenolic C▬O stretch [27–29]. The responsible and accurate sorption sites for Pb2+ adsorption onto synthesized adsorbents were ascertained by changes in FTIR band frequencies of assorted functional groups like ▬OH and ▬C═O, NH2, and ▬ NH(C═O)CH3.

TGA of raw chitosan showed two steps of degradation, initial with 5% weight loss and the second with 46.28% weight loss. At the end of 955°C, total weight loss of raw chitosan was 70%. TGA/DSC analysis of pure graphite showed high thermal stability and displayed only 2.5% weight loss at the end of temperature 955°C. TGA

**61**

clearly seen.

*Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions*

that this composite is less stable than raw chitosan [29, 30].

doped onto the surface of raw chitosan [7, 8, 18, 23].

change of surface morphology [5, 7, 8, 10, 18, 23, 24, 34].

found to be 9.923, 3.8, 6.984, 321, and 132 m2

of GDCC composite exhibited two steps of degradation, and at the end of 954.9°C, the total weight loss was found to be 35%. Thus, with respect to the raw chitosan, the GDCC showed more thermal stability. TGA/DSC analysis of IDCC indicated

Thermogravimetric analysis (TGA) of ACLF revealed the high thermal stability where at the end of 910°C, it exhibited total weight loss of only 25%. XRD analysis of raw chitosan showed the broad diffraction peak at 2θ = 20°. XRD pattern of GDCC exhibited that the peaks of both raw CS and powdered graphite indicated the formation of single-phase composite. The peaks were obtained at 2θ = 26.5° corresponding to graphite, and the broad peak at around 2θ = 20° that was due to the chitosan decreased in intensity in GDCC composite, which confirms that graphite is

In IDCC, the XRD pattern is slightly broaden and showed a small hump at 2θ = 25° and 2θ = 34°. The XRD pattern of IDCC after Pb2+ adsorption showed some additional crystalline peaks at 2θ = 30° corresponding to Pb2+ ion adsorption. XRD analysis of ACLF showed the amorphous structure with two broad diffraction peaks at 2θ = 24° and 2θ = 42°, which were the characteristic peaks of activated carbon. In ACLFCS biocomposite, the XRD pattern shows both the peaks of raw CS corresponding to 2θ = 19.28° and a small hump at 2θ = 42°, which was a characteristic peak of ACLF [2]. The result indicates the successful doping and incorporation of ACLF with raw CS. SEM morphology of raw chitosan depicts uneven texture with bumpiness and porous cavities. SEM images of GDCC revealed flaky, smooth, shiny, and porous morphology with small amount of voids or cavities. SEM morphology of IDCC revealed that the bumpiness corresponding to raw chitosan was lost after doping it with iodate [2, 4, 7]. Similarly, in IDCC, the adsorbent surface was highly irregular and porous in nature with large number of round or elliptical shape cavities [7, 8, 18, 23]. SEM morphology of ACLF depicts the porous texture. ACLFCS possesses porous texture with round and elliptical shaped voids that can provide the adsorption sites to the adsorbate. SEM images of lead loaded adsorbent namely raw chitosan (CS), GDCC, IDCC, ACLF, and ACLFCS showed complete

SEM image of lead loaded raw chitosan, IDCC, ACLF, and ACLFCS revealed

The adsorption of Pb2+ by GDCC adsorbent showed deposition of whitish, sharp, needle-shaped crystalline mass observed onto its proactive surfaces [24]. The BET surface area of raw chitosan (CS), GDCC, IDCC, ACLF, and ACLFCS was

The further lower in surface area in IDCC and GDCC with respect to raw chitosan and ACLFCS with respect to ACLF is due to doping of iodate and activated carbon of *Luffa cylindrica,* respectively, with raw chitosan structure. BET surface area of doped chitosan composites namely GDCC, IDCC, and ACLFCS was decreased due to blockage of internal porosities of adsorbents [2, 7, 8, 18, 23]. Adsorptive capacity of adsorbent for the removal of Pb2+ from water found increasing with rising surface area as viable for pure physisorption phenomenon [1–3, 5, 7, 8, 10, 18, 23, 25]. The physisorption was the limited phenomenon, while the chemisorption mechanism was mainly observed for all the synthesized bioadsorbents used for Pb2+ removal from water [2, 5, 7, 8, 18, 23]. The batch adsorption of Pb2+ as a function of pH, doses of adsorbent, initial Pb2+ concentration, and contact time has been carried out by using raw CS, GDCC, IDCC, ACLF, and ACLFCS bioadsorbents [1–8, 18, 23]. Maximum adsorption capacity of raw chitosan was found to be at an optimum parameter of pH 6, with 35 mg/L Pb2+ ion concentration at an adsorbent dose of

/g, respectively [1– 4, 6–8, 18, 23].

surface morphology where the porous structure is quite shallow and not

*DOI: http://dx.doi.org/10.5772/intechopen.93095*

#### *Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions DOI: http://dx.doi.org/10.5772/intechopen.93095*

*Lead Chemistry*

Langmuir and Freundlich models.

99% efficiency achieved in 4 h [18].

[5, 7, 8, 10, 23, 24, 34]. Due to its adsorptive potentiality, it has been popularly used for environmental cleanup or for the mitigation of toxic heavy metal ions from water/wastewater. Despite of its variety of advantages, it possesses some major inadequacies that impose an urge for its modification so as to allow its better fit for the wastewater treatment applications. The present research work dealt with the modification of chitosan by various techniques such as blending, impregnating, and doping it with inorganic/organic materials, and the resultant biocomposites can be effectively utilized for the mitigation of toxic Pb2+ from water. This case study used synthesized chitosan-doped composites which were characterizations through advanced techniques like X-ray diffraction (XRD), scanning electron microscopy (SEM), thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infra-red spectroscopy (FTIR), elemental analysis, BET, and BJH pore size distribution for better understanding of adsorption mechanism. The batch mode Pb2+ adsorption was studied as function of different operating parameters such as pH, adsorbent doses, initial Pb2+ concentration, and agitation/ contact time. The adsorption isothermal studies were conducted by means of

Adsorption kinetic studies conducted so as to know the time-dependent adsorption behavior of doped bioadsorbents toward the removal of Pb2+ from water. The adsorption kinetics revealed the existence of both heterogeneous surface and monolayer coverage of adsorbed Pb2+ ions via the pseudo-second-order kinetic process. Amid all biocomposites, iodate-doped composite bioadsorbent has been proved to be an effective adsorbent for the sorption of Pb2+ from water [5, 7, 8, 10, 33, 35]. An effective adsorbent dose of iodate-doped bioadsorbent was found to be 0.5 g/L with

The regeneration/desorption studies were done by desorption of exhausted adsorbents by means of several acid/alkali treatments, which provide the information about the respective utility of adsorbents in multifold cycles for batch mode adsorption of Pb2+ from water. Various studies demonstrated that the batch adsorption mode is used for the mitigation of Pb2+ from water using synthetically modified bioadsorbents namely raw chitosan (CS), GDCC, IDCC, ACLF, and ACLFCS [1–3, 7, 8, 18, 23, 29–31]. Chitosan-modified composites/biocomposites namely GDCC, IDCC, and ACLFCS were synthesized by means of impregnating/doping methodology [1–3, 7, 8, 18, 23, 24, 35]. Characterization studies of all synthesized chitosan composites/biocomposites were carried out by various instrumental techniques such as FTIR, TGA/DSC, XRD, BET surface area, BJH pore size distribution, SEM, and CHNS analysis. FTIR analysis of raw chitosan revealed that the absorption peaks are related to various functionalities namely ▬OH group, ▬NH2 bending in amide, and C═O stretch in amide, and these functional groups were also responsible for Pb2+ ion adsorption onto the raw chitosan. Functional groups ▬OH, C═O, and ▬NH2 were

concerned with adsorption performance of Pb2+ onto GDCC [18, 24, 34].

functional groups like ▬OH and ▬C═O, NH2, and ▬ NH(C═O)CH3.

Similarly, the functional groups ▬OH, C═O, C▬N, iodate, and ▬NH2 were responsible for Pb2+ adsorption onto IDCC. FTIR analysis of ACLF revealed that the absorption peaks are related to various functional groups namely ▬OH group, aromatic C▬H stretch, aromatic C═C stretch, and phenolic C▬O stretch [27–29]. The responsible and accurate sorption sites for Pb2+ adsorption onto synthesized adsorbents were ascertained by changes in FTIR band frequencies of assorted

TGA of raw chitosan showed two steps of degradation, initial with 5% weight loss and the second with 46.28% weight loss. At the end of 955°C, total weight loss of raw chitosan was 70%. TGA/DSC analysis of pure graphite showed high thermal stability and displayed only 2.5% weight loss at the end of temperature 955°C. TGA

**60**

of GDCC composite exhibited two steps of degradation, and at the end of 954.9°C, the total weight loss was found to be 35%. Thus, with respect to the raw chitosan, the GDCC showed more thermal stability. TGA/DSC analysis of IDCC indicated that this composite is less stable than raw chitosan [29, 30].

Thermogravimetric analysis (TGA) of ACLF revealed the high thermal stability where at the end of 910°C, it exhibited total weight loss of only 25%. XRD analysis of raw chitosan showed the broad diffraction peak at 2θ = 20°. XRD pattern of GDCC exhibited that the peaks of both raw CS and powdered graphite indicated the formation of single-phase composite. The peaks were obtained at 2θ = 26.5° corresponding to graphite, and the broad peak at around 2θ = 20° that was due to the chitosan decreased in intensity in GDCC composite, which confirms that graphite is doped onto the surface of raw chitosan [7, 8, 18, 23].

In IDCC, the XRD pattern is slightly broaden and showed a small hump at 2θ = 25° and 2θ = 34°. The XRD pattern of IDCC after Pb2+ adsorption showed some additional crystalline peaks at 2θ = 30° corresponding to Pb2+ ion adsorption. XRD analysis of ACLF showed the amorphous structure with two broad diffraction peaks at 2θ = 24° and 2θ = 42°, which were the characteristic peaks of activated carbon. In ACLFCS biocomposite, the XRD pattern shows both the peaks of raw CS corresponding to 2θ = 19.28° and a small hump at 2θ = 42°, which was a characteristic peak of ACLF [2]. The result indicates the successful doping and incorporation of ACLF with raw CS. SEM morphology of raw chitosan depicts uneven texture with bumpiness and porous cavities. SEM images of GDCC revealed flaky, smooth, shiny, and porous morphology with small amount of voids or cavities. SEM morphology of IDCC revealed that the bumpiness corresponding to raw chitosan was lost after doping it with iodate [2, 4, 7]. Similarly, in IDCC, the adsorbent surface was highly irregular and porous in nature with large number of round or elliptical shape cavities [7, 8, 18, 23]. SEM morphology of ACLF depicts the porous texture. ACLFCS possesses porous texture with round and elliptical shaped voids that can provide the adsorption sites to the adsorbate. SEM images of lead loaded adsorbent namely raw chitosan (CS), GDCC, IDCC, ACLF, and ACLFCS showed complete change of surface morphology [5, 7, 8, 10, 18, 23, 24, 34].

SEM image of lead loaded raw chitosan, IDCC, ACLF, and ACLFCS revealed surface morphology where the porous structure is quite shallow and not clearly seen.

The adsorption of Pb2+ by GDCC adsorbent showed deposition of whitish, sharp, needle-shaped crystalline mass observed onto its proactive surfaces [24]. The BET surface area of raw chitosan (CS), GDCC, IDCC, ACLF, and ACLFCS was found to be 9.923, 3.8, 6.984, 321, and 132 m2 /g, respectively [1– 4, 6–8, 18, 23]. The further lower in surface area in IDCC and GDCC with respect to raw chitosan and ACLFCS with respect to ACLF is due to doping of iodate and activated carbon of *Luffa cylindrica,* respectively, with raw chitosan structure. BET surface area of doped chitosan composites namely GDCC, IDCC, and ACLFCS was decreased due to blockage of internal porosities of adsorbents [2, 7, 8, 18, 23]. Adsorptive capacity of adsorbent for the removal of Pb2+ from water found increasing with rising surface area as viable for pure physisorption phenomenon [1–3, 5, 7, 8, 10, 18, 23, 25].

The physisorption was the limited phenomenon, while the chemisorption mechanism was mainly observed for all the synthesized bioadsorbents used for Pb2+ removal from water [2, 5, 7, 8, 18, 23]. The batch adsorption of Pb2+ as a function of pH, doses of adsorbent, initial Pb2+ concentration, and contact time has been carried out by using raw CS, GDCC, IDCC, ACLF, and ACLFCS bioadsorbents [1–8, 18, 23]. Maximum adsorption capacity of raw chitosan was found to be at an optimum parameter of pH 6, with 35 mg/L Pb2+ ion concentration at an adsorbent dose of

0.9 g/L achieved in contact time of 140 min. By using GDCC adsorbent, the maximum 98% removal of Pb2+ was observed at optimum pH 6. Results showed that the maximum adsorbent capacity was at a dose of 1 g/L and equilibrium time achieved at 120 min of contact time for 35 mg/L Pb2+ ion concentration. The batch adsorption studies for Pb2+ removal from water by using IDCC revealed maximum removal at optimum pH 6 with an adsorbent dose of 0.5 g/L in contact time of 240 min. The regeneration ability of IDCC adsorbent demonstrated 25–30% decreased percentage recovery of Pb2+ ions at the end of fourth adsorption-desorption cycle. The maximum adsorption of Pb2+ onto ACLF was exhibited at an optimum parameter of pH 5.5, with an adsorbent dose of 0.3 g/L achieved in 12 min of contact time for 35 mg/L Pb2+ concentration [2, 7, 8, 18, 23]. Batch adsorption of Pb2+ using ACLFCS biocomposite was pH dependent, and maximum 98–99% Pb2+ removal occurred at pH 5 in contact time of 15 min and at an optimum dose of 0.1 g/L [2].

The percentage recoveries of metal ions decreased by 28% at the end of fifth adsorption-desorption cycle due to saturation of adsorbent-binding sites [2, 8, 24]. Equilibrium adsorption experiments for all the adsorbents were studied at room temperature and data obtained fitted to Langmuir and Freundlich adsorption isotherm [1–8, 10, 18, 23, 29–31]. The maximum adsorption capacity for raw CS, GDCC, IDCC, ACLF, and ACLFCS was obtainesd as 8.77, 6.711, 22.22, 101.01, and 111.11 mg/g, respectively [2, 7, 8, 18, 23, 24]. The adsorption kinetics was analyzed using pseudo-first-order, pseudo-second-order, and intraparticle diffusion models [7, 8, 18, 23]. The adsorption experimental data better fitted with pseudo-secondorder kinetic model for all the adsorbents namely raw CS, GDCC, IDCC, ACLF, and ACLFCS [2, 7, 8, 18, 23, 24]. All these synthetically modified chitosan-doped composite/biocomposite has been proved to be effective and economic adsorbents for the adsorption of Pb2+ from water.

## **8. Conclusions**

Various methodologies are being developed for the mitigation of Pb2+ from water/wastewater including chemical precipitation, electrochemical reduction, ion exchange, reverse osmosis, membrane separation, and adsorption. All such approaches being developed must be cheaper and more effective with the concern of reducing further/secondary waste generations besides boosting the quality of treatments. Physicochemical adsorption is the preferred treatments seeking for cheap, biocompatible adsorbents get intensified nowadays. A number of techniques have been chosen for the treatment of Pb2+ polluted water/wastewater; however, the selected one must focus on certain crucial parameters such as pH, initial Pb2+ion concentration, efficiency, and overall output as compared to other existing technologies besides socioenvironmental impacts and economic parameters such as fund investment and functioning costs. Last but not the least, its technical applicability, plant simplicity, and low cost are also guiding factors that played vital roles in the selection of the most suitable treatments. All such factors are most effective for opting suitable treatment techniques so as to protect the nature/environment.

## **9. Futuristic research**

Following recommendations are made for the future scope:

• the modification of synthesized chitosan-based biocomposite should be investigated by using other techniques such as sol gel and hydrothermal;

**63**

**Author details**

Rajendra Sukhadeorao Dongre

Department of Chemistry, RTM Nagpur University, Nagpur, MS, India

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: rsdongre@hotmail.com

provided the original work is properly cited.

*Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions*

other toxic heavy metal ions can also be studied;

• synthesized chitosan-based bioadsorbents are investigated for the removal of other toxic heavy metal ions namely cobalt, mercury, zinc, copper, bismuth,

• bioadsorbents can also be investigated for the adsorption of Pb2+ contaminated

• the chitosan-based biocomposite modification can be investigated in order to

• the competitive removal of Pb2+ from water in its combined presence with

• batch mitigation of Pb2+ onto the synthesized adsorbents at various temperatures may be conducted so as to determine its thermodynamic parameters;

• shelf life of synthesized and regenerated adsorbents also anticipates for

The author would like to thank the Head, Department of Chemistry, R.T.M. Nagpur University, Nagpur for providing lab facilities to carry out this research study and the Vice Chancellor, Nagpur University, Nagpur for approval and sanction of a research project under University Research Project Scheme, No.

Dev./RTMNURP/AH/1672 (9), on dated September 24, 2016.

• column mode of Pb2+ removal from industrial wastewater as futuristic step.

increase its surface area for effective adsorption of pollutants;

*DOI: http://dx.doi.org/10.5772/intechopen.93095*

cadmium, chromium, and arsenic;

waters;

investigation; and

**Acknowledgements**

*Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions DOI: http://dx.doi.org/10.5772/intechopen.93095*


## **Acknowledgements**

*Lead Chemistry*

0.9 g/L achieved in contact time of 140 min. By using GDCC adsorbent, the maximum 98% removal of Pb2+ was observed at optimum pH 6. Results showed that the maximum adsorbent capacity was at a dose of 1 g/L and equilibrium time achieved at 120 min of contact time for 35 mg/L Pb2+ ion concentration. The batch adsorption studies for Pb2+ removal from water by using IDCC revealed maximum removal at optimum pH 6 with an adsorbent dose of 0.5 g/L in contact time of 240 min. The regeneration ability of IDCC adsorbent demonstrated 25–30% decreased percentage recovery of Pb2+ ions at the end of fourth adsorption-desorption cycle. The maximum adsorption of Pb2+ onto ACLF was exhibited at an optimum parameter of pH 5.5, with an adsorbent dose of 0.3 g/L achieved in 12 min of contact time for 35 mg/L Pb2+ concentration [2, 7, 8, 18, 23]. Batch adsorption of Pb2+ using ACLFCS biocomposite was pH dependent, and maximum 98–99% Pb2+ removal occurred at

pH 5 in contact time of 15 min and at an optimum dose of 0.1 g/L [2].

for the adsorption of Pb2+ from water.

**8. Conclusions**

**9. Futuristic research**

The percentage recoveries of metal ions decreased by 28% at the end of fifth adsorption-desorption cycle due to saturation of adsorbent-binding sites [2, 8, 24]. Equilibrium adsorption experiments for all the adsorbents were studied at room temperature and data obtained fitted to Langmuir and Freundlich adsorption isotherm [1–8, 10, 18, 23, 29–31]. The maximum adsorption capacity for raw CS, GDCC, IDCC, ACLF, and ACLFCS was obtainesd as 8.77, 6.711, 22.22, 101.01, and 111.11 mg/g, respectively [2, 7, 8, 18, 23, 24]. The adsorption kinetics was analyzed using pseudo-first-order, pseudo-second-order, and intraparticle diffusion models [7, 8, 18, 23]. The adsorption experimental data better fitted with pseudo-secondorder kinetic model for all the adsorbents namely raw CS, GDCC, IDCC, ACLF, and ACLFCS [2, 7, 8, 18, 23, 24]. All these synthetically modified chitosan-doped composite/biocomposite has been proved to be effective and economic adsorbents

Various methodologies are being developed for the mitigation of Pb2+ from water/wastewater including chemical precipitation, electrochemical reduction, ion exchange, reverse osmosis, membrane separation, and adsorption. All such approaches being developed must be cheaper and more effective with the concern of reducing further/secondary waste generations besides boosting the quality of treatments. Physicochemical adsorption is the preferred treatments seeking for cheap, biocompatible adsorbents get intensified nowadays. A number of techniques have been chosen for the treatment of Pb2+ polluted water/wastewater; however, the selected one must focus on certain crucial parameters such as pH, initial Pb2+ion concentration, efficiency, and overall output as compared to other existing technologies besides socioenvironmental impacts and economic parameters such as fund investment and functioning costs. Last but not the least, its technical applicability, plant simplicity, and low cost are also guiding factors that played vital roles in the selection of the most suitable treatments. All such factors are most effective for opting suitable treatment techniques so as to protect the nature/environment.

Following recommendations are made for the future scope:

• the modification of synthesized chitosan-based biocomposite should be inves-

tigated by using other techniques such as sol gel and hydrothermal;

**62**

The author would like to thank the Head, Department of Chemistry, R.T.M. Nagpur University, Nagpur for providing lab facilities to carry out this research study and the Vice Chancellor, Nagpur University, Nagpur for approval and sanction of a research project under University Research Project Scheme, No. Dev./RTMNURP/AH/1672 (9), on dated September 24, 2016.

## **Author details**

Rajendra Sukhadeorao Dongre Department of Chemistry, RTM Nagpur University, Nagpur, MS, India

\*Address all correspondence to: rsdongre@hotmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Dongre RS. Biological Activities & Application of Marine Polysaccharides. Croatia: IntechOpen; 2017. pp. 181- 206. ISBN: 978-953-51-2860-1. DOI: 10.5772/65786

[2] Gedam AH, Narnaware PK, Kinhikar V. Blended composites of chitosan: Adsorption profile for mitigation of toxic Pb(II) ions from water. In: Chitin-Chitosan Myriad Functionalities in Science and Technology. ISBN: 978-1-78923-407-7. e-Book (PDF) ISBN: 978-1-83881-519-6. DOI: 10.5772/intechopen.74790

[3] Dongre RS. Chitosan-derived synthetic ion exchangers: Characteristics and applications. In: New Trends in Ion Exchange Studies. IntechOpen; 2018. pp. 21-42. ISBN: 978-1-78984-248-7. DOI: 10.5772/ intechopen.78964

[4] Dongre RS. Rationally fabricated nanomaterials for desalination & water purification. In: Novel Nanomaterials. ISBN: 978-1-78923-089-5. e-Book ISBN: 978-1-83881-460-1. DOI: 10.5772/ intechopen.74738

[5] Baghel A, Singh B. Emerging potable water technologies: Review paper. Defence Life Science Journal. 2016;**01**(2):113-126. DOI: 10.14429/ dlsj.1.10739

[6] Dongre RS. Chitosan formulations: Chemistry, characteristics and contextual adsorption in unambiguous modernization of S&T. In: Hysteresis of Composites. ISBN: 978-1-78984-810-6. e-Book ISBN: 978-1-78984-811-3. DOI: 10.5772/intechopen.83391

[7] Dongre RS. Reinforced fabricated nano-composite matrixes for modernization of S&T in new millennium. Composite and Nanocomposite Materials—From Knowledge to Industrial Applications. IntechOpen: Croatia; 2020. DOI: 10.5772/intechopen.91305

[8] Dongre RS, Gedam A. Comparative study of sponge gourd derived biochar and activated carbon for bio-sorption and desorption of Pb(II) ions. Materials Today: Proceedings. 2019;**18**(1):887- 900. DOI: 10.1016/j.matpr.2019.06.521

[9] Adhikari N, Sinha N, Narayan R, et al. Lead-induced cell death in testes of young rats. Journal of Applied Toxicology. 2001;**21**:275-277

[10] Zhang M. China: War without rules. Bulletin of the Atomic Scientists (SAGE0 Journal). 1999;**55**(6):16-18

[11] Abadin HG, Hibbs BF, Pohl HR. Breast-feeding exposure of infants to cadmium, lead, and mercury: A public health viewpoint. Toxicology and Industrial Health. 1997;**15**(4):1-24

[12] Abadin HG, Wheeler JS, Jones DE. A framework to guide public health assessment decisions at lead sites. Journal of Clean Technology, Environmental Toxicology and Occupational Medicine. 1997;**6**:225-237

[13] Adinolfi M. The development of the human blood-CSF-brain barrier. Developmental Medicine and Child Neurology. 1985;**27**:532-537

[14] Abbate C, Buceti R, Munao F, et al. Neurotoxicity induced by lead levels: An electrophysiological study. International Archives of Occupational and Environmental Health. 1995, 1986;**66**:389-392

[15] Adebonojo FO. Hematologic status of urban black children in Philadelphia: Emphasis on the frequency of anemia & elevated blood lead levels. La Clinica Pediatrica. 1974;**13**:874-888

[16] Agency for Toxic Substances and Disease Registry. Decision guide

**65**

994-2 1

*Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions*

[24] Gedam AH, Dongre RS, Bansiwal AK. Synthesis and characterization of graphite doped chitosan composite for batch adsorption

of lead (II) ions from aqueous

S1006-1266(08)60054-1

2015;**6**(1):59-67

solution. Advanced Materials Letters.

[25] Liu Z-R, Zhou L-M, Wei P, Lan H-H. Competitive adsorption of heavy metal ions on peat. Journal of China University of Mining & Technology. 2008;**18**(2):255-260. DOI: 10.1016/

[26] Wanga S, Peng Y. Natural zeolites as effective adsorbents in water and wastewater treatment. Chemical Engineering Journal. 2010;**156**:11-24. DOI: 10.1016/j.cej.2009.10.029

[27] Dong L, Zhu Z, Qiu Y, Zhao J. Removal of lead from aqueous solution by hydroxyapatite/magnetite composite adsorbent. Chemical Engineering Journal. 2010;**165**(3):827-834

[28] Vilar VJ, Botelho CM, Boaventura RA. Influence of pH, ionic strength and temperature on lead biosorption by gelidium & agar extraction algal waste. Process Biochemistry. 2005;**40**(10):3267-3275

[29] Singanan M, Abebaw A, Vinodhini S. Removal of lead ions from industrial waste water by using biomaterials: A novel method. Bulletin of the Chemical Society of Ethiopia.

[30] Singh D, Tiwari A, Gupta R. Phytoremediation of lead from wastewater using aquatic plants. Journal of Agricultural Technology.

[31] Arbabi M, Hemati S, Amiri M. Removal of lead ions from industrial wastewater: A review of removal methods. International Journal of Epidemiologic Research.

2005;**19**(2):289-294

2012;**8**(1):1-11

2015;**2**(2):105-109

*DOI: http://dx.doi.org/10.5772/intechopen.93095*

for identifying substance specific data needs related to toxicological profiles; notice. Federal Register. 1989;**54**(174):37618-37634

[17] Agency for Toxic Substances and Disease Registry. Public Health Statement for Lead. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service; 1997

DOI: 10.1039/C5RA09899H

[19] Kiani G, Soltanzadeh M. High capacity removal of silver (I), lead (II) ions by modified

2014;**52**(16-18):3206-3218

2014;**20**(2):454-461

2013;**18**(1):70-76

[20] Ghasemi M, Naushad M,

[18] Gedam AH, Dongre RS. Adsorption characterization of Pb(II) ions onto iodate doped chitosan composite: Equilibrium & kinetic studies. RSC Advances. 2015;**5**(67):54188-54201.

polyacrylonitrile from aqueous solutions. Desalination and Water Treatment.

Ghasemi N, Khosravi-fard Y. A novel agricultural waste based adsorbent for the removal of Pb(II) from aqueous solution: kinetics, equilibrium and thermodynamic studies. Journal of Industrial and Engineering Chemistry.

[21] Acharya J, Kumar U, Meikap B. Thermodynamic characterization of adsorption of lead (II) ions on activated carbon developed from tamarind wood from aqueous solution. South African Journal of Chemical Engineering.

[22] Abdel-Halim SH, Shehata AM, El-Shahat MF. Removal of lead ions from industrial waste water by different types of natural materials. Water Research. 2003;**37**(7):1678-1683

[23] Dongre RS. Nanomaterials via reconfiguration of skeletal matrix, Chapter 8. In: Nanostructures. Croatia: IntechOpen; 2019. p. 168. DOI: 10.5772/ intechopen.86818. ISBN: 978-1-78923-

### *Lead: Toxicological Profile, Pollution Aspects and Remedial Solutions DOI: http://dx.doi.org/10.5772/intechopen.93095*

for identifying substance specific data needs related to toxicological profiles; notice. Federal Register. 1989;**54**(174):37618-37634

[17] Agency for Toxic Substances and Disease Registry. Public Health Statement for Lead. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service; 1997

[18] Gedam AH, Dongre RS. Adsorption characterization of Pb(II) ions onto iodate doped chitosan composite: Equilibrium & kinetic studies. RSC Advances. 2015;**5**(67):54188-54201. DOI: 10.1039/C5RA09899H

[19] Kiani G, Soltanzadeh M. High capacity removal of silver (I), lead (II) ions by modified polyacrylonitrile from aqueous solutions. Desalination and Water Treatment. 2014;**52**(16-18):3206-3218

[20] Ghasemi M, Naushad M, Ghasemi N, Khosravi-fard Y. A novel agricultural waste based adsorbent for the removal of Pb(II) from aqueous solution: kinetics, equilibrium and thermodynamic studies. Journal of Industrial and Engineering Chemistry. 2014;**20**(2):454-461

[21] Acharya J, Kumar U, Meikap B. Thermodynamic characterization of adsorption of lead (II) ions on activated carbon developed from tamarind wood from aqueous solution. South African Journal of Chemical Engineering. 2013;**18**(1):70-76

[22] Abdel-Halim SH, Shehata AM, El-Shahat MF. Removal of lead ions from industrial waste water by different types of natural materials. Water Research. 2003;**37**(7):1678-1683

[23] Dongre RS. Nanomaterials via reconfiguration of skeletal matrix, Chapter 8. In: Nanostructures. Croatia: IntechOpen; 2019. p. 168. DOI: 10.5772/ intechopen.86818. ISBN: 978-1-78923- 994-2 1

[24] Gedam AH, Dongre RS, Bansiwal AK. Synthesis and characterization of graphite doped chitosan composite for batch adsorption of lead (II) ions from aqueous solution. Advanced Materials Letters. 2015;**6**(1):59-67

[25] Liu Z-R, Zhou L-M, Wei P, Lan H-H. Competitive adsorption of heavy metal ions on peat. Journal of China University of Mining & Technology. 2008;**18**(2):255-260. DOI: 10.1016/ S1006-1266(08)60054-1

[26] Wanga S, Peng Y. Natural zeolites as effective adsorbents in water and wastewater treatment. Chemical Engineering Journal. 2010;**156**:11-24. DOI: 10.1016/j.cej.2009.10.029

[27] Dong L, Zhu Z, Qiu Y, Zhao J. Removal of lead from aqueous solution by hydroxyapatite/magnetite composite adsorbent. Chemical Engineering Journal. 2010;**165**(3):827-834

[28] Vilar VJ, Botelho CM, Boaventura RA. Influence of pH, ionic strength and temperature on lead biosorption by gelidium & agar extraction algal waste. Process Biochemistry. 2005;**40**(10):3267-3275

[29] Singanan M, Abebaw A, Vinodhini S. Removal of lead ions from industrial waste water by using biomaterials: A novel method. Bulletin of the Chemical Society of Ethiopia. 2005;**19**(2):289-294

[30] Singh D, Tiwari A, Gupta R. Phytoremediation of lead from wastewater using aquatic plants. Journal of Agricultural Technology. 2012;**8**(1):1-11

[31] Arbabi M, Hemati S, Amiri M. Removal of lead ions from industrial wastewater: A review of removal methods. International Journal of Epidemiologic Research. 2015;**2**(2):105-109

**64**

*Lead Chemistry*

**References**

10.5772/65786

[1] Dongre RS. Biological Activities & Application of Marine Polysaccharides. Croatia: IntechOpen; 2017. pp. 181- 206. ISBN: 978-953-51-2860-1. DOI:

IntechOpen: Croatia; 2020. DOI: 10.5772/intechopen.91305

[8] Dongre RS, Gedam A. Comparative study of sponge gourd derived biochar and activated carbon for bio-sorption and desorption of Pb(II) ions. Materials Today: Proceedings. 2019;**18**(1):887- 900. DOI: 10.1016/j.matpr.2019.06.521

[9] Adhikari N, Sinha N, Narayan R, et al. Lead-induced cell death in testes of young rats. Journal of Applied Toxicology. 2001;**21**:275-277

[10] Zhang M. China: War without rules. Bulletin of the Atomic Scientists (SAGE0 Journal). 1999;**55**(6):16-18

[11] Abadin HG, Hibbs BF, Pohl HR. Breast-feeding exposure of infants to cadmium, lead, and mercury: A public health viewpoint. Toxicology and Industrial Health. 1997;**15**(4):1-24

[12] Abadin HG, Wheeler JS, Jones DE. A framework to guide public health assessment decisions at lead sites. Journal of Clean Technology, Environmental Toxicology and Occupational Medicine.

[13] Adinolfi M. The development of the human blood-CSF-brain barrier. Developmental Medicine and Child

[14] Abbate C, Buceti R, Munao F, et al. Neurotoxicity induced by lead levels: An electrophysiological study. International Archives of Occupational and Environmental Health. 1995,

[15] Adebonojo FO. Hematologic status of urban black children in Philadelphia: Emphasis on the frequency of anemia & elevated blood lead levels. La Clinica

Neurology. 1985;**27**:532-537

Pediatrica. 1974;**13**:874-888

[16] Agency for Toxic Substances and Disease Registry. Decision guide

1997;**6**:225-237

1986;**66**:389-392

[2] Gedam AH, Narnaware PK, Kinhikar V. Blended composites of chitosan: Adsorption profile for mitigation of toxic Pb(II) ions from water. In: Chitin-Chitosan Myriad Functionalities in Science and

Technology. ISBN: 978-1-78923-407-7. e-Book (PDF) ISBN: 978-1-83881-519-6.

DOI: 10.5772/intechopen.74790

[3] Dongre RS. Chitosan-derived synthetic ion exchangers:

intechopen.78964

intechopen.74738

dlsj.1.10739

Characteristics and applications. In: New Trends in Ion Exchange Studies. IntechOpen; 2018. pp. 21-42. ISBN: 978-1-78984-248-7. DOI: 10.5772/

[4] Dongre RS. Rationally fabricated nanomaterials for desalination & water purification. In: Novel Nanomaterials. ISBN: 978-1-78923-089-5. e-Book ISBN: 978-1-83881-460-1. DOI: 10.5772/

[5] Baghel A, Singh B. Emerging potable water technologies: Review paper. Defence Life Science Journal. 2016;**01**(2):113-126. DOI: 10.14429/

[6] Dongre RS. Chitosan formulations:

contextual adsorption in unambiguous modernization of S&T. In: Hysteresis of Composites. ISBN: 978-1-78984-810-6. e-Book ISBN: 978-1-78984-811-3. DOI:

[7] Dongre RS. Reinforced fabricated

Chemistry, characteristics and

10.5772/intechopen.83391

nano-composite matrixes for modernization of S&T in new millennium. Composite and Nanocomposite Materials—From Knowledge to Industrial Applications.

## *Lead Chemistry*

[32] Mondal MK. Removal of Pb(II) ions from aqueous solution using activated tea waste: Adsorption on a fixed-bed column. Journal of Environmental Management. 2009;**90**(11):3266-3271

[33] Singha B, Das SK. Removal of Pb(II) ions from aqueous solution and industrial effluent using natural biosorbents. Environmental Science and Pollution Research. 2012;**19**(6):2212-2226

[34] Hu J, Zhao D, Wang X. Removal of Pb(II) & Cu(II) from aqueous solution using multiwalled carbon nanotubes/ iron oxide magnetic composites. Water Science and Technology. 2011;**63**(5):917- 923. DOI: 10.2166/wst.2011.270

[35] Gedam AH, Dongre RS. Activated carbon from *Luffa cylindrica* doped chitosan for mitigation of lead (ii) from an aqueous solution. RSC Advances. 2016;**6**(27):22639-22652

**67**

Section 2

Lead Oxide Nanoparticles

Section 2
