**2. EDCs and male infertility**

The focus of male infertility is that our environment is contaminated by natural and synthetic chemicals. These chemicals could interact with the endocrine system [1]. People's exposure to chemicals is thought to be extensive, especially to EDCs, which supposed to alter the male reproductive tract. Mass industrial production and widespread use of EDCs have resulted in worldwide contamination.

morphological tail defects, decreased and increased respectively with higher plasma p,p′- DDE concentration. Insufficient sperm chromatin condensation was observed in 46.6% of participants and the most severe category of incomplete DNA condensation was also positively correlated with p,p′-DDE concentration [11]. Therefore, nonoccupational exposure to DDT, as assessed by plasma p,p′-DDE concentrations, is associated with poorer semen parameters in men, indicating adverse effects on testicular function and/or the regulation of

Environmental Factors and Male Infertility http://dx.doi.org/10.5772/intechopen.71553 161

Dioxins had been shown to exhibit antiestrogenic activity [12]. The association between dioxins/dioxin-like compounds exposure and impaired reproductive function had been strengthened by both epidemiological evidence and experimental studies [13–15]. Sexually mature laboratory animals exposed to relatively high doses of dioxin displayed decreased spermatogenesis, decreased testicular weight, and abnormal testes with reduced fertility [11]. By using gas chromatography/high-resolution mass spectrometry (GC/HRMS), Galimova et al. examined the concentration of dioxin-like compounds in semen of infertile males and fertile controls [14]. They found the dioxin/furan level in seminal fluid of infertile males was higher than that of fertile controls. The toxicity of dioxins is mediated by the AhR/ARNT receptor complex. The effects of high exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and "TCDD-like" compounds on important sites for the development and reproduction have been recognized for years. The reproductive system has even been thought as the most sensi-

It is beyond argument that cadmium and lead can induce male reproductive toxicity. World Health Organization (WHO) indicated that even low-level exposure to lead and cadmium (400 μg/l and 10 μg/l, respectively) can enable the semen has a significant quality descend, although it did not show conclusive evidence of male hormonal changes in

Typically, testicular toxins and various derivatives in the animal model do harm to the testis by causing a severe damage to the seminiferous epithelium. However, cadmium prefers the way of damaging the Sertoli cells, causing testicular damage directly. The morphological changes under the scanning electron microscopy can account for this mechanism. It also works in a way by interfering with the normal functioning of mitochondrial enzymes [16].

Results from testicular biopsies, such as vacuolation, peritubular fibrosis, and oligospermia, prove that lead has direct testicular toxicity, and some researchers found that lead exposure can also have an effect on hormonal feedback mechanism at the hypothalamic pituitary level. But further investigation should be done as these studies are insufficient to make detailed

reproductive hormones.

tive "end point" for dioxin.

**2.4. Heavy metal**

reproduction.

evaluations in humans.

**2.3. Dioxins and dioxin-like compounds**

EDCs are exogenous agents with the ability to mimic endogenous hormones, interfering with their biosynthesis, metabolism, and normal functions. These natural hormones are responsible for self-balance, reproduction, development and behavior of natural hormone synthesis, secretion, and transport. They mimic and inhibit the action of natural endogenous hormones or alter the normal regulatory function of the endocrine system and have potential hazardous effects on male reproductive axis causing infertility [2]. EDCs are estrogen-like and antiandrogenic chemicals in the environment. Bisphenol A (BPA), phthalates, polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT), dioxin, and some pesticides are the representatives of EDCs [2]. The first estrogenic and antiandrogenic endocrine disruptors that were reported to have transgenerational effects of spermatogenic failure were methoxychlor and vinclozolin [3].

#### **2.1. Bisphenol A (BPA)**

BPA is used in industries to synthesize polycarbonate and epoxy resins. Since the 1960s, it has been used in the manufacturing of plastic bottles, suction cup, inner coating of food and beverage cans, and so on. BPA is ubiquitous, from mineral water bottles, medical devices to food packaging, and has its shadow. This widespread chemical can do great harm to male fertility, having the potential of causing cryptorchidism, hypospadias, low sperm counts, or even testicular cancer [4–6]. It was also one of the important causes of occupational infertility [7]. Acting as an endocrine and metabolic disruptor, BPA can mimic the effect of endogenic estrogen. Even a very low dose of BPA can make the animals develop precocious puberty, low sperm count, prostatic hyperplasia, and so on [8]. It was reported that BPA could have greater impact on the development of human fetal testis [9]. Due to its potential harm to not only the reproductive ability but also the functions of other organs, BPA was banned from being used in baby care in many countries.

#### **2.2. DDT**

As an effective pesticide, DDT was widely used in agriculture and forestry. Its metabolites (p,p′-DDT, and p,p′-DDE) have estrogenic effects in males by blocking the androgen receptors [10]. DDT exposure was estimated by the level of p,p′-dichlorodiphenyl dichloroethylene in blood plasma, the major metabolite of DDT. Crude regression analysis showed that several sperm motion parameters, including the percentage of motile sperm and sperm with morphological tail defects, decreased and increased respectively with higher plasma p,p′- DDE concentration. Insufficient sperm chromatin condensation was observed in 46.6% of participants and the most severe category of incomplete DNA condensation was also positively correlated with p,p′-DDE concentration [11]. Therefore, nonoccupational exposure to DDT, as assessed by plasma p,p′-DDE concentrations, is associated with poorer semen parameters in men, indicating adverse effects on testicular function and/or the regulation of reproductive hormones.

#### **2.3. Dioxins and dioxin-like compounds**

Dioxins had been shown to exhibit antiestrogenic activity [12]. The association between dioxins/dioxin-like compounds exposure and impaired reproductive function had been strengthened by both epidemiological evidence and experimental studies [13–15]. Sexually mature laboratory animals exposed to relatively high doses of dioxin displayed decreased spermatogenesis, decreased testicular weight, and abnormal testes with reduced fertility [11]. By using gas chromatography/high-resolution mass spectrometry (GC/HRMS), Galimova et al. examined the concentration of dioxin-like compounds in semen of infertile males and fertile controls [14]. They found the dioxin/furan level in seminal fluid of infertile males was higher than that of fertile controls. The toxicity of dioxins is mediated by the AhR/ARNT receptor complex. The effects of high exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and "TCDD-like" compounds on important sites for the development and reproduction have been recognized for years. The reproductive system has even been thought as the most sensitive "end point" for dioxin.

#### **2.4. Heavy metal**

**2. EDCs and male infertility**

worldwide contamination.

160 Spermatozoa - Facts and Perspectives

chlor and vinclozolin [3].

**2.1. Bisphenol A (BPA)**

in baby care in many countries.

**2.2. DDT**

The focus of male infertility is that our environment is contaminated by natural and synthetic chemicals. These chemicals could interact with the endocrine system [1]. People's exposure to chemicals is thought to be extensive, especially to EDCs, which supposed to alter the male reproductive tract. Mass industrial production and widespread use of EDCs have resulted in

EDCs are exogenous agents with the ability to mimic endogenous hormones, interfering with their biosynthesis, metabolism, and normal functions. These natural hormones are responsible for self-balance, reproduction, development and behavior of natural hormone synthesis, secretion, and transport. They mimic and inhibit the action of natural endogenous hormones or alter the normal regulatory function of the endocrine system and have potential hazardous effects on male reproductive axis causing infertility [2]. EDCs are estrogen-like and antiandrogenic chemicals in the environment. Bisphenol A (BPA), phthalates, polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT), dioxin, and some pesticides are the representatives of EDCs [2]. The first estrogenic and antiandrogenic endocrine disruptors that were reported to have transgenerational effects of spermatogenic failure were methoxy-

BPA is used in industries to synthesize polycarbonate and epoxy resins. Since the 1960s, it has been used in the manufacturing of plastic bottles, suction cup, inner coating of food and beverage cans, and so on. BPA is ubiquitous, from mineral water bottles, medical devices to food packaging, and has its shadow. This widespread chemical can do great harm to male fertility, having the potential of causing cryptorchidism, hypospadias, low sperm counts, or even testicular cancer [4–6]. It was also one of the important causes of occupational infertility [7]. Acting as an endocrine and metabolic disruptor, BPA can mimic the effect of endogenic estrogen. Even a very low dose of BPA can make the animals develop precocious puberty, low sperm count, prostatic hyperplasia, and so on [8]. It was reported that BPA could have greater impact on the development of human fetal testis [9]. Due to its potential harm to not only the reproductive ability but also the functions of other organs, BPA was banned from being used

As an effective pesticide, DDT was widely used in agriculture and forestry. Its metabolites (p,p′-DDT, and p,p′-DDE) have estrogenic effects in males by blocking the androgen receptors [10]. DDT exposure was estimated by the level of p,p′-dichlorodiphenyl dichloroethylene in blood plasma, the major metabolite of DDT. Crude regression analysis showed that several sperm motion parameters, including the percentage of motile sperm and sperm with It is beyond argument that cadmium and lead can induce male reproductive toxicity. World Health Organization (WHO) indicated that even low-level exposure to lead and cadmium (400 μg/l and 10 μg/l, respectively) can enable the semen has a significant quality descend, although it did not show conclusive evidence of male hormonal changes in reproduction.

Typically, testicular toxins and various derivatives in the animal model do harm to the testis by causing a severe damage to the seminiferous epithelium. However, cadmium prefers the way of damaging the Sertoli cells, causing testicular damage directly. The morphological changes under the scanning electron microscopy can account for this mechanism. It also works in a way by interfering with the normal functioning of mitochondrial enzymes [16].

Results from testicular biopsies, such as vacuolation, peritubular fibrosis, and oligospermia, prove that lead has direct testicular toxicity, and some researchers found that lead exposure can also have an effect on hormonal feedback mechanism at the hypothalamic pituitary level. But further investigation should be done as these studies are insufficient to make detailed evaluations in humans.

#### **2.5. Phthalates**

Phthalates are substances used in the manufacturing of automobiles, medical supplies, plastics, beverage containers, coating of metal cans, and so on. Data have demonstrated that perinatal exposure to a variety of phthalate esters alters the development of the male reproductive tract in an antiandrogenic way, causing underdevelopment and agenesis of the epididymis at relatively low doses [16]. Environmental exposure to di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP) may contribute to a decline in semen quality [17]. Additionally, our recent study demonstrated that prenatal exposure to DBP has transgenerational effects of impaired spermatogenesis. We also revealed that metabolic and epigenetic changes induced by the aberrant expression of betaine homocysteine S-methyltransferase (BHMT) represent a novel mechanism linking in utero DBP exposure to transgenerational spermatogenesis failure [18].

It is possible that these environmental agents such as alkyl phenol ethylate and their degradation products, chlorinated dibenzodioxins, and PCBs can induce irreversible decline in male

Environmental Factors and Male Infertility http://dx.doi.org/10.5772/intechopen.71553 163

In general, lifestyle factors affect male reproductive system in various ways. In today's society, male infertility has become a more and more important problem. People's unhealthy lifestyle may be one of the great reasons. Sperm needs a suitable internal and external environment to complete several physiological links such as occurrence, development, maturity, and transportation. Some physical and chemical factors can lead to the damage of the testis and accessory glands, the disorders of the internal environment, and spermatogenesis dysfunction to some extent. Several studies have found that occupation, behavioral habit, dietary habit, and other factors can play a role in the decreased fertility. The following discussion focuses on the association between male infertility and lifestyle factors such as smoking, alco-

As we know, smoking is associated with variable diseases, including respiratory diseases, cardiovascular diseases and cancer of the lung, kidney, urinary bladder, pancreas, and so on [25, 26]. The relationship between smoking and infertilities has been studied for several years.

A vast amount of studies showed the negative effects of smoking on various parameters of semen analysis. In an experiment conducted in Denmark from 1987 to 2004, 2562 men participated; researchers found that heavy smokers had a 19% lower sperm concentration than nonsmokers [27]. Moreover, in another cohort study which involves 1786 men, researchers proved that smoking was associated with a significant decrease in sperm density, total sperm count, total number of motile sperm, and citrate concentration. In addition, sperm vitality, ejaculate volume, and fructose concentration were slightly but nonsignificantly affected [28]. In other aspects, smokers had a significantly decreased semen volumes, sperm motility, and viability compared with nonsmokers. All sperm motion parameters were lower in the smokers except for beat-cross frequency (Hz). Further, the percentage of normal morphology sperm was decreased significantly in smokers, and the sperm morphology was worse with increasing degree of smoking [29]. The

experiments have already shown that smoking in daily life damages the semen quality.

Existing data indicate that varicocele plays an important role in male infertility. There are also experiments trying to figure out the relationship between varicocele and smoking. In a study conducted in Iran, percentage of varicocele was significantly higher in smokers compared

The mechanism behind the negative effect of smoking on semen quality remains vague until today. There are evidences showing that people who smoke possess a higher proportion

fertility [2].

hol consumption, and diet.

with nonsmokers [30].

**3.1. Smoking**

**3. Lifestyle factors and male infertility**

#### **2.6. Mechanism(s) of action of endocrine disruptions on hypothalamic-pituitary-gonadal (HPG) axis**

A large amount of substances has the ability to inhibit the biosynthesis of a variety of hormones. Some substances can inhibit the specific enzymes in steroidogenesis such as aminoglutethimide, cyanoketone, and ketoconazole. Some fungicides inhibit estrogen synthesis by inhibiting aromatase activity in the testis, which has an effect on testosterone to estrogen. Through a set of signals at transcriptional and translational levels, EDCs make further efforts to transform the biosynthesis of protein mediated by gonadal steroids [19].

Hormones react with their target tissues directly by interacting with membrane-bound receptors or intracellular receptors. The vital procedure in the function of hormones is the specific binding of natural ligand to its receptors. Intracellular or nuclear receptors interact with specific DNA sequences regulating gene transcription in a ligand-dependent pattern. This procedure might be changed by many environmental factors through mimicking the natural ligand and serving as an agonist or inhibiting the binding and serving as an antagonist. The most notable examples are methoxychlor, chlordecone, DDT, some polychlorinated biphenyls, and alkylphenols, which can disturb the function of estrogen receptors [20].

Epigenetic modifications characterized by DNA methylation, histone modifications, and chromatin remodeling are important regulators in spermatogenesis. Studies have shown that aberrant epigenetic modifications are associated with disturbed spermatogenesis and male infertility [21–23]. Exposure of gametes to environmental factors may cause alterations in sperm. In addition, more and more studies have demonstrated that many EDCs have transgenerational effect of spermatogenic failure through epigenetic mechanism [3, 24].

Clearly, there should be more studies to explore the data gaps. In addition to a few exceptions (e.g., diethylstilbestrol [DES]), the causal relationship between exposure to specific agents and endocrine disruptor-mediated adverse health effects has not been determined. The development and validation of short-term screening studies should be used to clarify the mechanism. It is possible that these environmental agents such as alkyl phenol ethylate and their degradation products, chlorinated dibenzodioxins, and PCBs can induce irreversible decline in male fertility [2].
