**2. Male infertility**

The psychological, social, and economic consequences of reduced male capacity to have children are often severe and extend beyond individuals to entire families and society at large. The previously discussed subject of decline in male fertility is no longer controversial because many studies over the past 10 years have shown a decrease in semen quality [4, 17–19]. EDCs affect the maturation, function, and viability of sperm by acting directly on the sperm or altering the function of the epididymis as well as the sperm's ability to fertilize an egg. In normal human males, the number of sperm is close to what is normally required for fertility. While acute exposure can cause significant changes in spermatogenesis, it appears to occur with low-dose, chronic exposures to EDCs that impair spermatogenesis [5, 17, 20]. Therefore, even a small decrease in daily sperm production can cause infertility. Semen parameters are used to measure sperm quality and they are very important because they can be used to predict male infertility [5, 20]. However, for many reason, semen may be the least understood body fluid in terms of the distribution of its normal values in the general population. Since it is difficult to obtain semen fluid, men are not included in the study, therefore not many studies can be conducted to reveal the relationship between semen quality and chemical substances [21].

About 15% of couples worldwide are infertile and half is the male factor. Male infertility is considered as primary cause of infertility in 20% of couples and a contributing factor in 30–40% of cases. Infertility is caused by changes in the hypothalamic-pituitary-gonadal (HPG) axis or by direct effects on sperm and other semen parameters [4, 17]. Men with sperm parameters below the values specified in WHO are considered to have male factor infertility. The most important of these are low sperm concentration (oligospermia), poor sperm motility (asthenospermia),

and abnormal sperm morphology (teratospermia). Other factors less correlated with infertility include semen volume and other seminal markers [15].

In a large review of international studies conducted by authors, it is reported that the average sperm count in men decreased from 113 million/mL to 66 million/mL and significant anomalies in sperm morphology/motility in 50 years (1940–1990) in the world [7, 22].

Sperm function is affected by reactive oxygen species (ROS) produced during the metabolism of these chemicals, which is another possible effect of infertility including EDCs. Oxidative stress plays an important role in the mechanism of male infertility. Oxidative stress is a balance between the production of ROS and the natural antioxidant defense of semen. Increased ROS levels can be due to many factors such as environmental pollutants and lifestyle factors [23, 24].

The effect of EDCs in testicles is mediated mainly by the nuclear estrogen receptors (ESR1 and ESR2) expressed by Sertoli and germ cells. These cells secrete masculinizing hormones that regulate sperm production, [6, 10, 25]. Because hormones tightly control the male reproductive system, anti-androgens or EDCs that mimic estrogens can interfere with spermatogenesis and have a profound effect on healthy sperm production [16]. Men exposed to estrogenic EDCs may reduce fertility and develop female secondary sex characteristics such as gynecomastia [13].

Different mechanisms of action related to the hormone-disrupting effects of pesticides are discussed, but the most common mention is the interaction with the recognition and binding of reproductive hormone receptors. Most EDCs are substances with estrogenic/anti-androgenic activity that act by interfering with the estrogen receptors (ER) or the androgen receptor (AR), which are commonly found in male reproductive tissues [26, 27]. For the last been, it has focused on the estrogenic effect of EDCs and it has been determined that many substances are "environmental estrogens." It is though that increased exposure to estrogens not only causes prenatal testicular damage, but may also contributes to postpartum inhibition of testicular function and spermatogenesis. Environmental estrogens affect fetal development by inhibiting the development of Sertoli cells, which determine the lifetime capacity of sperm production. These estrogens can also inhibit enzymes in testosterone synthesis and directly affect testosterone production [28–30].

#### **2.1 Heavy metal (LEAD-Pb)**

Rapid industrialization and over-growing urbanization and the toxic effects of heavy metals on the male reproductive system have become an important public health all over the world. Reproductive problems in males due to metal exposure are one of the most important areas of concern in toxicology [31]. In epidemiological and clinical studies, it has been found to be associated with impaired semen quality as a result of the direct effect of heavy metals on testicular function or hormonal changes**.** One of the heavy metals of greatest concern is lead (Pb). Lead exposure can cause toxicity to both the male and female reproductive systems. Pb is a natural compound and is regularly used in mining, smelting, refining, leaded gasoline (petrol), lead-acid batteries, paints, jewelry, children's products, and many other products. The general population is exposed to Pb through contaminated food and water and inhalation of airborne Pb. Lead in seminal plasma may increase with environmental pollutions, and industrial and dietary exposure [6, 32, 33].

In toxicology studies, it is argued that the determination of heavy metal levels in the seminal fluid may better indicate exposure, due to the accumulation of these

#### *Endocrine Disruptors and Infertility DOI: http://dx.doi.org/10.5772/intechopen.104403*

substances in the male reproductive organs, rather than the determination of heavy metal levels in the blood [31, 32]. At low levels of occupational exposure in smelting industry workers, lead has been associated with reduced semen concentration, motility, and viability. Heavy metals cause toxicity by affecting the HPG axis, testicular function, spermatogenesis, and steroidogenic processes either directly or through the endocrine system [17, 31, 34].

Strong evidences confirm that male infertility in metal-exposed humans is mediated *via* various mechanisms such as production of reactive oxygen species (ROS). It is known that smoking causes oxidative stress by increasing oxidant levels or decreasing antioxidant levels in seminal plasma [34, 35]. Kiziler et al. [35] investigated Pb levels in blood and seminal plasma of the infertile and fertile groups. Pb levels in seminal plasma and blood were significantly higher in infertile men than those in fertile groups. It was revealed that sperm count, motility, and morphology were significantly decreased in infertile smokers than in non-smoker infertile and fertile men. He et al. [36] investigated whether oxidative stress is an intermediate mediator in regulating the associations between heavy metal exposure and impaired semen quality. A significant inverse relationship was found between Pb exposure and the percentage of normal sperm morphology [36], and a negative correlation was detected with the sperm count and motility [37]. Lead levels of non-occupational lead exposure in 341 infertile men were investigated by Wu et al. [32]. The research results showed a significant inverse correlation between the lead concentration in seminal plasma and the sperm count. These results showed a negatively correlation with standard semen parameters and biomarkers of sperm function. Therefore, the authors postulate that unexplained male infertility may be due to increased Pb levels [38].

It is known that semen quality has an effect on sperm motility, which is one of the most important factors in infertility [39]. Sperm motility depends on the synchronized movements proteins, sugars, ions, and small organic molecules. It is one of the main factors that facilitate the journey of sperm toward the egg and the subsequent fertilization process. Defects in sperm motility are a common reason for infertility in humans [34]. Li et al. [40] examined the positively relationship between increased blood Pb levels and low semen quality. Li et al. [41] also found a negative correlation between Pb concentrations and sperm motility. Therefore, authors suggest that among the semen parameters, sperm motility can be a sensitive indicator of semen quality.

It has been reported that 90% of male infertility problems are related to sperm count, and there is also a positive relationship between sperm count and semen parameters [15]. Famurewa and Ugwuja [42] found that seminal plasma Pb was significantly (p < 0.05) higher in oligospermic and normospernic men than in azospermic men. Significant inverse associations (p < 0.01) were found between blood lead and sperm count.

In conclusion, lead shows its effect on reproductive hormones by changing the reproductive hormone axis and hormonal control over spermatogenesis rather than having a direct toxic effect on the seminiferous tubules of testicles [43]. The overall results of these studies indicate that even considerably low levels of blood and seminal plasma Pb might reduce the human semen quality, it potentially reduces male fertility; however, more infertility studies are needed to show that lead has a direct effect on male infertility [42].
