**3.1 Effects of EDCs on sperm production, morphology, motility and velocity**

Several studies have been published regarding the association of exposure to phenols and human semen quality [53–55]. A case–control study was conducted to evaluate the association between exposure to phenols and idiopathic male infertility [55]. For that, the authors recruited idiopathic infertile men and fertile controls and measured urinary levels of BPA, benzophenone-3, pentachlorophenol, TCS, 4-*tert*octylphenol (4-*t*-OP), 4-*n*-octylphenol (4-*n*-OP) and 4-*n*-nonylphenol (4-*n*-NP) and semen parameters. The authors found that exposure to 4-*t*-OP, 4-*n*-OP and 4-*n*-NP was associated with idiopathic male infertility, and exposure to 4-*t*-OP and 4-*n*-NP was also associated with abnormal semen quality parameters. However, in this study the authors did not find more relationships between exposure to other phenols and idiopathic male infertility. In another study, urinary BPA concentrations were associated with declines in sperm concentration, motility and morphology [53]. An increasing urine BPA level was associated with lower semen concentration, lower total sperm count, lower sperm vitality and lower sperm motility [54]. Moreover, the authors demonstrated a dose–response relationship between increasing urine BPA level and reduction in semen quality. Lassen et al. [10] also found an inverse association between BPA concentrations and progressive motility, but in this study, BPA excretion was not associated with semen volume, sperm concentration, total sperm count or percentage morphologically normal forms. However, some authors did not find any association between urinary BPA concentrations and some semen parameters, such as semen volume or sperm morphology [8, 54].

TCS has been shown to decrease sperm density probably due to reduced testicular spermatogenesis [18]. A reduced sperm density was observed in the lumina of epididymal tubule from the treated rats. Rats treated with high doses of TCS (50 and 200 mg/kg) showed a significant decrease in the daily sperm production and an increase in the percentage of sperm abnormalities, which included elevated ratios of abnormal sperm head and tails [4]. Zhu et al. [56] performed a cross-sectional study to evaluate the association between exposure to TCS measured by urinary TCS concentration and semen quality in humans. The authors found an association between urinary TCS concentrations and poor semen quality parameters; namely, the authors found an inverse association between urinary TCS concentrations and percentage of sperm motility, sperm count, sperm concentration and percentage of normal morphology, suggesting that environmental exposure to TCS may have impact on semen quality.

Regarding exposure to PCBs, several studies showed an inverse association between exposure to PCB 153 and sperm motility, while relationships with sperm concentration or total sperm count were inconsistent [57–59]. Additionally, Hauser et al. [60] found an inverse dose–response relationship between PCB 138 and sperm concentration, motility and morphology.

The correlation between exposure to metals and adverse consequences for human and animal fertility is not completely established. Several studies determined the effects of exposure to metals on male gametes. In vitro studies, using bovine sperm, determined the effect of direct exposure to Hg on male gametes [61, 62]. Arabi et al. [61] showed that exposure to Hg (50, 100, 200, and 300 μmol/l) induced LPO (lipid peroxidation), decreased the glutathione (GSH) content and decreased the percentage of viable spermatozoa. Additionally, a more recent study showed that bovine sperm exposed to Hg at 8 nM and 8 μM have less motility and have impaired sperm

membrane integrity, increasing levels of reactive oxygen species (ROS) and LPO and decreasing the antioxidant activity and diminished fertility ability [62]. Regarding human fertility, in a cross-sectional study, participants with high blood Hg level had lower sperm with a normal morphology [63]. Cd is another male reproductive toxicant that exerts effects even at low levels of exposure by several mechanisms [64]. In vitro studies on human spermatozoa obtained through ejaculation allow to evaluate the effect of Cd treatment in semen parameters [65, 66]. Cd decreased sperm motility and sperm viability and induced detrimental effects on spermatozoa metabolism by inhibition of the activity of glycogen phosphorylase, glucose-6-phosphatase, fructose-1,6-diphosphatase, glucose-6-phosphate isomerase, amylase, Mg2+− dependent ATPase and lactic and succinic acid dehydrogenases. As reviewed by de Angelis et al. [33], significant negative correlations were found between Cd levels and semen parameters, including total sperm count, concentration, motility and morphology. Results from a meta-analysis indicate that men with low fertility had higher semen Pb and Cd levels and lower semen Zn levels [67]. Sperm motility was significantly decreased in men occupationally exposed to Mn [47].

Occupational exposure to pesticides increased the risk of morphological abnormalities in sperm in addition with a decline in sperm count and a decreased percentage of viable spermatozoa. For instance, the exposure to pesticides reduced the seminal volume, sperm motility and concentration and increased the seminal pH and the abnormal sperm head morphology [68–70]. A study showed that young Swedish men exposed to phthalates presented a decrease in progressive sperm motility [71]. Additionally, levels of urinary phthalates and insecticides were also associated with lower sperm concentration, lower motility and increased percentage of sperm with abnormal morphology [72–75]. These results confirmed the results obtained by in vitro and in vivo studies [76, 77].

### **3.2 Sperm DNA damage**

Sperm DNA integrity is essential for the correct transmission of genetic information [78]. Damage at sperm DNA level may result in male infertility. Sperm DNA damage is caused by oxidative stress that causes impairment in the sperm membrane [79]. It is well-known that some EDCs may induce oxidative stress and decrease the cellular levels of GSH and protein-sulfhydryl groups. Preclinical studies with male rats showed that exposure to BPA was associated with a significant increase in sperm DNA damage [80]. A statistically significant positive association between urinary concentrations of parabens and BPA and sperm DNA damage was found in male partners of subfertile couples [53, 81]. Contrary results were obtained by Goldstone et al. [8] that found a negative relationship between BPA and DNA fragmentations.

Additionally, other EDCs such as heavy metals (e.g., Hg), PCBs and insecticides induce sperm DNA damage [59, 61, 73, 75, 82–84]. Urinary levels of Hg and nickel in infertile men were associated with increasing trends for tail length, and the levels of Mn were associated with increasing trend for tail distributed moment [82]. The adverse effects of phthalates on sperm DNA were assessed by several studies among infertile men [75, 84]. Urinary concentrations of phthalate metabolites were associated with sperm DNA damage. These studies suggest that environmental and occupational exposure to EDCs may be associated with increased sperm DNA damage.

### **4. Conclusions**

The results yielded in this chapter showed that both environmental and occupational exposures to EDCs affect male reproductive function at multiple levels.

**29**

*The Role of Endocrine-Disrupting Chemicals in Male Fertility Decline*

In human populations, the majority of studies point toward an association between exposure to EDCs and male reproduction system disorders, such as infertility, testicular cancer, poor sperm quality and/or function. Exposure to EDCs was associated with declined semen quality, increased sperm DNA damage, alterations in testis morphology and endocrine function. However, there are studies exploring the effect of EDCs on male reproductive health including semen quality, reproductive hormones and male fertility that produced inconsistent results probably due to small-sized study populations and lack of control for potential confounding variables. These contrary results highlight the need to discuss and investigate the effect of environmental pollutants in the male reproductive health. Moreover, the identification of the sequence of events and mechanisms might be important to better understand the effect of exposure to EDCs on male reproductive system and

Thanks are due to the support of iBiMED (UID/BIM/04501/2013, UID/ BIM/04501/2019 and POCI-01-0145-FEDER-007628), CESAM (UID/

AMB/50017/2019 and POCI-01-0145-FEDER-007638) and FCT/MEC through national funds. We are also thankful to FCT of the Portuguese Ministry of Science and Higher Education by an individual grant to M.C.H. (SFRH/BD/131846/2017).

*DOI: http://dx.doi.org/10.5772/intechopen.88330*

their contribution to male fertility decline.

The authors declare no conflicts of interest.

ACP acyl carrier protein ALT alanine aminotransferase AR androgen receptor

Bcl-2 B-cell lymphoma 2

BTB blood-testis barrier

CdCl2 cadmium chloride

FAI free androgen index

LDH lactate dehydrogenase

DDT diphenyl-dichloro-trichloroethane

EDCs endocrine-disrupting chemicals

FSH follicle-stimulating hormone GnRH gonadotropin-releasing hormone

BP bisphenols BPA bisphenol A BPS bisphenol S

Cd cadmium

E2 estradiol

GSH glutathione Hg mercury LC Leydig cells

AST aspartate aminotransferase Bax Bcl-2-associated X protein

**Acknowledgements**

**Conflict of interest**

**Abbreviations**

*The Role of Endocrine-Disrupting Chemicals in Male Fertility Decline DOI: http://dx.doi.org/10.5772/intechopen.88330*

In human populations, the majority of studies point toward an association between exposure to EDCs and male reproduction system disorders, such as infertility, testicular cancer, poor sperm quality and/or function. Exposure to EDCs was associated with declined semen quality, increased sperm DNA damage, alterations in testis morphology and endocrine function. However, there are studies exploring the effect of EDCs on male reproductive health including semen quality, reproductive hormones and male fertility that produced inconsistent results probably due to small-sized study populations and lack of control for potential confounding variables. These contrary results highlight the need to discuss and investigate the effect of environmental pollutants in the male reproductive health. Moreover, the identification of the sequence of events and mechanisms might be important to better understand the effect of exposure to EDCs on male reproductive system and their contribution to male fertility decline.
