**2.1 Changes in volume/weight of reproductive organs**

The volume/weight of the male reproductive organs is an important indicator of the integrity of this system. Several animal studies showed a significant decrease in the weight of the testes and sex accessory tissues in animals exposed to EDCs [4, 18–23]. For instance, male rats treated with 10 and 20 mg/(kg day) of TCS revealed a significant decrease in the weight of the testes, epididymis, ventral prostate, vas deferens and seminal vesicles [18]. However, an administration of 5 mg/(kg day) of TCS did not cause significant change in the testes and sex accessory tissues [18]. Recently, Lan et al. [4] showed that the absolute

weights of testes and epididymis of rats treated with 10, 50 or 200 mg/kg of TCS were not significantly affected.

Rodents were exposed to BPA by the oral route or subcutaneous injections [24, 25]. A dose of 2 ng/g body weight induced a decrease in epididymal weight and an increase in prostate weight. Bisphenol S (BPS), considered a safe substitute for BPA, has chemical similarities with BPA and may act as an EDC. Thus, a recent work compared the effects of BPA and BPS on the morphology and physiology of the ventral prostate of adult gerbils [26]. Animals treated with BPA and BPS showed no alterations in prostate weight. Regarding histopathology, BPS-treated animals showed intense prostatic hyperplasia; increased relative frequency of epithelium, muscular stroma and non-muscular stroma; and decreased luminal compartment, and BPA-treated animals showed increased occurrence of hyperplastic growth. But, in general the authors found that BPS promoted more structural and histopathological changes than BPA.

Exposure to metals also induced effects on testes size. A dose of 5 mg/kg body weight of cadmium chloride (CdCl2) administered to rats by oral gavage caused a significant decrease in testes and epididymis weight [19]. Moreover, Hg and zinc (Zn) significantly decreased the absolute and relative testicular weights in murine, with Hg producing the highest reduction in weight [27]. Similar results were obtained by Narayana et al. [22] and Geng et al. [23] that showed a decrease in the weights of reproductive organs of rats exposed to pesticides.

Rats exposed to phthalates demonstrated reduced testicular weights and histologic changes in the seminiferous tubules [20, 21]. Moreover, rats exposed to phthalates during the prenatal period developed reproductive anomalies, namely, smaller testes and penis size [28].

Human studies related to the effects of exposure to EDCs on testicular volume/ weight are limited but in accordance with animal studies. For instance, in a study in Croatian men, no occupational exposures were exposed to metals, and blood Cd was negatively correlated with testes size, suggesting that this metal exerts toxicity on human testes [29].

### **2.2 Alterations in testicular morphology**

Experimental studies showed that exposure to EDCs had adverse effects on testes, resulting in testicular damage at structural and consequently functional level. Male rats treated with 20 mg/(kg day) of TCS exhibited several histopathological malformations in the testes and sex accessory tissues [18]. Lumen of vas deferens from the treated rats exhibited the presence of stereocilia detached from the epithelium and the presence of eosinophilic bodies. Moreover, the stereocilia were found to be thin, few or absent in the epithelium of TCS-treated rats. Rats treated with a high dose of TCS (200 mg/kg) showed changes in the cauda epididymis and in the testis compared with the control group [4]. In the cauda epididymis, the alterations included vacuolated and exfoliated epithelial cells. Moreover, these authors identified the absence of sperm tails in the seminiferous tubules in the TCS-treated groups.

Mice exposed to BPA showed the formation of morphologically multinucleated giant cells in testicular seminiferous tubules [30], disruption of the blood-testis barrier (BTB) and impaired spermatogenesis [31, 32]. Similar results were obtained by other study using pesticides that induced severe degenerative changes in seminiferous tubules [23]. Metals, such as Cd and Hg, also induced structural alterations in the testis structure, including damage in the vascular endothelium and in the BTB integrity and necrosis and disintegration of spermatocytes [27, 33]. In general, these animal studies showed that EDCs induced changes in testicular morphology, which may be a reason for the decline of male fertility. For instance, damage in epididymis

**25**

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

compromise the transport of testicular sperm out of the testis, the acquisition of progressive spermatozoa motility and the sperm storage. Moreover, damage at SC and LC levels compromise the structure of the BTB and seminiferous tubules.

The two main functions of the testes are spermatogenesis (exocrine function) and steroidogenesis (endocrine function). In normal conditions the gonadotrophinreleasing hormone (GnRH) is secreted by the hypothalamus, stimulating the synthesis of LH and the follicle-stimulating hormone (FSH) [34]. LH is recognized by LH receptors in LC stimulating T biosynthesis (steroidogenesis). FSH is recognized by FSH receptors in SC having an important role in spermatozoa production (spermatogenesis). Several studies showed that these functions are affected by exposure to EDCs (**Figure 1**) [10, 18, 35–39]. Prenatal exposure to EDCs was associated with testicular anomalies later in life, which includes reduced semen volume and quality, increased incidence of cryptorchidism and hypospadias and increased incidence of testicular cancer [40]. EDCs reduced SC number and impaired LC development, inducing testicular anomalies at morphological and functional level [39]. This section presents the studies that assessed the relationship between animal and human exposure to EDCs and testicular dysfunction, including alterations in

Evidences from animal studies suggest that TCS reduces the production of T in LC and disturbs the function of major steroidogenic enzymes [41, 42]. Male rats treated with TCS or pesticides showed a significant decrease in the levels of serum LH, FSH, cholesterol, pregnenolone and T compared to control [18, 23]. Regarding human studies, a case-control study showed that urinary levels of phthalates and TCS were negatively associated with inhibin B and positively with LH [39]. Additionally, an inverse association was found between urinary levels of phthalates or BPA and testosterone and estradiol (E2) [38, 39]. Similar results were obtained by Meeker et al. [35] that showed an inverse association between BPA concentrations in urine and serum levels of inhibin B and E2:T ratio in men recruited through an infertility clinic. Moreover, a positive association between BPA concentrations in urine and FSH and FSH:inhibin B ratio was found. Hanoaka et al. [36] did not found an association between exposure to BPA and free T and LH concentrations in men. However, a significant decrease in FSH concentrations was found in the BPA exposed men. Urinary levels of BPA were not associated with sperm quality in fertile men but were associated with markers of androgenic action [37]. A significant inverse association was found between urinary levels of BPA and free androgen index (FAI) levels and the FAI:LH ratio. Further, a significant positive association between BPA and sex hormone-binding globulin (SHBG) was found in fertile men. Recently, Lassen et al. [10] examined associations between urinary BPA concentration and reproductive hormones in young men from the general population. The authors found positive associations between urinary BPA concentrations and T, E2, LH and free T levels. BPA and BPS induced significant changes in T and estradiol [26].

Meeker et al. [38] demonstrated that exposure to phthalates may be associated with altered male endocrine function. Urinary concentrations of some phthalates

Metals, namely, Cd, also affect the development of the male reproductive system and testis function. Mice prenatal exposed to Cd showed defects on the development of gonads, depletion of germ cells and impairment of spermatozoa maturation [43]. Cd also induces testicular dysfunction, which results of the functional impairment of SC and LC. Regarding human studies, the effect of Cd exposure to male endocrine function was assessed by several authors (as reviewed by de Angelis et al. [33]).

were inversely associated with T, E2 and FAI.

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

reproductive hormone levels.

**2.3 Testicular dysfunction due to EDC exposure**

compromise the transport of testicular sperm out of the testis, the acquisition of progressive spermatozoa motility and the sperm storage. Moreover, damage at SC and LC levels compromise the structure of the BTB and seminiferous tubules.
