The hypothalamus is located at the base of the brain, beneath the thalamus and third ventricle, but above the optic chiasma It is an extremely complex cerebral structure that forms a functional unity with the hypophysis gland to coordinate such functions of the organism as somatic growth, maturation and gonadal function, among others (36). Its neurosecretory cells synthesize and secrete the GnRH neurohormone, which is responsible for stimulating the HHT axis (37, 38). GnRH is a decapeptide secreted by approximately 1000 neurons located in the hypothalamus (arcuate nucleus and middle eminence). It is responsible for stimulating the secretion of gonadotrophins (FSH and LH) by bonding to the membrane receptors in the gonadotrophs of the hypophysis. The neurovascular linkage between the hypothalamus and hypophysis is the hypophysis stalk, which contains the hypothalamic-hypophyseal portal system. The hypophysis gland is located immediately below the hypothalamus, resting on a depression in the base of the cranium called the sella turcica. It is divided into the anterior and posterior hypophysis (39). The FSH and LH secreted by the anterior hypophysis belong to a family of dimeric glycoprotein hormones that share certain structural characteristics (40). Each hormone consists of two sub-units: subunit-α and subunit-β, which are bonded non-covalently. Subunit-α is common to all glycoprotein hormones, but each subunit-β presents a specific sequence of amino acids –111 for FSH and 121 for LH– which gives each one its biological specificity (41). Both FSH and LH act through the classic mechanisms of the protein hormone receptor, which involves transmembrane receptors associated with the G proteins located in organs like the testicle (42).

Several studies have shown that Cd at different concentrations can alter the neuroendocrine function of the hypothalamic-hypophysis axis and so affect the release of various hormones (43-46). While few studies have analyzed Cd’s effects on the hypothalamic secretion of GnRH, some reports indicate that Cd exposure increases the expression of ARNm for GnRH 1 and GnRH 2 in salmon, and of GnRH 2 in Micropterus salmoides (47, 48), while chronic administration (4 weeks) of 5 mg/kg of CdCl₂ in male rats decreased plasma GnRH levels (49).

Regarding Cd’s effect on concentrations of hypophysis hormones, studies in humans show contradictory results. Research on males exposed to Cd in the workplace has found that it reduces FSH secretion after only short exposure periods (50). Other working groups, however, report positive correlations between plasma Cd values and serum LH concentrations, but not with FSH (51). But Cd also reduces concentrations of intrahypophyseal LH (52). Studies in men who suffer from azoospermia or oligospermia associated with infertility have found positive correlations between serum and seminal Cd concentrations and concentrations of FSH (53), but other work failed to find correlations between Cd levels and concentrations of FSH or LH (54-56). Chronic exposure to 50 ppm of Cd introduced into rats’ drinking water reduced serum LH concentrations, but increased FSH (57), while chronic intraperitoneal administration of 1 or 5 mg/kg of CdCl₂ decreased concentrations of both gonadotrophins (49, 58). However, the administration of high doses (4 or 6 mg/kg) in an acute or sub-chronic scheme reduced FSH and LH concentrations (59). It is well-known that Cd produces apoptosis in cells of the anterior hypophysis (60) through the mechanisms described above, and that it modifies total lipid content (44). These effects could, therefore, affect the functions performed by the testicle.

Neurosecretion of GnRH in the hypothalamus is regulated by multiple factors, including neurotransmitters, since it receives information from neurons that produce noradrenaline, dopamine, serotonin (5HT), γ-aminobutyric acid (GABA) and glutamate. There are reports that glutamate and noradrenaline stimulate the HHT axis, while GABA, dopamine and serotonin seem to inhibit it (38, 61-63). Glutamate is an important neurotransmitter that stimulates the GnRH neurons, which are innervated directly by glutamatergic neurons. We also know that the GnRH neurons express receptors for α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate and, though to a lesser extent, N-methyl-D-aspartate receptors (NMDA) (64). Hence, it is considered an activator in the pulsatile release of GnRH, since some reports suggest that stimulation of the NMDA receptors leads to early-onset puberty in rats and monkeys. The increases in glutamate synthesis in the hypothalamus initiate puberty in those species (37, 65, 66). In adult rats, stimulating the NMDA receptors triggers the release of LH via GnRH (67).

GABA, meanwhile, is the neurotransmitter that inhibits mature neurons, though it can also perform inhibiting or stimulating functions on GnRH secretion, depending on changes in its receptors during the development of different individuals (68, 69). GnRH neurons express the GABA_A (70, 71) and GABA_B (72) receptors. In rodents, administering bicuculline (a GABA_A antagonist) and phaclofen (a GABA_B antagonist) reduces the release of GnRH in young animals, but increases it in adults (73).

Regarding noradrenaline, we know that this neurotransmitter contributes to facilitating an increase in the release of GnRH/LH. Also, activation of the α1-adrenergic receptor facilitates the release of noradrenaline, but not α2 or β, while infusions of the α1-adrenergic blocker prazosin into the middle eminence suppress GnRH release (74).

With respect to dopamine, the precise role that it plays in initiating puberty has not yet been established completely, though research has demonstrated that hypothalamic concentrations of dopamine increase before and around puberty onset (75).

Turning to 5HT, we find that it has an inhibitory effect on GnRH synthesis, and there are reports that treatment with 5HT or agonists of the serotonin 1A receptor (5HT1A) and serotonin 2 receptor (5HT2) receptors in male rats reduces the neurons that contain ARNm and codify for GnRH (61).

Exposure to Cd modifies the amounts of neurotransmitters, as has been reported in adult male rats under chronic exposure to high doses of CdCl₂ (25 mg/kg) in drinking water, as they suffered a reduction in 5HT, dopamine and noradrenaline concentrations in the hypothalamus (43, 76). We also know that acute treatment with this same dose of CdCl₂ decreases GABA concentrations in the striate of rats (77), and that chronic treatment in drinking water reduces glutamate concentrations, though without affecting GABA in the hypothalamus (78). These modifications of neurotransmitters could affect GnRH secretion.

Testicle development is controlled by a hormonal balance in a microenvironment of somatic and germinal cells that involves cell-to-cell interactions and hormonal signaling by the FSH and LH secreted by the hypophysis (79). It is well-known that while FSH is important for controlling the proliferation of Sertoli cells and inducing spermatogenesis (39, 80, 81), LH is required for steroidogenesis because it stimulates the membrane receptor in the Leydig cells which, in turn, stimulates the enzymatic conversion of cholesterol into T (39). T synthesis and spermatozoid production are the testicle’s principle functions, and both are affected by exposure to Cd. The decrease of androgens can alter not only the morphology and functioning of the testicle but also the morphophysiology of the epididymis and accessory glands and reproductive parameters, including fertility.

4.3.1. The testicle

The testicle is the organ that generates gametes; that is, the male sexual cells called spermatozoids. But it is also capable of synthesizing T; hence, it is considered the primary male sex gland. Testicles are found in pairs, are oval-shaped and covered by a layer of connective tissue called the tunica albuginea that invaginates inside the testicular body to form the testicular mediastinum and septa. The septa separate the testicle into lobes that contain the seminiferous tubules, the site where spermatogenesis –or spermatozoid synthesis– takes place. Spermatogenesis refers to the process of spermatozoid production and their subsequent differentiation from round diploid cells to haploid cells with the characteristic form of spermatozoids. This process is divided into three main phases: 1) mitosis; 2) meiosis; and 3) differentiation. The first phase is also called spermatocytogenesis. During this process, type A spermatogonia divide repeatedly by mitosis to produce other spermatogonia of the same type, which serves to maintain a cellular reserve. These type A spermatogonia then give rise to the type B spermatogonia, which are also divided by mitosis to produce more type B spermatogonia. Studies speak of the “maturation” of the type B spermatogonia because they increase in size and will be transformed into primary spermatocytes. Upon reaching this state, they migrate to the adluminal compartment of the seminiferous tubule, where they will undergo the first meiotic division. Secondary spermatocytes are obtained as a result of this first meiotic division, while spermatids result from the second meiotic division. The phase of differentiation, or spermiogenesis, occurs when the round spermatids are differentiated into spermatozoids. Sertoli cells are of great importance in this, and all, stages of spermatogenesis. They are located in the seminiferous tubules where they provide physical support for germinal cells and maintain the tubular environment to allow the differentiation of spermatocytes into spermatozoids (82).

Although Cd can damage several organs, the testicles are the main targets of Cd toxicity (83, 84), since this metal can migrate to, and cause alterations in, these organs (85) because they are particularly susceptible to the effects of oxidative stress due to their high content of polyunsaturated fatty acids (86). Figure 2 summarizes the principle affectations of the testicle caused by Cd exposure, especially the reduction of testicular size and mass (87-89). Cd exposure reduces the diameter and length of the seminiferous tubules (88, 90, 91). This is explained by their high content of germinal cells that die by apoptosis (89, 92-102), which in some cases is observed as vacuolization of the epithelium, or even the complete loss of cell layers from the germinal epithelium (88, 99). This causes interstitial edema and hemorrhaging, together with a marked reduction in the height of the epithelium and its calcification (90, 91, 103). In this regard, alterations have been seen in all cells of the germinal epithelium, including unusual morphologies in all cell types and decreases in the number of spermatogonia and spermatocytes (90, 91, 104-106). But Cd also induces poor orientation and the loss of cellular polarity in the development of spermatids in adult rats (107); a finding that may be associated with failures in spermiation (107) caused by the release of immature cells (104-106).

Figure 2

Principle damage that cadmium causes in the testicles. All these forms of damage can be explained by the involvement of reactive oxygen species (ROS), because exposure to Cd increases oxidative stress in the testicle, determined as lipoperoxidation.

Sertoli cells play a crucial role in the process of spermatogenesis by participating from the differentiation stage of the germinal cells through to their maturation as spermatozoids. Thus, any changes that these cells suffer due to Cd exposure will affect this process directly. There are reports that, like Leydig cells, Sertoli cells are highly vulnerable to damage by Cd (105, 108), which can even inhibit their proliferation (109) and decrease the number of cells available (90). This can occur because Cd has been identified as an apoptosis-inducer (110). Other reports on Sertoli cells indicate that Cd causes an expansion of the endoplasmic reticulum, mitochondrial dilatation, vacuolization and DNA damage in birds and mammals like rodents and hogs (100,106,109,111). Another well-known effect of Cd is that it interacts with extracellular Ca binding domains present in E-cadherins (103), which are the principle molecules of cellular adhesion like those found between Sertoli cells as part of the blood-testicle barrier (BTB), and between Sertoli cells and germinal cells. The union of E-cadherin with Cd interrupts this cell-cell binding (100). Also, Sertoli cells from human cells, after forming an epithelium, were used as a model to determine the effects of Cd on BHT. In this study, Sertoli cells were sensitive to Cd toxicity, as well as changes in localization in cell adhesion proteins caused by alterations in the cytoskeleton, especially the depolarization of the F-actin filaments caused by the delocalization of the proteins: Eps8 (substrate of the epidermal growth factor 8 receptor pathway) and the branched actin polymerization protein. Furthermore, Cd prevented endocytic vesicle trafficking and the delocalization of c-Src and annexin II proteins (actin regulatory proteins) (112). In addition, administering Cd can reduce spermatogenesis by affecting the permeability of the BTB (107, 113), which is regulated by certain tight bonds: occludin, N-cadherin and vimentin (100). Leydig cells can also be affected in males exposed to Cd, for studies show abnormalities and reductions in the number of cells in those individuals (87, 90). These affectations include dilatation of the mitochondria, vacuolization in the cytoplasm and DNA damage (114, 115).

Additionally, to these effects Cd reduces the effectiveness of the antioxidant defense system by decreasing the enzymatic activity of SOD, CAT and GPX, as well as that of GSH. This means that levels of oxidative stress in rats’ testicles will rise due to alterations of the antioxidant system (116). For this reason, when organisms have been exposed to Cd, Zn can be utilized to reduce this metal’s effects by competing with Cd. However, many enzymes require Zn to be activated (117), so it has been associated with numerous enzymes in the body that can prevent damage by activating the antioxidant system (118-121).

Most reports on Cd’s effects on sperm quality are based on studies of humans exposed to Cd, or experiments that exposed rats and mice to this metal (Table 1). Observations show that individuals exposed to Cd have low sperm concentrations, motility and vitality, accompanied by a higher number of sperm abnormalities (159-163). In addition, infertile patients have Cd in the bloodstream, and studies have determined that as Cd concentrations rise, sperm concentrations and motility decline (162,164). In this regard, when Cd is administered to rats and mice, they also present low sperm concentrations and motility, accompanied by an increase in the incidence of sperm abnormalities (124, 136, 152, 159, 162). Research on another sperm parameter studied in mice exposed to Cd –apart from concentration, motility and vitality, all of which decrease under exposure to Cd– has found marked increases in the number of abnormalities in

the heads of the spermatozoids, associated with a premature acrosomal reaction and an increase in DNA fragmentation (165). Certain studies help us understand the mechanisms through which Cd causes alterations in sperm parameters. Thus, we know that while sperm motility can be affected by various mechanisms, one of the most important ones is Cd, because it is the principle competitor of Ca, an especially important regulator of sperm motility (166, 167). Here, studies with mice have demonstrated that the activity of the CatSper channel is modified by Cd exposure and that this affects sperm motility (136, 168). In addition to this, however, Cd can also reduce levels of sialic acid (the terminal carbohydrate of the glycoproteins) in spermatozoids (169). Sialic acid is important because it enhances sperm motility by preventing “friction”. But Cd also increases ROS concentrations (149) that, according to some reports, can cause oxidative stress that damages the spermatozoids’ membrane and alters tyrosine phosphorylation in the sperm. This further diminishes sperm motility and their capacity to fuse with the oocyte, thus interfering with the fertilization process (170). Cd, however, is not an active metal in the redox system; that is, it does not generate ROS through a pathway similar to the Fenton reaction. Rather, Cd can bond to the sulfhydryl groups of ROS regulators, like GSH, to prevent them from functioning as antioxidants. This allows the ROS to increase –indirectly– and generate greater oxidative stress (171, 172).

Puberty is a period that comprises a complex series of changes that lead to sexual maturation and the acquisition of reproductive capacity (179). Its onset is controlled by a sophisticated regulatory system in which the brain centers –hypothalamus and hypophysis– govern the peripheral sex glands: the testicles in males. GnRH secretion is of two distinct types: pulsatile and cascade (180), but the latter occurs only in females. The pulsatile mode refers to the episodic release of GnRH through distinct pulsations of GnRH secretion into the circulation portal, while GnRH levels are undetectable during the inter-pulse intervals (181). The precise neuroendocrine detonator of puberty is GnRH which, in turn, is stimulated by kisspeptin (KISS1) (39). During this process, the HHT axis is characterized by a marked increase in the secretion of pulsations of LH that stimulate the testicles to secrete T (39). As puberty advances, the gonadotropins begin to secrete continuously, bringing sexual development to completion (39). KISS1 was identified in 2003 as a 54-amino acid codified peptide and, with its receptor (KISS1R, or GPR54), is now recognized as the key actor in the HHT axis (182). KISS1 is synthesized and secreted by hypothalamic nuclei in the arcuate nucleus and anteroventral periventricular nucleus (183). There are reports that stimulation of the GnRH neurons by KISS1 activates the hypothalamic-hypophysis-gonad (HHG) axis and secretion of gonadotrophins in the hypophysis (184). We also know that the expression of KISS1 and its receptor increases during puberty in rodents and primates (185, 186). Therefore, administering KISS1 in animals –both males and females– can stimulate the secretion of GnRH and gonadotropins (187).

The rat is a useful animal for studying sexual development, and one widely used to analyze the mechanisms that underlie the process of sexual maturation, which are quite similar across numerous species and so can be extrapolated to other animals, including humans. The mechanisms involved in sexual development include the onset of gonadotropin secretion, the action mechanisms of the sex steroids, and positive and negative feedback circuits (188). In male rats, puberty is considered the stage in which fertility becomes evident, which occurs between days 42 and 49 of postnatal life (188, 189). This phase is associated with behavioral events like genital grooming (GG), which consists of licking the testicles, penis and anogenital region. This behavior intensifies between 46 and 48 days of age (190-192), and its frequency is regulated by LH and T levels (193).

Turning now to the context of male sexual behavior, studies have described that for intromissions to occur, there must be penile reflexes that include erections and dorsiflexion of the penis, described as fast whipping (190, 194). This also requires the formation of a cup in the penis (i.e., the broadening of the glans penis associated with the moment of ejaculation). It is well-known that in prepubescent male rats there is a close relation between circulating T concentrations and the development of penile reflexes (195, 196). Another marker of puberty in males is preputial separation (PS), which occurs in the peripubertal stage, and becomes evident when the prepuce begins to gradually retract from day 41 to day 47 of life (192, 197).

There are reports that peripubertal exposure to Cd affects the functioning of the HHT axis by reducing the weight of the male sex organs –testicles, epididymis, seminal vesicle, prostate– and decreasing blood T levels in adulthood (132). We also know that prenatal administration of Cd affects some puberty markers in male rats, and studies report that administering high doses of CdCl₂ (10 and 20 mg/Kg) to gestating mothers delays the descent of the testicles in their offspring (198), although other reports have found that maternal exposure to Cd advances this parameter (199). Several other puberty markers, however, remain to be evaluated, including PS and GG, so that exposure to Cd in the perinatal stage could still be found to affect the onset of puberty. Studies in young humans living in contaminated zones of Italy found a delay in the onset of puberty accompanied by a decrease in testicular volume and low T levels (200). However, no one has yet analyzed whether these findings affect the first pulse of GnRH or KISS1 in this stage. In this regard, some studies have found that exposure to Cd and other contaminants increases the expression of KISS1 in the human placenta (201).

In recent years, we have learned that many environmental compounds mimic the physiological activity of estrogens. These include xenoestrogens, phytoestrogens and metalloestrogens (217). Cd is a predominant environmental contaminant that is reported to have effects as a potent metalloestrogen (218) which mimics the activity of the estrogenic hormones (219-222) by bonding to the nuclear-type ERs denominated ERα and estrogen receptor beta (ERβ) (216, 220, 223-229), and to the transmembrane estrogen receptor GPR30 (228, 230). ERα and ERβ are codified by distinct genes and their expression varies with the type of tissue involved. ERα is expressed predominantly in reproductive organs like the uterus, breast and ovaries, as well as in the liver and central nervous system, while the β form is expressed mainly in other tissues, including bone, the endothelium, the lung and the urogenital tract, but also the ovaries, the central nervous system and the prostate (231, 232). In the absence of the hormone, ERα is sequestered in an inactive compound and repressed by such molecular chaperones as thermal shock proteins. But the union with the hormone induces a change in the conformation of the ligand-binding domain that releases the receptor from the inactive compound and, as a result, eliminates the masking effect of the ligand-binding domain. The receptor is dimerized and later bonds to the response elements of the DNA in a complex process that requires recruiting coactivators of steroid receptors (SRC-1, SRC-2 and SRC-3) (233). Once bonded, the coactivators recruit the co-integrator p300/CBP (CREB-binding protein). The co-regulator compound then stimulates transcription by remodeling the chromatin through its ability to acetylate histones and interact with the machinery of basal transcription (234).

Using transitory transfection assays to block the union of 17βestradiol to ERα in a non-competitive manner, studies have demonstrated that Cd activates ERα (219, 220, 225, 227). This suggests that it interacts with the receptor’s ligand-binding domain. The amino acids cys381, cys447, glu523, his524 and asp538 have been identified as possible interaction sites of Cd with the ERα's ligand-binding domain (235). These amino acids, which play a role in the interaction of Cd with ERα, are located in the H4, H8, H11 helixes and the interface of the loop with the H12 helix. In this way, Cd’s interaction with different amino acids can promote localized folding, as in the case of the zinc finger domain, or the assemblage of different regions of the protein in a domain (235). Finally, the effects of Cd can be blocked by an anti-estrogen, suggesting that this metal’s effects are mediated by the genomic ERα pathway and activate the non-genomic ERα pathway through ERK1/2 and Akt (216, 228).

Like E₂, Cd induces cellular proliferation (216, 219, 225) and increases the transcription and expression of estrogen-regulated genes, such as the progesterone receptor (PR) (216, 219, 225). In fact, in studies with rodents Cd begins to mimic the effects of E₂ in target organs (236) after just one intraperitoneal injection of 5 μg/kg of CdCl₂. In ovariectomized female Sprague-Dawley rats, an increase in the net uterine weight was observed, accompanied by a proliferative response by the endometrium, which promotes the growth and development of the mammary glands and induces hormone-regulated genes. Also, the female descendants of those rats experienced early onset puberty (236).

Various reports indicate that Cd has a potential role in the development of hormone-dependent cancers (218, 219, 221, 222, 230). For example, in utero exposure to Cd increases the risk of developing breast cancer. Parodi et al. (237) observed that treating pregnant female rats with Cd altered the development of the mammary gland before the onset of puberty in female offspring by increasing the number of mother/progenitor cells, cell density and REα expression, all of which increase the risk of developing breast cancer. Finally, in vitro tests have demonstrated that Cd has proliferative action in human prostate cells through an estrogen-dependent mechanism that increases ERα and ERβ expression independently of the androgens (238).

Other research has shown that prostate tumors can be induced experimentally by oral exposure to Cd (157). While some important epidemiological reports indicate a relation between Cd exposure and rates of prostate cancer, their findings have been refuted (239). Over the past decade, research has shown that Cd has potent androgenic-type activities both in vivo and in vitro by bonding directly to AR. In transfection assays, Cd activates a chimera that contains the ligand-binding domain of AR (240), allowing it to bond to the ligand-binding domain with a high degree of affinity (240, 241) and to block androgen’s union to the receptor. Moreover, it can compete with DHT, the natural ligand of AR (240). The union of Cd with AR modifies the conformation of the receptor (242), and so could change its transcription potential. Scatchard analysis demonstrated that Cd binds to AR with a dissociation constant in an equilibrium of 1.19 × 10^-10 M. Work with cell lines has shown changes in AR activity or AR expression when cells are exposed to Cd (240, 243-245). Epidemiological studies evaluating the relation between Cd and AR have analyzed blood, toenails and urine, exposure to Cd and indirect measurements of the function of AR, such as the level of the specific prostate antigen in serum (246-249). To date, however, these approaches have produced only mixed results, while failing to confirm any clear interaction between Cd exposure and AR signaling in the human prostate. Evidence from basic scientific studies suggests that Cd may play a role in prostate cancer by interrupting AR, a hormone-activated transcription factor that is the key driver of the progression of cancer in that organ (250) although, ironically, AR is necessary for normal prostate growth and development. Finally, research has demonstrated that prostate tumors can be induced experimentally by oral exposure to Cd (251).

Testosterone (4-androstenol, 14-ol, 3-one) is a steroid hormone belonging to the family of the androgens, with a structure derived from cyclopentanoperhydrophenanthrene. It is composed of 19 carbon atoms, with methyl groups at carbons 10 and 13, and a hydroxyl group at carbon 17 (252). This hormone is synthesized from cholesterol in the Leydig cells in the testicles (253). The biosynthesis of T is subject to short-term regulation controlled by LH, which binds to specific receptors on the surface of the Leydig cells and stimulates cAMP production. cAMP performs two principle activities in controlling steroidogenesis in the Leydig cells. The first is to acutely stimulate the biosynthesis of T by translocating cholesterol from the external mitochondrial membrane towards the internal one, which generates the synthesis of pregnenolone through the action of the cytochrome enzyme P450scc/CYP11A1 (cholesterol side cleavage enzyme), which is found in the internal mitochondrial membrane. cAMP’s second action is to activate A kinase (PKA) that, through the phosphorylation of transcription factors related to the activation of genes that codify for steroidogenic enzymes, phosphorylates proteins involved in transporting cholesterol towards the mitochondria, as is the case of the StAR protein (steroidogenic acute regulatory protein) (254). Pregnenolone is biotransformed into progesterone by the 3βhydroxysteroid dehydrogenase Δ4-5 isomerase enzyme (3β-HSD) (252). Then the progesterone obtained through the Δ4 pathway is transformed into androstenedione by the enzymatic compound 17α hydroxylase C17-20 lyase, which is dependent on cytochrome P-450 (P-450c17). The final step in T synthesis is regulated by the microsomal enzyme 17β-hydroxysteroid dehydrogenase (17βHSD), which catalyzes the conversion of androstenedione into T. The endogenous production of steroids in the Leydig cells regulates the expression of the enzymes involved in T biosynthesis (253).

Multiple studies show that exposure to Cd can affect various enzymes that participate in T synthesis; for example, chronic exposure to CdCl₂ in adult male rats increased testicular cholesterol (255) but, in contrast, decreased expression of the ARNm of class B type I Scavenger receptor (SR-BI), which facilitates the capture of cholesterol esters (256) from the StAR protein (257, 258), since Cd increases the activation of the cAMP-responsive element-binding protein (CREB) transcription factor (258). In addition, Cd reduces the expression and activity of the 3β-HSD and 17β-HSD enzymes (255, 259), while decreasing the expression ARNm by the CYP11A1, 17α-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD), which intervene in steroidogenesis in the Leydig cells (256) (Figure 3). The result of this complex process is a decrease in T synthesis that has been amply reported after exposure to Cd (132).

Figure 3

Damage of cadmium in testicular steroidogenesis. Cadmium can affect various enzymes that participate in T synthesis by reducing the expression and activity of 3β-HSD and 17β-HSD, which interfere in steroidogenesis, specially in the Leydig cells, the result of this process is a decrease in T.