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Noteworthily, the chemical structure of BPA is lipophilic; therefore, the effects on adipocytes could be amplified and maintained by its retention in fat mass, establishing a possible vicious circle (96). In the complex and bidirectional relationship between obesity and low testosterone, it is well-demonstrated that adipocytes express aromatase activity which is responsible for testosterone conversion into estradiol (91), which can exert a synergistic inhibitory effect on pituitary secretion of luteinizing hormone (LH) (92, 93). In a study by Matthews et al. (83), BPA, but not the soluble product of its glucuronidation, was able to displace tritiated 17-β estradiol from the estrogenic alpha and beta receptors (ERα and ERβ, respectively). BPA is qualified as a xenoestrogen because it mimics estrogen effects due to its characteristic polycyclic phenolic chemical structure, similar to estradiol (77). It might partially be due to differences in susceptibility to BPA effects across rodent species and strains. A large between-studies heterogeneity in both cumulative effective doses and tolerable daily intakes was observed. Of note, while almost all of bloodstream circulating BPA following oral ingestion is in the conjugated form (50–52), after entering the body via a transdermal route, BPA bypasses the liver metabolism, resulting in significantly higher concentrations of unconjugated form in the bloodstream (50, 53–56).
To investigate the relationship between the inhibition of testosterone synthesis and RCT in mice following BPA exposure, the mRNA expression of Apoa1, Apoa2, and Apoc3 in the testicles was detected using RT-qPCR. These results suggest that the exposure to BPA may enhance RCT, reduce cholesterol levels and lipid droplet accumulation, and ultimately inhibit testosterone synthesis and secretion in mouse testes. In addition, lipid droplet accumulation and free cholesterol (FC) levels in TM3 cells and testes, as well as changes in testosterone synthesis will be assessed. The present study aims to investigate the effects of BPA exposure on the expression of genes and proteins related to cholesterol transport using in vivo and in vitro experiments. As spermatogenesis requires both high intratesticular levels of testosterone and an adequate functionality of the AR (101, 102), it is not surprising that the effects of BPA on testosterone biosynthesis and activity could affect spermatogenic function. Interestingly, the perinatal phase would represent a sensitive exposure window (3), as the treatment of pregnant and nursing dams with BPA decreased intratesticular (77) and circulating (82) testosterone levels of male offspring in adulthood. Effect of BPA exposure on testosterone synthesis in TM3 cells.
Interestingly, authors also found a negative independent association between urinary BPA levels and global methylation degree of sperm DNA, pointing to possible epigenetic consequences of BPA exposure, as already suggested by in vitro studies (125, 126). The in vitro treatment of Leydig cells from adult rat with BPA decreased testosterone biosynthesis as a result of decreased expression of steroidogenic enzymes (77, 86). An interference at hypothalamic–pituitary level of the gonadal axis has been clearly demonstrated in the rat, where, with a few exceptions (65, 76), the administration of BPA significantly lowered both the expression of the GnRH gene in cells of preoptic area (64) and circulating levels of gonadotropins and/or testosterone (64, 69, 70, 77–81). In the last decades, results of preclinical research revealed endocrine-disrupting effects of BPA on male reproductive functions, clarifying possible mechanisms by which BPA can interfere with the regulation of spermatogenesis mainly throughout the hypothalamic–pituitary–gonadal axis.
Similarly, seminal BPA concentrations were positively correlated with E2 and estriol (E3. The evident divergence and, sometimes, opposed association between steroids and BPA in both fluids plasma and seminal suggests that their composition is significantly different . On the other hand, BPA in men with impaired fertility appears to alter hormones levels with detriment of semen parameters. No significant associations were found between any semen parameters and urinary BPA concentration .|However, studies conducted by Stoker et al. and Alboghobeish et al. found a decrease in E2 levels in the blood circulation of adult male rats exposed to BPA. The activation of aromatase is exhibited by the increased gene and protein expression of CYP19A1, which leads to the activation of cAMP. Decreasing testosterone synthesis activates the backdoor pathway, whereby dehydroepiandrosterone (DHEA) is converted into androstenedione (AD). An in vitro study conducted by Eladak et al. found that BPF and BPS at the highest dose (10,000 nmol/L) caused a decrease in the expression of HSD3β1 and CYP17A1 in mFeTA after three days of exposure. BPF and BPAF exposure decreased CYP17 expression in the testis of zebrafish, while 17βHSD was found to be decreased in the testis of adult male zebrafish after 21 days of exposure to BPF 56,74. The 17β-HSD, 3β-HSD, and CYP17A1 protein expression also decreased in the testis of male Sprague-Dawley rats exposed to BPA .}
In this review, we briefly describe the effects of BPA on male reproductive health and discuss the use of antioxidants to prevent or revert the BPA-induced toxicity and infertility in men. Recent studies explored potential approaches to treat or prevent BPA-induced testicular toxicity and male infertility. This compound seems to disrupt hormone signalling even at low concentrations, modifying the levels of inhibin B, oestradiol, and testosterone.
Indeed, it was estimated that at least for humans, the range of exposure to BPA is between 0.4 and 5 ug/kg/day. Several conditions may increase ROS production in testis and sperm, like varicocele or infections, as well as environmental factors or lifestyle (smoking, alcoholism, medication, radiation). Moreover, spermatozoa produce small amounts of ROS as a by-product of the electron transfer chain in mitochondria 109,120. Reduced TRX (TRX-(SH)2) catalyses the reduction of disulphides (S-S) within oxidized proteins, including Prx - Prx-(SH)2.
In particular, male mice exposed to BPA during the preimplantation period (days 1–5 of gestation), showed a reduction of serum and testicular testosterone levels when euthanized at 24 postnatal days and an increase of GnRH mRNA at 35 and 50 postnatal days . This type of studies may be interesting to study the immediate effects of an acute exposure to high levels of BPA; however, whether the concentration and the exposure time used demonstrate what happens at the physiological level and have biological relevance remains questionable. The in vitro exposure of Acipenser ruthenus spermatozoa to concentrations of BPA possibly occurring in nature (0.5–10 µg/kg) resulted in a significant reduction in sperm motility and velocity and an increase in DNA fragmentation, together with higher levels of protein and lipid oxidation and increased SOD activity .

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