An Investigation of the Endocrine-Disruptive Effects of Bisphenol A in Human and Rat Fetal Testes

Abstract

Few studies have been undertaken to assess the possible effects of bisphenol A (BPA) on the reproductive hormone balance in animals or humans with often contradictory results. We investigated possible direct endocrine disruption by BPA of the fetal testes of 2 rat strains (14.5–17.5 days post-coitum) and humans (8–12 gestational weeks) and under different culture conditions. BPA concentrations of 10-8M and 10-5M for 72h reduced testosterone production by the Sprague-Dawley fetal rat testes, while only 10-5M suppressed it in the Wistar strain. The suppressive effects at 10-5M were seen as early as 24h and 48h in both strains. BPA at 10-7-10-5M for 72h suppressed the levels of fetal rat Leydig cell insulin-like factor 3 (INSL3). BPA exposure at 10-8M, 10-7M, and 10-5M for 72h inhibited testosterone production in fetal human testes. For the lowest doses, the effects observed occurred only when no gonadotrophin was added to the culture media and were associated with a poorly preserved testicular morphology. We concluded that (i) BPA can display anti-androgenic effects both in rat and human fetal testes; (ii) it is essential to ascertain that the divergent effects of endocrine disruptors between species in vitro do not result from the culture conditions used, and/or the rodent strain selected; (iii) the optimization of each in vitro assay for a given species should be a major objective rather than the search of an hypothetical trans-species consensual model-system, as the organization of the testis is intrinsically different between mammalian species; (iv) due to the uncertainty existing on the internal exposure of the human fetal testis to BPA, and the insufficient number of epidemiological studies on the endocrine disruptive effects of BPA, caution should be taken in the extrapolation of our present results to the human reproductive health after fetal exposure to BPA.

Parallel assessment of the effects of bisphenol A and several of its analogs on the adult human testis

“…Therefore, the dose of 10 -5 M of BPA, which was found to significantly inhibit testosterone here, was much higher than the concentrations recorded in the body fluids. The significant BPA-induced anti-androgenicity observed at 10 -5 M in adult human testes was consistent with that obtained with human fetal testes when cultured in the presence of trophic hormone (hCG or LH), which optimizes the organ's integrity (histology and hormone production) during the culture periods investigated both in terms of histology (Ben Maamar et al, 2015) and hormone production (Ben-Maamar et al, 2015;Eladak et al, 2015). The fact that BPA or BPA-A can impact the production of testosterone by the human fetal testis at doses lower than 10 -5 M only appeared in the absence of trophic hormones (N' Tumba-Byn et al, 2012;Ben-Maamar et al, 2015;Eladak et al, 2015).…”

“…The significant BPA-induced anti-androgenicity observed at 10 -5 M in adult human testes was consistent with that obtained with human fetal testes when cultured in the presence of trophic hormone (hCG or LH), which optimizes the organ's integrity (histology and hormone production) during the culture periods investigated both in terms of histology (Ben Maamar et al, 2015) and hormone production (Ben-Maamar et al, 2015;Eladak et al, 2015). The fact that BPA or BPA-A can impact the production of testosterone by the human fetal testis at doses lower than 10 -5 M only appeared in the absence of trophic hormones (N' Tumba-Byn et al, 2012;Ben-Maamar et al, 2015;Eladak et al, 2015). According to the human exposure studies available on BPA-A, equivalent values to those of BPA were found in urine for BPS and BPF, at average levels of about 10 -9 -10 -10 M, (Zhou et al, 2014).…”

“…BPA biotransformation was studied by high-performance liquid chromatography (HPLC) coupled to an online radioactivity detection system using [ 3 H]-BPA as already described (Ben-Maamar et al, 2015).…”

Bisphenol S instead of bisphenol A: a story of reproductive disruption by regretable substitution - a review

“…In a comparative study by Maamar et al (2015), the influence of BPA was studied both on rats and on human fetal testes, and it was determined that in both cases BPA had dose-dependent anti-androgenic effects. Nevertheless, the authors urge caution in interpreting the results obtained on rodents and their application in human medicine (Maamar et al 2015).…”

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“…Endocrine disruptors can cause cancerous tumors, birth defects and other developmental disorders. BPA was shown to be associated with breast and prostate cancers, genital defects in males [6][7][8]. Due to possible low dose effects of unknown toxicological relevance and weekly oestrogenic BPA is the subject of many investigating assessing, its potential toxicity and human exposure for a more conclusive risk assessment [9,10].…”