2012 Study Abstract
Endocrine disruptors (ED) have been incriminated in the current increase of male reproductive alterations. Bisphenol A (BPA) is a widely used weak estrogenic environmental ED and it is debated whether BPA concentrations within the average internal exposure are toxic. In the present study we investigated the effects of 10−12 to 10−5 M BPA concentrations on fetal Leydig cell function, as fetal life is a critical period of sensitivity to ED effects on male reproductive function. To this aim, fetal testes from human at 6.5–10.5 gestational weeks (GW) or from rat and mouse at a comparable critical period of development (14.5 days post-coitum (dpc) for rat and 12.5 dpc for mouse) were explanted and cultured using our validated organotypic culture system in the presence or absence of BPA for 1–3 days. BPA concentrations as low as 10−8 M reduced testosterone secretion by human testes from day 1 of culture onwards, but not by mouse and rat testes where concentrations equal to 10−5 M BPA were required. Similarly, 10−8 M BPA reduced INSL3 mRNA levels only in human cultured testes. On the contrary, 10−5 and 10−6 M diethylstilbestrol (DES), a classical estrogenic compound, affected testosterone secretion only in rat and mouse testis cultures, but not in human testis cultures. Lastly, contrarily to the DES effect, the negative effect of BPA on testosterone produced by the mouse fetal testis was maintained after invalidation of estrogen receptor α (ERα). In conclusion, these results evidenced i) a deleterious effect of BPA on fetal Leydig cells function in human for concentrations from 10−8 M upwards, ii) species-specific differences raising concerns about extrapolation of data from rodent studies to human risk assessment, iii) a specific signaling pathway for BPA which differs from the DES one and which does not involve ERα.
2012 Study Conclusions
We show here for the first time that concentrations of BPA as low as 10−8 M are sufficient to reduce fetal testis endocrine activity in humans. The mechanism of action of BPA will need further investigation, but it is likely to involve non-classical estrogen receptors.
The negative effect of BPA on testosterone production and Insl 3 expression during fetal life observed here during the “masculinization programming window”, may have several consequences as it can impair the masculinization of internal and external genitalia , , . Our present results should encourage prospective epidemiological studies to investigate the possible association between environmental exposure to BPA during pregnancy and anogenital distance at birth. Furthermore, BPA-induced reduction of fetal testosterone production may have long-term consequences. Although brain masculinization and the onset of male-specific sexual behaviors start during the second half of pregnancy, we can’t exclude that BPA-induced reduction of fetal testosterone production during the first trimester of pregnancy may influence these parameters . It may also affect the germ cell lineage since androgens control gonocyte development . Thus, it will be relevant to study the effect of BPA on gonocytes since alterations of the germ cell lineage may result in testicular cancer or in reduced sperm production ,  and may also explain the recently reported multigenerational effects of BPA .
Finally, our findings challenge the widespread use of rodent models to assess the toxic effects of EDs and highlight the need for setting up specific tools to study reprotoxicity in humans.
Sources and Full Study
- Differential Effects of Bisphenol A and Diethylstilbestrol on Human, Rat and Mouse Fetal Leydig Cell Function, PLOS one, DOI: 10.1371/journal.pone.0051579, December 17, 2012.
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