Université Paris Diderot, Sorbonne Paris Cité, Laboratory of Development of the Gonads, Unit of Stem Cells and Radiation, Fontenay-aux-Roses, France.
PLoS One. 2012;7(12):e51579. doi: 10.1371/journal.pone.0051579. Epub 2012 Dec 17.
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.
内分泌干扰物 (ED) 被认为是当前男性生殖系统改变的罪魁祸首。双酚 A (BPA) 是一种广泛使用的弱雌激素环境内分泌干扰物，目前仍存在争议，即平均内暴露浓度的 BPA 是否具有毒性。在本研究中，我们研究了 10(-12) 至 10(-5) M BPA 浓度对胎儿睾丸间质细胞功能的影响，因为胎儿期是对 ED 影响男性生殖功能敏感性的关键时期。为此，我们从人类妊娠 6.5-10.5 周 (GW) 或大鼠和小鼠的发育关键时期 (大鼠 14.5 天妊娠 (dpc)，小鼠 12.5 dpc) 取出胎儿睾丸，并用我们验证的器官型培养系统进行离体培养，在有或无 BPA 的情况下培养 1-3 天。低至 10(-8) M 的 BPA 浓度从培养第 1 天开始就降低了人类睾丸的睾酮分泌，但对大鼠和小鼠睾丸没有影响，需要 10(-5) M 的 BPA 浓度。同样，10(-8) M 的 BPA 仅降低了人类培养睾丸中的 INSL3 mRNA 水平。相反，10(-5) 和 10(-6) M 己烯雌酚 (DES)，一种经典的雌激素化合物，仅影响大鼠和小鼠睾丸培养物中的睾酮分泌，而不影响人类睾丸培养物。最后，与 DES 作用相反，BPA 对小鼠胎儿睾丸产生的睾酮的负面影响在雌激素受体 α (ERα) 失活后仍然存在。综上所述，这些结果表明：i) BPA 对人类胎儿睾丸间质细胞功能的有害影响，浓度从 10(-8) M 开始，ii) 种属特异性差异引起对从啮齿动物研究外推到人类风险评估的关注，iii) BPA 的特定信号通路不同于 DES 的信号通路，不涉及 ERα。
