Reproductive Toxicology Branch, TA Division, National Health and Environmental Effects Research Laboratory, ORD, U.S. Environmental Protection Agency Office of Research and Development, Research Triangle Park, North Carolina 27711, USA.
Toxicol Sci. 2010 Mar;114(1):133-48. doi: 10.1093/toxsci/kfp266. Epub 2009 Oct 28.
Many chemicals released into the environment display estrogenic activity including the oral contraceptive ethinyl estradiol (EE2) and the plastic monomer bisphenol A (BPA). EE2 is present in some aquatic systems at concentrations sufficient to alter reproductive function of fishes. Many concerns have been raised about the potential effects of BPA. The National Toxicology Program rated the potential effects of low doses of BPA on behavior and central nervous system (CNS) as an area of "some concern," whereas most effects were rated as of "negligible" or "minimal" concern. However, the number of robust studies in this area was limited. The current study was designed to determine if maternal exposure to relatively low oral doses of EE2 or BPA in utero and during lactation would alter the expression of well-characterized sexually dimorphic behaviors or alter the age of puberty or reproductive function in the female Long-Evans rat offspring. Pregnant rats were gavaged with vehicle, EE2 (0.05-50 microg/kg/day), or BPA (2, 20, and 200 microg/kg/day) from day 7 of gestation to postnatal day (PND) 18, and the female offspring were studied. EE2 (50 microg/kg/day) increased anogenital distance and reduced pup body weight at PND2, accelerated the age at vaginal opening, reduced F1 fertility and F2 litter sizes, and induced malformations of the external genitalia (5 microg/kg). F1 females exposed to EE2 also displayed a reduced (male-like) saccharin preference (5 microg/kg) and absence of lordosis behavior (15 microg/kg), indications of defeminization of the CNS. BPA had no effect on any of the aforementioned measures. These results demonstrate that developmental exposure to pharmacologically relevant dosage levels of EE2 can permanently disrupt the reproductive morphology and function of the female rat.
许多释放到环境中的化学物质具有雌激素活性，包括口服避孕药炔雌醇（EE2）和塑料单体双酚 A（BPA）。EE2 存在于某些水生系统中，浓度足以改变鱼类的生殖功能。人们对 BPA 的潜在影响提出了许多担忧。国家毒理学计划将低剂量 BPA 对行为和中枢神经系统（CNS）的潜在影响评为“值得关注”的领域，而大多数影响则被评为“微不足道”或“最小”的关注。然而，该领域的大量研究数量有限。本研究旨在确定母体在宫内和哺乳期暴露于相对低剂量的 EE2 或 BPA 是否会改变特征明显的性二态行为的表达，或改变雌性长耳大仓鼠后代的青春期或生殖功能的年龄。从妊娠第 7 天到产后第 18 天，给怀孕的大鼠灌胃载体、EE2（0.05-50μg/kg/天）或 BPA（2、20 和 200μg/kg/天），并对雌性后代进行研究。EE2（50μg/kg/天）增加了肛殖距离，降低了出生后第 2 天的幼鼠体重，加速了阴道开口的年龄，降低了 F1 的生育力和 F2 的窝产仔数，并诱导了外生殖器的畸形（5μg/kg）。暴露于 EE2 的 F1 雌性也表现出蔗糖偏好减少（5μg/kg）和缺乏背屈行为（15μg/kg），表明中枢神经系统去女性化。BPA 对上述任何指标均无影响。这些结果表明，发育过程中暴露于药理学相关剂量水平的 EE2 可永久性破坏雌性大鼠的生殖形态和功能。
