Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
Toxicol Appl Pharmacol. 2013 May 1;268(3):300-8. doi: 10.1016/j.taap.2013.02.011. Epub 2013 Feb 27.
Bisphenol-A (BPA), a polymer used in plastics manufacturing, and methoxychlor (MXC), a pesticide, are endocrine disrupting compounds with estrogenic and anti-androgenic properties. Prenatal BPA or MXC treatment induces reproductive defects in sheep with BPA causing prepubertal luteinizing hormone (LH) hypersecretion and dampening of periovulatory LH surges and MXC lengthening follicular phase and delaying the LH surge. In this study, we addressed the underlying neuroendocrine defects by testing the following hypotheses: 1) prenatal BPA, but not MXC reduces sensitivity to estradiol and progesterone negative feedback, 2) prenatal BPA, but not MXC increases pituitary responsiveness to gonadotropin releasing hormone (GnRH), and 3) prenatal BPA dampens LH surge response to estradiol positive feedback challenge while prenatal MXC delays the timing of the LH surge. Pregnant sheep were treated with either 1) 5mg/kg/day BPA (produces approximately twice the level found in human circulation, n=8), 2) 5mg/kg/day MXC (the lowest observed effect level stated in the EPA National Toxicology Program's Report; n=6), or 3) vehicle (cotton seed oil: C: n=6) from days 30 to 90 of gestation. Female offspring of these ewes were ovariectomized at 21months of age and tested for progesterone negative, estradiol negative, estradiol positive feedback sensitivities and pituitary responsiveness to GnRH. Results revealed that sensitivity to all 3 feedbacks as well as pituitary responsiveness to GnRH were not altered by either of the prenatal treatments. These findings suggest that the postpubertal reproductive defects seen in these animals may have stemmed from ovarian defects and the steroidal signals emanating from them.
双酚 A（BPA）是一种用于塑料制造的聚合物，甲氧滴滴涕（MXC）是一种杀虫剂，它们都是具有雌激素和抗雄激素特性的内分泌干扰化合物。产前 BPA 或 MXC 处理会导致绵羊的生殖缺陷，BPA 导致青春期前促黄体生成素（LH）分泌过多，并抑制排卵前 LH 激增和 MXC 延长卵泡期并延迟 LH 激增。在这项研究中，我们通过测试以下假设来解决潜在的神经内分泌缺陷：1）产前 BPA 但不是 MXC 降低了对雌二醇和孕酮负反馈的敏感性，2）产前 BPA 但不是 MXC 增加了垂体对促性腺激素释放激素（GnRH）的反应性，3）产前 BPA 抑制了 LH 对雌二醇正反馈的反应，而产前 MXC 延迟了 LH 激增的时间。从妊娠第 30 天到第 90 天，给怀孕的绵羊用以下药物进行处理：1）5mg/kg/天 BPA（产生大约是人类循环中发现的水平的两倍，n=8），2）5mg/kg/天 MXC（美国环保署国家毒理学计划报告中规定的最低观察到的效应水平；n=6），或 3）载体（棉籽油：C：n=6）。这些母羊的雌性后代在 21 个月大时被卵巢切除术，并进行孕激素负反馈、雌二醇负反馈、雌二醇正反馈敏感性以及垂体对 GnRH 的反应性测试。结果表明，这两种产前处理都没有改变对所有 3 种反馈的敏感性以及对 GnRH 的垂体反应性。这些发现表明，这些动物出现的青春期后生殖缺陷可能源于卵巢缺陷和源自卵巢的类固醇信号。
