State Key Laboratory of Reproductive Medicine Department of Physiology, Nanjing Medical University, Hanzhong Road 140, Nanjing 210029, China MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
J Endocrinol. 2014 Apr 22;221(2):201-13. doi: 10.1530/JOE-13-0475. Print 2014 May.
Bisphenol-A (BPA), an environmental estrogen, adversely affects female reproductive health. However, the underlying mechanisms remain largely unknown. We found that oral administration (p.o.) of BPA (20 μg/kg) to adult female mice at proestrus, but not at estrus or diestrus, significantly increased the levels of plasma E₂, LH and FSH, and Gnrh mRNA within 6 h. The administration of BPA at proestrus, but not at diestrus, could elevate the levels of Kiss1 mRNA and kisspeptin protein in anteroventral periventricular nucleus (AVPV) within 6 h. In contrast, the level of Kiss1 mRNA in arcuate nucleus (ARC) was hardly altered by BPA administration. In addition, at proestrus, a single injection (i.c.v.) of BPA dose-dependently enhanced the AVPV-kisspeptin expression within 6 h, this was sensitive to E₂ depletion by ovariectomy and an estrogen receptor α (ERα) antagonist. Similarly, the injection of BPA (i.c.v.) at proestrus could elevate the levels of plasma E₂, LH, and Gnrh mRNA within 6 h in a dose-dependent manner, which was blocked by antagonists of GPR54 or ERα. Injection of BPA (i.c.v.) at proestrus failed to alter the timing and peak concentration of LH-surge generation. In ovariectomized mice, the application of E₂ induced a dose-dependent increase in the AVPV-Kiss1 mRNA level, indicating 'E₂-induced positive feedback', which was enhanced by BPA injection (i.c.v.). The levels of Erα (Esr1) and Erβ (Esr2) mRNAs in AVPV and ARC did not differ significantly between vehicle-and BPA-treated groups. This study provides in vivo evidence that exposure of adult female mice to a low dose of BPA disrupts the hypothalamic-pituitary-gonadal reproductive endocrine system through enhancing AVPV-kisspeptin expression and release.
双酚 A（BPA），一种环境雌激素，对女性生殖健康有不良影响。然而，其潜在机制在很大程度上尚不清楚。我们发现，在动情前期给成年雌性小鼠口服（p.o.）BPA（20μg/kg），而不是在动情期或动情后期，可在 6 小时内显著增加血浆 E₂、LH 和 FSH 水平以及 Gnrh mRNA 的水平。在动情前期给予 BPA 可在 6 小时内增加前脑室下核（AVPV）中 Kiss1 mRNA 和 kisspeptin 蛋白的水平，而在动情后期则不行。相比之下，BPA 给药对弓状核（ARC）中 Kiss1 mRNA 的水平几乎没有影响。此外，在动情前期，单次注射（i.c.v.）BPA 可在 6 小时内剂量依赖性地增强 AVPV-kisspeptin 的表达，这对卵巢切除术引起的 E₂耗竭和雌激素受体 α（ERα）拮抗剂敏感。同样，在动情前期给予 BPA（i.c.v.）可在 6 小时内以剂量依赖性方式升高血浆 E₂、LH 和 Gnrh mRNA 的水平，这一作用被 GPR54 或 ERα 的拮抗剂阻断。在动情前期给予 BPA（i.c.v.）注射未能改变 LH 激增产生的时间和峰值浓度。在卵巢切除小鼠中，E₂的应用引起 AVPV-Kiss1 mRNA 水平的剂量依赖性增加，表明“E₂诱导的正反馈”，这一作用被 BPA 注射（i.c.v.）增强。AVPV 和 ARC 中的 Erα（Esr1）和 Erβ（Esr2）mRNA 水平在对照组和 BPA 处理组之间没有显著差异。本研究提供了体内证据，表明暴露于低剂量 BPA 的成年雌性小鼠通过增强 AVPV-kisspeptin 的表达和释放来破坏下丘脑-垂体-性腺生殖内分泌系统。
