Bisphenol A enhances kisspeptin neurons in anteroventral periventricular nucleus of female mice

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 mg/kg) to adult female mice at proestrus, but not at estrus or diestrus, significantly increased the levels of plasma E-2, 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 alpha(ER alpha) 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 ER alpha. 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 Er alpha (Esr1) and Er beta (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.