THE XENOESTROGEN BISPHENOL-A INDUCES GROWTH, DIFFERENTIATION, AND C-FOS GENE-EXPRESSION IN THE FEMALE REPRODUCTIVE-TRACT

The xenoestrogen bisphenol A (BPA) has been shown to mimic estrogen bo th in vivo and in vitro. BPA stimulates PRL secretion and the expressi on of a PRL regulating factor from the posterior pituitary in the estr ogen-sensitive Fischer 344 rat (F344), but not in Sprague-Dawley (SD) rats. The goal of the present studies was to examine the in vivo actio ns of BPA on the reproductive tract. The specific objectives were 1) t o characterize the short term effects of BPA on cell proliferation and c-fos expression in the uterus and vagina, and 2) to compare the effe cts of prolonged exposure to low doses of BPA on the reproductive trac t of F344 and SD rats. Treatment with single high doses of BPA induced cell proliferation in the uterus and vagina of ovariectomized F344 ra ts, as determined by bromodeoxyuridine immunostaining. This proliferat ion was dose dependent (from 37.5-150 mg/kg) and followed a time cours e similar to that of estradiol (E-2). Quantitative RT-PCR revealed tha t both BPA and E-2 increased c-fos messenger RNA levels in the uterus 14- to 16-fold within 2 h, which returned to basal levels after 6 h. I n the vagina, BPA-induced c-fos expression remained elevated for up to 6 h, compared with the transient increase caused by E-2. Treatment of F344 rats for 3 days with continuous release capsules that supplied a much lower dose of BPA (similar to 0.3 mg/kg day) resulted in hypertr ophy, hyperplasia, and mucus secretion in the uterus and hyperplasia a nd cornification of the vaginal epithelium. The reproductive tract of SD rats did not respond to this treatment paradigm with BPA. These stu dies demonstrate that 1) the molecular and morphological alterations i nduced by BPA in the uterus and vagina are nearly identical to those i nduced by estradiol; 2) the vagina appears to be especially sensitive to the estrogenic actions of BPA; 3) the reproductive tract of the inb red F344 rat appears more sensitive to BPA than that of the outbred SD rat; and 4) continuous exposure to microgram levels of BPA is suffici ent for exerting estrogenic actions.