The Xenoestrogen Bisphenol A Induces Growth, Differentiation, and c-fos Gene Expression in the Female Reproductive Tract*

Abstract

The xenoestrogen bisphenol A (BPA) has been shown to mimic estrogen both in vivo and in vitro. BPA stimulates PRL secretion and the expression of a PRL regulating factor from the posterior pituitary in the estrogen-sensitive Fischer 344 rat (F344), but not in Sprague-Dawley (SD) rats. The goal of the present studies was to examine the in vivo actions of BPA on the reproductive tract. The specific objectives were 1) to characterize the short term effects of BPA on cell proliferation and c-fos expression in the uterus and vagina, and 2) to compare the effects of prolonged exposure to low doses of BPA on the reproductive tract of F344 and SD rats. Treatment with single high doses of BPA induced cell proliferation in the uterus and vagina of ovariectomized F344 rats, as determined by bromodeoxyuridine immunostaining. This proliferation was dose dependent (from 37.5-150 mg/kg) and followed a time course similar to that of estradiol (E2). Quantitative RT-PCR revealed that both BPA and E2 increased c-fos messenger RNA levels in the uterus 14- to 16-fold within 2 h, which returned to basal levels after 6 h. In the vagina, BPA-induced c-fos expression remained elevated for up to 6 h, compared with the transient increase caused by E2. Treatment of F344 rats for 3 days with continuous release capsules that supplied a much lower dose of BPA (approximately 0.3 mg/kg x day) resulted in hypertrophy, hyperplasia, and mucus secretion in the uterus and hyperplasia and cornification of the vaginal epithelium. The reproductive tract of SD rats did not respond to this treatment paradigm with BPA. These studies demonstrate that 1) the molecular and morphological alterations induced by BPA in the uterus and vagina are nearly identical to those induced by estradiol; 2) the vagina appears to be especially sensitive to the estrogenic actions of BPA; 3) the reproductive tract of the inbred F344 rat appears more sensitive to BPA than that of the outbred SD rat; and 4) continuous exposure to microgram levels of BPA is sufficient for exerting estrogenic actions.

A Synthetic Antagonist for the Peroxisome Proliferator-activated Receptor γ Inhibits Adipocyte Differentiation

“…BADGE is also present in sealants used in dentistry (14). Because bisphenol A is a known xenoestrogen (15) and endocrine disrupter, it will therefore be important to monitor the possible environmental implications (16) of BADGE exposure in light of its new function as a PPAR␥ antagonist.…”

The Endocrine Disrupters Butyl Benzyl Phthalate and Bisphenol A Increase the Expression of Progesterone Receptor Messenger Ribonucleic Acid in the Preoptic Area of Adult Ovariectomized Rats

“…Most of these studies suggest that BBP and BPA exposure during differentiating and developmental stages exert irreversible effects on the reproductive organs as well as on the hypothalamic structures controlling reproductive functions. Very few data, however, are available as to their possible action on the hypothalamo-pituitary-gonadal axis in adults, except one report claiming that injection of BPA induced c-fos expression in the uterus and the vagina of adult ovariectomized (OVX) Fisher 344 rats [8]. …”

Nongenomic actions of estrogens and xenoestrogens by binding at a plasma membrane receptor unrelated to estrogen receptor α and estrogen receptor β

“…Yet, a direct link between an estrogen membrane binding site (9) and xenoestrogen actions is still a matter of debate. Moreover, despite the great number of studies about nongenomic actions of estrogens, a clear outline of the membrane receptor involved is still elusive.We have chosen three widely used xenoestrogens for our study: bisphenol-A (BPA), which is found in the content of canned food, dental sealants, and composites; diethylstilbestrol (DES), a synthetic estrogen used between the 1940s and the 1970s to prevent miscarriages; and the well-known pesticide (3,(10)(11)(12). We have focused our research on the effect of these agents on the signaling system of pancreatic ␤ cells, which are fundamental for the endocrine pancreas function.…”