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Department of Cell Biology, University of Cincinnati College of Medicine (N.A.M., D.L.A., N.B.J.), Cincinnati, Ohio 45267; and the Department of Obstetrics and Gynecology, Indiana University School of Medicine (R.S., A.G., R.M.B.), Indianapolis, Indiana 46202
Address all correspondence and requests for reprints to: Dr. Nira Ben-Jonathan, Department of Cell Biology, University of Cincinnati Medical School, 231 Bethesda Ave, Cincinnati, Ohio 45267-0521.
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 (
0.3 mg/kg·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.
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