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Toxicological Sciences 56, 332-339 (2000)
Copyright © 2000 by the Society of Toxicology

Bisphenol A-Induced Increase in Uterine Weight and Alterations in Uterine Morphology in Ovariectomized B6C3F1 Mice: Role of the Estrogen Receptor

Andriana D. Papaconstantinou*, Thomas H. Umbreit{ddagger}, Benjamin R. Fisher{ddagger},1, Peter L. Goering{ddagger}, Nicholas T. Lappas{dagger} and Ken M. Brown*,2

* Departments of Biological Sciences and {dagger} Forensic Sciences, George Washington University, Washington, DC 20052; and {ddagger} Center for Devices and Radiological Health, Food and Drug Administration, Rockville, Maryland, 20857

The ability of the environmental xenoestrogen bisphenol A (BPA) to increase uterine wet weight in the rodent remains controversial, and few studies have previously examined the effects of BPA on uterine morphology. Furthermore, it is not known whether BPA-induced uterotrophic effects are, similarly to ß-estradiol (E2), mediated through the estrogen receptor (ER). In this study, we compared the effects of BPA on uterine wet weight and morphology to those of E2 in the B6C3F1 ovariectomized mouse. To examine whether these effects were mediated through the ER, the antiestrogen ICI 182,780 (ICI) was co-administered with BPA or E2. We report that subcutaneous administration of BPA at doses between 0.8 and 8 mg/day over 4 days significantly increased mean uterine wet weights above those of vehicle (corn oil)-treated mice. The uterine weight data suggest that BPA acts as a partial agonist with an EC50 of 0.72 mg/day compared to 19.4 ng/day for E2. BPA (2 mg/day) and E2 (40 ng/day) induced a significant increase in luminal epithelial height and in the thickness of both the stromal and myometrial layers of the uterus. The effects of 40 ng E2/day on all endpoints studied were reversed by 20 µg ICI/day. ICI at 200, but not 20 µg/day, was able to reverse the BPA (2 mg/day)-induced increase in both uterine wet weight and luminal epithelial height. ICI alone at 200 µg/day stimulated an increase in thickness of both the stroma and myometrium and did not reverse the effects of BPA (2 mg/day) on these layers. These results suggest that the BPA-induced increase in uterine wet weight and in luminal epithelial height in the ovariectomized B6C3F1 mouse are mediated by the ER.

Key Words: bisphenol A (BPA); ICI 182,780 (ICI); ß-estradiol (E2); estrogen receptor (ER); uterotrophic effects; uterine weight; myometrium; stroma; luminal epithelium; B6C3F1 mouse.


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