Effects of Early Exposure to Xenoestrogens on the Prostate GlandEPA Grant Number: R826299
Title: Effects of Early Exposure to Xenoestrogens on the Prostate Gland
Investigators: Prins, Gail S.
Institution: University of Illinois at Chicago
EPA Project Officer: Fields, Nigel
Project Period: December 29, 1997 through December 28, 2000
Project Amount: $586,384
RFA: Endocrine Disruptors (1997) RFA Text | Recipients Lists
Research Category: Economics and Decision Sciences , Endocrine Disruptors , Health , Safer Chemicals
Past work with animal models has clearly indicated that brief exposure to natural estrogens during the early developmental period results in permanent alterations of the prostate and dysplasia, hyperplasia and adenoma formation with aging. The present project is designed to test the hypothesis that exposure to certain environmental xenoestrogens during the developmental critical period also permanently imprints the fate of the prostate gland and promotes dysplasia or tumor formation with aging.
A biologically-based-dose-response model will be used in the present studies to determine the mechanism of action of the xenoestrogens on the male prostate gland at the molecular, cellular and functional level resulting from exposure during development. A rat animal model will be used to examine doses of xenoestrogens which permanently alter the prostate gland into adulthood. Negative controls (oil), positive controls (estradiol) and xenoestrogens (methoxychlor, dieldrin and endosulfan, TCB and bisphenyl A) will be administered to newborn rat pups and prostates will be examined by morphometry, histology, flow cytometry and biochemically on days 10, 35, 90 and at 18 months (aged) to identify imprints. Chemicals that imprint the prostate will be further examined for mechanistic details. Imprints of the classic estrogen receptor, the novel estrogen receptor a and the androgen receptor will be evaluated by immunocytochemistry, western analysis, RT-PCR and in-situ hybridization. Finally, the estrogen receptor knock-out mice will be used to discriminate between estrogen receptor a mediated events and those mediated by the newly discovered estrogen receptor a.
Data collected from the proposed experiments will help to elucidate the biological effects of direct exposure to environmental estrogens during the developmentally critical period on the prostate gland. We predict that one or several of the compounds which we test will imprint the prostate in a dose-response manner. Since these chemicals interact with the estrogen receptors, we believe that they may affect the prostate gland in a similar mechanism as natural estrogen when given neonatally. If so, we predict that prostates will exhibit signs of differentiation defects, will bear these imprints into adulthood and may be predisposed to dysplasia and adenoma formation in the aging animal. Thus present proposal will develop an effective animal model for endocrine disruptor-induced human diseases which includes prostate cancer.