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Published online on May 2, 2005, 10.1073/pnas.0502544102 OPEN ACCESS ARTICLE


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Physiology
Estrogenic chemicals in plastic and oral contraceptives disrupt development of the fetal mouse prostate and urethra

( bisphenol A | ethinylestradiol | urogenital sinus )

Barry G. Timms *, Kembra L. Howdeshell {dagger}, Lesley Barton *, Sarahann Bradley *, Catherine A. Richter {dagger}, and Frederick S. vom Saal {dagger}{ddagger}

*Division of Basic Biomedical Sciences, University of South Dakota School of Medicine, Vermillion, SD 57069; and {dagger}Division of Biological Sciences, University of Missouri, Columbia, MO 65211

Communicated by Howard A. Bern, University of California, Berkeley, CA, March 28, 2005 (received for review November 2, 2004)

Exposure of human fetuses to man-made estrogenic chemicals can occur through several sources. For example, fetal exposure to ethinylestradiol occurs because each year {approx}3% of women taking oral contraceptives become pregnant. Exposure to the estrogenic chemical bisphenol A occurs through food and beverages because of significant leaching from polycarbonate plastic products and the lining of cans. We fed pregnant CD-1 mice ethinylestradiol (0.1 µg/kg per day) and bisphenol A (10 µg/kg per day), which are doses below the range of exposure by pregnant women. In male mouse fetuses, both ethinylestradiol and bisphenol A produced an increase in the number and size of dorsolateral prostate ducts and an overall increase in prostate duct volume. Histochemical staining of sections with antibodies to proliferating cell nuclear antigen and mouse keratin 5 indicated that these increases were due to a marked increase in proliferation of basal epithelial cells located in the primary ducts. The urethra was malformed in the colliculus region and was significantly constricted where it enters the bladder, which could contribute to urine flow disorders. These effects were identical to those caused by a similar dose (0.1 µg/kg per day) of the estrogenic drug diethylstilbestrol (DES), a known human developmental teratogen and carcinogen. In contrast, a 2,000-fold higher DES dose completely inhibited dorsolateral prostate duct formation, revealing opposite effects of high and low doses of estrogen. Acceleration in the rate of proliferation of prostate epithelium during fetal life by small amounts of estrogenic chemicals could permanently disrupt cellular control systems and predispose the prostate to disease in adulthood.

Author contributions: B.G.T. and F.S.v.S. designed research; B.G.T., K.L.H., L.B., S.B., C.A.R., and F.S.v.S. performed research; B.G.T., L.B., S.B., C.A.R., and F.S.v.S. analyzed data; and B.G.T., K.L.H., C.A.R., and F.S.v.S. wrote the paper.

Freely available online through the PNAS open access option.

{ddagger}To whom correspondence should be addressed.

Frederick S. vom Saal, E-mail: vomsaalf{at}missouri.edu

www.pnas.org/cgi/doi/10.1073/pnas.0502544102
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