Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses

Proceedings of the national Academy of Sciences v.94, pp.2056-61 Mar97

(androgen receptors / benign prostatic hyperplasia / dose-response)

Frederick S. vom Saal^1,5, Barry G. Timms³, Monica M. Montano¹, Paola Palanza⁴, Kristina A. Thayer¹, Susan C. Nagel¹, Minati D. Dhar¹, V. K. Ganjam², Stefano Parmigiani⁴, and Wade V. Welshons²

¹ Division of Biological Sciences and ² Department of Veterinary Biomedical Sciences, University of Missouri-Columbia, Columbia, MO 65211; ³ Department of Anatomy and Structural Biology, University of South Dakota, Vermillion, SD 57069; and ⁴ Department of Evolutionary and Functional Biology, University of Parma, Parma, Italy 43100

⁵To whom reprint requests should be addressed at: 114 Lefevre Hall, Division of Biological Sciences, University of Missouri, Columbia, MO 65211. e-mail: vomsaal@biosci.mbp.missouri.edu

Communicated by R. Michael Roberts, University of Missouri, Columbia, MO, December 18, 1996 (received for review October 16, 1996)

ABSTRACT

On the basis of results of studies using high doses of estrogens, exposure to estrogen during fetal life is known to inhibit prostate development. However, it is recognized in endocrinology that low concentrations of a hormone can stimulate a tissue, while high concentrations can have the opposite effect. We report here that a 50% increase in free-serum estradiol in male mouse fetuses (released by a maternal Silastic estradiol implant) induced a 40% increase in the number of developing prostatic glands during fetal life; subsequently, in adulthood, the number of prostatic androgen receptors per cell was permanently increased by 2-fold, and the prostate was enlarged by 30% (due to hyperplasia) relative to untreated males. However, as the free serum estradiol concentration in male fetuses was increased from 2- to 8-fold, adult prostate weight decreased relative to males exposed to the 50% increase in estradiol. As a model for fetal exposure to man-made estrogens, pregnant mice were fed diethylstilbestrol (DES) from gestation days 11 to 17. Relative to controls, DES doses of 0.02, 0.2, and 2.0 ng per g of body weight per day increased adult prostate weight, whereas a 200-ng-per-g dose decreased adult prostate weight in male offspring. Our findings suggest that a small increase in estrogen may modulate the action of androgen in regulating prostate differentiation, resulting in a permanent increase in prostatic androgen receptors and prostate size. For both estradiol and DES, prostate weight first increased then decreased with dose, resulting in an inverted-U dose-response relationship.

source: http://www.pnas.org/cgi/content/full/94/5/2056 4jun01