Toxicological Sciences 58, 324-338 (2000)
Copyright © 2000 by the Society of Toxicology
Reproductive and Developmental Toxicology |
2,3,7,8-Tetrachlorodibenzo-p-dioxin Inhibits Luminal Cell Differentiation and Androgen Responsiveness of the Ventral Prostate without Inhibiting Prostatic 5
-Dihydrotestosterone Formation or Testicular Androgen Production in Rat Offspring
,1,3
* School of Pharmacy and
Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin 53706
In utero and lactational exposure to a single maternal dose of 1 µg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg causes some overt toxicity and impairs prostate growth in male offspring. As similar effects on the ventral prostate can be caused by decreased testosterone production during perinatal development, we determined whether intratesticular testosterone content, testicular responsiveness to gonadotropin stimulation, or plasma testosterone concentrations were reduced in fetal and newborn rats. Because these endpoints were not affected, the ability of TCDD exposure to inhibit synthesis of the proximal androgen in prostate development, 5
-dihydrotestosterone (DHT), from the circulating precursor testosterone and 5-androstane-3,17ß-diol (3-Diol), was studied on postnatal days (PNDs) 14, 21, and 32. The ability of the ventral prostate to form DHT from 3-Diol was slightly impaired on PND 14, but this transient effect was not statistically significant, and recovery was evident by PND 21. Subsequent experiments used organ culture to study the effects of in vivo TCDD exposure on androgen metabolism, androgen responsiveness, androgen receptor expression, and luminal epithelial cell differentiation after in vitro exposure to graded androgen concentrations. In utero and lactational TCDD exposure had no effect on DHT formation in organ culture, but transiently reduced the androgen -induced expression of prostatic-binding protein subunit C3, decreased ventral prostate epithelial cell androgen receptor expression, and inhibited the formation of androgen responsive luminal epithelial cells. These results suggest that TCDD exposure impairs prostate growth and androgen responsiveness by inhibiting prostatic epithelial cell differentiation.
Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin; rat, prostate; development; impaired epithelial differentiation; 5-dihydrotestosterone-forming enzymes; testicular testosterone production.
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