2,3,7,8-Tetrachlorodibenzo-p-dioxin Inhibits Luminal Cell Differentiation and Androgen Responsiveness of the Ventral Prostate without Inhibiting Prostatic 5alpha-Dihydrotestosterone Formation or Testicular Androgen Production in Rat Offspring

Abstract

In utero and lactational exposure to a single maternal dose of 1 microg 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, 5alpha-dihydrotestosterone (DHT), from the circulating precursor testosterone and 5alpha-androstane-3alpha,17ss-diol (3alpha-Diol), was studied on postnatal days (PNDs) 14, 21, and 32. The ability of the ventral prostate to form DHT from 3alpha-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.

Anabolic effects of testosterone are preserved during inhibition of 5α-reductase

“…Prostate DHT was extracted by the method of Theobald et al (42). Briefly, homogenates were extracted twice with 10 volumes of anhydrous ethyl ether.…”

Maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and the body burden in offspring of long-evans rats

“…Among the reproductive endpoints affected, the reduced ventral prostate weight was sensitive and consistent with previous studies using the same experimental protocol. Effects of in utero TCDD exposure on the development of ventral prostate were intensively studied (26)(27)(28)(29)(30). It is suggested that TCDD exposure impairs prostate growth and androgen responsiveness by inhibiting prostatic epithelial cell differentiation (28).…”

Prostate cancer in US Air Force veterans of the Vietnam war

“…Interactive effects of TCDD and DDE on male reproductive tract development were also observed in rats suggesting that exposure to both these chemicals may potentiate their individual actions although by different mechanism since DDE is not an Ah-receptor agonist (Loeffler and Peterson, 1999). Other studies suggest that TCDD exposure impairs prostate growth and androgen responsiveness by inhibiting prostatic epithelial cell differentiation and morphogenesis (Theobald et al, 2000;Ko et al, 2002;Timms et al, 2002).…”