Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on prostate development in the mouse

In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) inhibited prostate growth and development in C57BL/6J mice. The effects were lobe specific such that the ventral prostate was more severely affected than other prostate lobes. Region specific effects of TCDD also were observed on prostatic epithelial bud formation in the urogenital sinus (UGS) which was more severely inhibited in the ventral than dorsolateral region of the UGS. In utero and lactational TCDD exposure differentially inhibited branching morphogenesis in the ventral, dorsal, lateral, and anterior prostate lobes. The ventral prostate never developed any ductal structure while TCDD reduced ductal tips and main duct number in the dorsolateral prostate. However, reductions in ductal tip number were secondary to reductions in the number of main ducts. Unlike other prostate lobes, TCDD had no effect on main duct number in the anterior prostate but weight, ductal tip number, and number of ductal tips per main duct were all substantially reduced, demonstrating that anterior prostate branching morphogenesis was inhibited. In utero and lactational TCDD exposure did not affect neonatal testicular androgen content and adult plasma androgen concentration suggesting that TCDD may inhibit responsiveness of the UGS to androgens. An androgen responsive reporter assay, and analysis of androgen regulated gene expression were conducted to test the hypothesis that TCDD inhibits prostatic bud formation by interrupting androgen signaling. However, androgen-dependent luciferase activity was not affected by TCDD in primary UGS mesenchymal cells and androgen regulated gene expression in the UGS also was not affected. These findings suggest that TCDD inhibits prostatic bud formation by interrupting androgen signaling downstream of the androgen receptor (AR) and/or by an androgen independent mechanism. TCDD inhibition of androgen-induced prostatic bud formation was only observed in UGS tissue recombinants when aryl hydrocarbon receptor (AHR) was expressed in the mesenchyme. Thus, mesenchymal AHR alone was sufficient to mediate the inhibitory TCDD effect on prostatic bud formation by inhibition of androgen signaling downstream of the AR and/or by an androgen-independent mechanism.