Neonatal Estrogen Down-Regulates Prostatic Androgen Receptor through a Proteosome-Mediated Protein Degradation Pathway

Abstract

Brief exposure of male rats to estrogens during the neonatal period interrupts normal prostate development, alters epithelial cell differentiation, and predisposes this gland to hyperplasia and severe dysplasia analogous to prostatic intraepithelial neoplasia (PIN) with aging. Previous work demonstrated that the reduced growth, secretory activity, and androgen sensitivity that are observed in the adult ventral lobe are a function of reduced androgen receptor (AR) levels. Down-regulation of AR protein was found to occur immediately following neonatal exposure to estradiol benzoate (EB) and persist through adulthood and aging, indicating a permanent imprint on the ability of the prostate to express normal AR levels. To determine the intracellular mechanism of AR down-regulation by estrogens, the present study examined the effect of neonatal EB on AR gene transcription, mRNA levels, protein translation, and protein degradation in the d 10 ventral prostate glands. Nuclear run-on assays showed no alteration in AR gene transcription following exposure to EB on d 1-5 compared with controls. In situ hybridization and quantitative (q) RT-PCR revealed no difference in mRNA levels in the stromal or epithelial cells in response to estrogen exposure which, taken together, indicate that estrogen down-regulation of AR is mediated at the posttranscriptional level. AR translation was assessed with an in vitro transcription-translation assay in the presence of prostatic lysates from oil and estrogen-exposed animals, and no treatment effect was noted. AR degradation was examined in an in vitro assay validated with adult intact and castrate prostates. Prostatic lysates from intact rats initiated AR degradation with a t1/2 of 2.31 h, whereas proteins from castrate rats accelerated AR degradation to a t1/2 of 1.34 h (P < 0.001). Prostatic lysates from control d 10 prostates induced AR degradation with a t1/2 of 1.49 h, whereas estrogenized prostates increased AR degradation to a t1/2 of 1.11 h (P < 0.001). Proteosome inhibitors MG132 and ALLnL were able to reverse AR degradation induced by prostatic lysates from adult intact and castrate rats as well as from developing and estrogenized prostates, indicating that AR degradation was mediated through the proteosome pathway. Furthermore, the proteosome-mediated AR degradation in the estrogenized d 10 prostate was associated with a marked suppression of Akt phosphorylation that has been linked to AR degradation in other systems. Taken together, the present data show that exposure to neonatal estrogens down-regulates AR protein levels in the ventral prostate gland by accelerating AR degradation, which is mediated through the proteosome pathway.

Differential hormonal regulation of estrogen receptors ERα and ERβ and androgen receptor expression in rat efferent ductules

“…These data indicate that the mechanism underlying AR regulation by androgens involves differential transcriptional and/or post-transcriptional events, which will likely be cell-and tissue-specific (Yeap et al 1999). In this sense, recent findings in the prostate gland showed that AR is down-regulated by androgen withdrawal as well as estrogen treatment, through a post-transcriptional pathway mediated by proteasome (Woodham et al 2003). In the present study, ligation of the efferent ductule did not affect levels of immunodetectable AR, nor did unilateral castration.…”

Developmental estrogen exposures predispose to prostate carcinogenesis with aging☆

“…It was observed in early studies that the activational response to androgens during adulthood is permanently blunted in estrogenized rats (46) and we determined that this effect is mediated, in part, through an immediate and permanent reduction in prostatic AR expression (15,48,58,59). Furthermore, the temporal expression patterns and quantitative levels of several other members of the steroid receptor superfamily are dysregulated by early exposure to high doses of estradiol.…”

Estrogen receptor-α mediates estrogen-inducible abnormalities in the developing penis

“…Additionally, neonatal estrogen exposure downregulates androgen receptor level in male reproductive organs (Prins & Birch 1995, Woodham et al 2003 and lowers plasma testosterone (Sharpe et al 1998, Atanassova et al 2000. Testosterone coadministration with estrogen mitigates developmental abnormalities affecting the male reproductive tract (Rivas et al 2003).…”