Estrogen imprinting of the developing prostate gland is mediated through stromal estrogen receptor α: Studies with αERKO and βERKO mice

Neonatal exposure of rodents to high doses of estrogen permanently imprints the growth and function of the prostate and predisposes this gland to hyperplasia and severe dysplasia analogous to prostatic intraepithelial neoplasia with aging. Because the rodent prostate gland expresses estrogen receptor (ER)-α within a subpopulation of stromal cells and ERβ within epithelial cells, the present study was undertaken to determine the specific ER(s) involved in mediating prostatic developmental estrogenization. Wild-type (WT) mice, homozygous mutant ER (ERKO) α -/- mice, and βERKO -/- mice were injected with 2 μg of diethylstilbestrol (DES) or oil (controls) on days 1, 3, and 5 of life. Reproductive tracts were excised on days 5 or 10 (prepubertal), day 30 (pubertal), day 90 (young adult), or with aging at 6, 12, and 18 months of age. Prostate complexes were microdissected and examined histologically for prostatic lesions and markers of estrogenization. Immunocytochemistry was used to examine expression of androgen receptor, ERα, ERβ, cytokeratin 14 (basal cells), cytokeratin 18 (luminal cells), and dorsolateral protein over time in the treated mice. In WT-DES mice, developmental estrogenization of the prostate was observed at all of the time points as compared with WT-oil mice. These prostatic imprints included transient up-regulation of ERα, down-regulation of androgen receptor, decreased ERβ levels in adult prostate epithelium, lack of DLP secretory protein, and a continuous layer of basal cells lining the ducts. With aging, epithelial dysplasia and inflammatory cell infiltrate were observed in the ventral and dorsolateral prostate lobes. In contrast, the prostates of αERKO mice exhibited no response to neonatal DES either immediately after exposure or throughout life up to 18 months of age. Furthermore, neonatal DES treatment of βERKO mice resulted in a prostatic response similar to that observed in WT animals. The present findings indicate that ERα is the dominant ER form mediating the developmental estrogenization of the prostate gland. If epithelial ERβ is involved in some component of estrogen imprinting, its role would be considered minor and would require the presence of ERα expression in the prostatic stromal cells.