Estrogen Receptor-α Mediates Diethylstilbestrol-Induced Feminization of the Seminal Vesicle in Male Mice

BACKGROUND: Studies have shown that perinatal exposure to the synthetic estrogen diethylstilbestrol (DES) leads to feminization of the seminal vesicle (SV) in male mice, as illustrated by tissue hyperplasia, ectopic expression of the major estrogen-inducible uterine secretory protein lactoferrin (LF), and reduced expression of SV secretory protein IV (SVS IV). OBJECTIVES: The present study was designed to evaluate the role of the estrogen receptor (ER) in this action by using ER-knockout (ERKO) mice. METHODS: Wild-type (WT), ER alpha-null (alpha ERKO), and ER beta-null (beta ERKO) male mice were treated with either vehicle or DES (2 mu g/day) on neonatal days 1-5. These mice were divided into two groups: In the first group, intact mice were sacrificed at 10 weeks of age; in the second group, mice were castrated at 10 weeks of age, allowed to recover for 10 days, treated with dihydrotestosterone (DHT) or placebo, and sacrificed 2 weeks later. Body weights and SV weights were recorded, and mRNA expression levels of Ltf(lactoferrin), Svs4, and androgen receptor (Ar) were assessed. RESULTS: In DES-treated intact mice, SV weights were reduced in WT and beta ERKO mice but not in alpha ERKO mice. DES-treated WT and beta ERKO males, but not alpha ERKO males, exhibited ectopic expression of LF in the SV. DES treatment resulted in decreased SVS IV protein and mRNA expression in WT males, but no effect was seen in alpha ERKO mice. In addition, DES-treated beta ERKO mice exhibited reduced Svs4 mRNA expression but maintained control levels of SVS IV protein. In DES-treated castrated mice, DHT implants restored SV weights to normal levels in alpha ERKO mice but not in WT mice, suggesting full androgen responsiveness in alpha ERKO mice. CONCLUSIONS: These data suggest that DES-induced SV toxicity and feminization are primarily mediated by ER alpha; however, some aspects of androgen response may require the action of ER beta.