These 2012 data suggest that DES-induced SV toxicity and feminization are primarily mediated by ERα; however, some aspects of androgen response may require the action of ERβ
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).
Estrogen receptor-α mediates diethylstilbestrol-induced feminization of the seminal vesicle in male mice, US National Library of Medicine National Institutes of Health, Environmental health perspectives, NCBI PubMed PMID: 22275727, 2012 Apr.
Image credit NCBI PMC3339448 figure/f2.
The present study was designed to evaluate the role of the estrogen receptor (ER) in this action by using ER-knockout (ERKO) mice.
Wild-type (WT), ERα-null (αERKO), and ERβ-null (βERKO) male mice were treated with either vehicle or DES (2 μg/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.
In DES-treated intact mice, SV weights were reduced in WT and βERKO mice but not in αERKO mice. DES-treated WT and βERKO males, but not αERKO 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 αERKO mice. In addition, DES-treated βERKO 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 αERKO mice but not in WT mice, suggesting full androgen responsiveness in αERKO mice.
The data presented here demonstrate that ERα plays a role in the developmental effects resulting from DES toxicity in the SV. ERα is involved in the lack of androgen responsiveness determined by increases in SV weight after DHT treatment and by SVS IV protein and Svs4 gene expression, but this does not appear to be due to down-regulation of the AR itself. Therefore, other factors that control androgen signaling must be affected. In addition, this study definitively shows that ERα is necessary for the molecular feminization of the SV after neonatal exposure to DES, because we did not observe aberrant LF expression in αERKO mice.
Irrespective of the underlying mechanisms, the toxicological effects of DES that lead to androgen resistance and feminization in the SV are dependent on functional ERα. Furthermore, this is clearly a toxicological effect of aberrant stimulation of ERα signaling in the SV during development, as unexposed αERKO males invariably exhibited overly well-maintained SVs, thus indicating that normal development and function of the tissue are not dependent on functional ERα.
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