Estrogen receptor-α-mediates the detrimental effects of neonatal diethylstilbestrol (DES) exposure in the murine reproductive tract
Estrogen receptor-α-mediates the detrimental effects of neonatal diethylstilbestrol (DES) exposure in the murine reproductive tract
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DOI：
10.1016/j.tox.2004.06.046
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发表时间：
2004-12-01
期刊：
影响因子：
4.5
通讯作者：
Korach, KS
中科院分区：
文献类型：
--
作者：
Couse, JF;Korach, KS
合成雌激素己烯雌酚（diethylstilbestrool， DES）的发育作用一般认为有雌激素受体依赖性和非依赖性通路参与介导。然而，每种途径对所导致的病理的确切作用和程度仍然未知。我们使用雌激素受体敲除（ERKO）小鼠，缺乏雌激素受体- α (alphaERKO)或雌激素受体- β (betaERKO)，以深入了解每个er依赖途径在小鼠雌性和雄性生殖道组织中介导新生儿DES暴露的作用。雌激素受体-雌性小鼠对新生儿DES暴露的慢性影响表现出完全的抗性，这在暴露的野生型动物中很明显，包括子宫萎缩和上皮鳞状化生；输卵管的增生性病变；阴道上皮持续锥形化。des介导的暴露期间野生型女性子宫Hoxa10、Hova11和Wnt7a表达的减少在alphaERKO女性中也不存在。在雄性小鼠中，alphaERKO小鼠表现出完全抵抗新生儿DES暴露对前列腺的慢性影响，包括雄激素受体水平降低、上皮增生和基底细胞增殖增加。尽管ERbeta在前列腺上皮中高度表达，暴露于DES的betaERKO雄性表现出新生儿DES暴露的所有影响，这些影响在类似暴露的野生型雄性中观察到。因此，DES对alphaERKO子宫和前列腺的基因表达和组织分化缺乏影响，这为erα介导小鼠生殖道新生儿DES暴露的有害作用提供了明确的证据。2004爱思唯尔爱尔兰有限公司版权所有。
It is generally believed that estrogen receptor-dependent and -independent pathways are involved in mediating the developmental effects of the synthetic estrogen, diethylstilbestrol (DES). However, the precise role and extent to which each pathway contributes to the resulting pathologies remains unknown. We have employed the estrogen receptor knockout (ERKO) mice, which lack either estrogen receptor-alpha (alphaERKO or estrogen receptor-beta (betaERKO), to gain insight into the contribution of each ER-dependent pathway in mediating the effects of neonatal DES exposure in the female and male reproductive tract tissues of the mouse. Estrogen receptor-a female mice exhibited complete resistance to the chronic effects of neonatal DES exposure that were obvious in exposed wild-type animals, including atrophy and epithelial squamous metaplasia in the uterus; proliferative lesions of the oviduct; and persistent cornification of the vaginal epithelium. DES-mediated reduction in uterine Hoxa10, Hova11 and Wnt7a expression that occurs wild-type females during the time of exposure was also absent in alphaERKO females. In the male, alphaERKO mice exhibited complete resistance to the chronic effects of neonatal DES exposure on the prostate, including decreased androgen receptor levels, epithelial hyperplasia, and increased basal cell proliferation. Although ERbeta is highly expressed in the prostate epithelium, DES-exposed betaERKO males exhibited all of the effects of neonatal DES exposure that were observed in similarly exposed wild-type males. Therefore, the lack of DES-effects on gene expression and tissue differentiation in the alphaERKO uterus and prostate provides unequivocal evidence of an obligatory role for ERalpha in mediating the detrimental actions of neonatal DES exposure in the murine reproductive tract. (C) 2004 Elsevier Ireland Ltd. All rights reserved.