Estrogen actions in the male reproductive system involve estrogen response element-independent pathways.
Estrogen actions in the male reproductive system involve estrogen response element-independent pathways.
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DOI：
10.1210/en.2008-0122
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发表时间：
2008-12
期刊：
影响因子：
4.8
通讯作者：
J. Weiss;Miranda L. Bernhardt;M. M. Laronda-M.;L. Hurley;C. Glidewell-Kenney;S. Pillai;Minghan Tong;K. Korach;J. Jameson
中科院分区：
文献类型：
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作者：
J. Weiss;Miranda L. Bernhardt;M. M. Laronda-M.;L. Hurley;C. Glidewell-Kenney;S. Pillai;Minghan Tong;K. Korach;J. Jameson
雌激素受体-α(ERα)通过多种途径发挥作用，包括雌激素反应元件(ERE)依赖(经典)和ERE非依赖性(非经典)机制。我们之前创建了一个小鼠模型，该模型含有DNA结合域(E207A，G208A)的两个氨基酸突变，排除了ERα与ERE的直接结合。在杂合突变小鼠与ERAlpha基因敲除(ERKO)系杂交后，与ERKO小鼠(-/-)和野生型(+/+；WT)相比，可以评估分离的ERAlpha非经典等位基因(-/AA；AA)对生理拯救的程度。在8个月大的雄性Erko小鼠中，睾酮水平很高，尽管黄体生成素水平与WT相似。AA小鼠体内睾酮正常，表明AA等位基因挽救了ERKO小鼠体内增强的睾酮生物合成。雄性Erko小鼠在2-3个月龄时就表现出曲细精管扩张，这是由于输出管水吸收减少的结果。到3-4个月龄时，ERKO小鼠大约40%的小管精子发生受损，精子数量和活动率随着组织学改变而下降。在AA小鼠中，组织学缺陷大大减少或消失，精子数量和活力得到挽救。ERKO小鼠的水通道蛋白1和9水平降低，AA小鼠部分或完全恢复，而另一种水转运蛋白钠氢交换器-3在ERKO和AA小鼠中均降低。我们的结论是，非ERE依赖的雌激素途径足以挽救在ERKO小鼠中观察到的有缺陷的精子发生，并在睾丸的ERAlpha作用中发挥显著作用，包括调节水吸收和雄激素生物合成的途径。
The estrogen receptor-alpha (ERalpha) acts through multiple pathways, including estrogen response element (ERE)-dependent (classical) and ERE-independent (nonclassical) mechanisms. We previously created a mouse model harboring a two-amino-acid mutation of the DNA-binding domain (E207A, G208A) that precludes direct binding of ERalpha to an ERE. After crossing heterozygous mutant mice with an ERalpha knockout (ERKO) line, it was possible to assess the degree of physiological rescue by the isolated ERalpha nonclassical allele (-/AA; AA) when compared with ERKO mice (-/-) and to wild type (+/+; WT). In male ERKO mice up to 8 months of age, testosterone levels were high, although LH levels were similar to WT. Testosterone was normal in the AA mice, indicating that the AA allele rescues the enhanced testosterone biosynthesis in ERKO mice. Male ERKO mice exhibited distention of the seminiferous tubules as early as 2-3 months of age as a consequence of decreased water resorption in the efferent ducts. By 3-4 months of age, ERKO mice had impaired spermatogenesis in approximately 40% of their tubules, and sperm counts and motility declined in association with the histological changes. In the AA mice, histological defects were greatly reduced or absent, and sperm counts and motility were rescued. Levels of aquaporins 1 and 9, which contribute to water uptake in the efferent ducts, were reduced in ERKO mice and partially or fully rescued in AA mice, whereas another water transporter, sodium-hydrogen exchanger-3, was decreased in both ERKO and AA mice. We conclude that non-ERE-dependent estrogen pathways are sufficient to rescue the defective spermatogenesis observed in ERKO mice and play a prominent role in ERalpha action in the testis, including pathways that regulate water resorption and androgen biosynthesis.