Oral Administration of a Retinoic Acid Receptor Antagonist Reversibly Inhibits Spermatogenesis in Mice
Oral Administration of a Retinoic Acid Receptor Antagonist Reversibly Inhibits Spermatogenesis in Mice
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DOI：
10.1210/en.2010-0941
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发表时间：
2011-06-01
期刊：
影响因子：
4.8
通讯作者：
Wolgemuth, Debra J.
中科院分区：
文献类型：
--
作者：
Chung, Sanny S. W.;Wang, Xiangyuan;Wolgemuth, Debra J.
在这里，我们研究了一种通过使用低剂量的泛视黄酸受体 (RAR) 拮抗剂 BMS-189453 操纵类视黄醇信号传导来抑制小鼠模型精子发生的药理学方法。精子发生被破坏，精子细胞排列和精子释放失败，生殖细胞进入管腔，这些异常类似于缺乏维生素 A 和 RAR α 基因敲除的睾丸。重要的是，诱导的不育是可逆的。使用系统修改的给药方案观察到疗效增强，不孕期延长，精子发生完全恢复。血液学、血清化学以及激素和病理学评估显示，除了明显的睾丸病理学之外，没有可检测到的异常或不良副作用。我们的结果表明，睾丸对类维生素A信号传导的破坏非常敏感，并且RAR拮抗剂可能代表开发非类固醇男性避孕药的新先导分子。 （内分泌学152：2492-2502，2011）
Here we investigated a pharmacological approach to inhibit spermatogenesis in the mouse model by manipulating retinoid signaling using low doses of the pan-retinoic acid receptor (RAR) antagonist BMS-189453. Spermatogenesis was disrupted, with a failure of spermatid alignment and sperm release and loss of germ cells into lumen, abnormalities that resembled those in vitamin A-deficient and RAR alpha-knockout testes. Importantly, the induced sterility was reversible. Enhanced efficacy and a lengthened infertility period with full recovery of spermatogenesis were observed using systematically modified dosing regimens. Hematology, serum chemistry, and hormonal and pathological evaluations revealed no detectable abnormalities or adverse side effects except the distinct testicular pathology. Our results suggest that testes are exquisitely sensitive to disruption of retinoid signaling and that RAR antagonists may represent new lead molecules in developing nonsteroidal male contraceptives. (Endocrinology 152: 2492-2502, 2011)