Inhibition of Retinoic Acid Biosynthesis by the Bisdichloroacetyldiamine WIN 18,446 Markedly Suppresses Spermatogenesis and Alters Retinoid Metabolism in Mice
Inhibition of Retinoic Acid Biosynthesis by the Bisdichloroacetyldiamine WIN 18,446 Markedly Suppresses Spermatogenesis and Alters Retinoid Metabolism in Mice
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DOI：
10.1074/jbc.m113.540211
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发表时间：
2014-05-23
影响因子：
4.8
通讯作者：
Amory, John K.
中科院分区：
文献类型：
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作者：
Paik, Jisun;Haenisch, Michael;Amory, John K.
睾丸视黄酸合成调控的知识对于理解其在精子发生中的作用至关重要。双二氯乙酰二胺强烈抑制精子发生。我们以前报道过，这些化合物之一，WIN 18，446，通过抑制视黄酸的合成而有效地抑制家兔精子发生。为了了解WIN 18，446如何抑制视黄酸合成，我们在体外表征了其对人视网膜脱氢酶ALDH1A2的作用，以及使用小鼠在体内表征了其对类维生素A代谢的作用。WIN 18，446在体外强烈且不可逆地抑制ALDH1A2。在体内，WIN 18，446治疗在治疗4周后完全消除精子发生，并适度减少喂食普通饲料的小鼠的肥胖。WIN 18，446对类维生素A浓度的影响具有组织依赖性。尽管在WIN 18，446处理的动物中肺和肝视黄酯浓度较低，但处理后脂肪视黄酯水平增加。有趣的是，与对照小鼠相比，用WIN 18，446治疗的动物具有显著更高的循环视黄醇浓度。WIN18，446对精子发生的影响不能通过同时用维甲酸处理来阻止，而对其他组织的影响则部分或完全逆转。停止WIN 18，446治疗4周可逆转除精子发生抑制外的大多数类维生素A相关表型。我们的数据表明，WIN 18，446可能是系统性获得性维甲酸缺乏症的有用模型。鉴于我们研究中观察到的效果，抑制视黄酸生物合成可能与肥胖症的治疗和新型男性避孕药的开发有关。
Knowledge of the regulation of testicular retinoic acid synthesis is crucial for understanding its role in spermatogenesis. Bisdichloroacetyldiamines strongly inhibit spermatogenesis. We reported previously that one of these compounds, WIN 18,446, potently inhibited spermatogenesis in rabbits by inhibiting retinoic acid synthesis. To understand how WIN 18,446 inhibits retinoic acid synthesis, we characterized its effects on human retinal dehydrogenase ALDH1A2 in vitro as well as its effects on retinoid metabolism in vivo using mice. WIN 18,446 strongly and irreversibly inhibited ALDH1A2 in vitro. In vivo, WIN 18,446 treatment completely abolished spermatogenesis after 4 weeks of treatment and modestly reduced adiposity in mice fed a chow diet. Effects of WIN 18,446 on retinoid concentrations were tissue-dependent. Although lung and liver retinyl ester concentrations were lower in WIN 18,446-treated animals, adipose retinyl ester levels were increased following the treatment. Interestingly, animals treated with WIN 18,446 had significantly higher circulating retinol concentrations compared with control mice. The effect on spermatogenesis by WIN18,446 was not prevented by simultaneous treatment with retinoic acid, whereas effects on other tissues were partially or completely reversed. Cessation of WIN 18,446 treatment for 4 weeks reversed most retinoid-related phenotypes except for inhibition of spermatogenesis. Our data suggest that WIN 18,446 may be a useful model of systemic acquired retinoic acid deficiency. Given the effects observed in our study, inhibition of retinoic acid biosynthesis may have relevance for the treatment of obesity and in the development of novel male contraceptives.