Paik Jisun, Haenisch Michael, Muller Charles H, Goldstein Alex S, Arnold Samuel, Isoherranen Nina, Brabb Thea, Treuting Piper M, Amory John K
From the Departments of Comparative Medicine,
From the Departments of Comparative Medicine.
J Biol Chem. 2014 May 23;289(21):15104-17. doi: 10.1074/jbc.M113.540211. Epub 2014 Apr 7.
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 WIN 18,446 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.
了解睾丸视黄酸合成的调节机制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。我们之前报道过，其中一种化合物WIN 18,446通过抑制视黄酸合成有效抑制了兔子的精子发生。为了了解WIN 18,446如何抑制视黄酸合成，我们在体外研究了其对人视网膜脱氢酶ALDH1A2的影响，并使用小鼠在体内研究了其对类视黄醇代谢的影响。WIN 18,446在体外强烈且不可逆地抑制ALDH1A2。在体内，WIN 18,446处理4周后完全消除了精子发生，并适度降低了喂食普通饲料小鼠的肥胖程度。WIN 18,446对类视黄醇浓度的影响具有组织依赖性。虽然WIN 18,446处理的动物肺和肝视黄酯浓度较低，但处理后脂肪组织视黄酯水平升高。有趣的是，与对照小鼠相比，WIN 18,446处理的动物循环视黄醇浓度显著更高。同时用视黄酸处理并不能阻止WIN 18,446对精子发生的影响，而对其他组织的影响则部分或完全逆转。停止WIN 18,446处理4周后，除了对精子发生的抑制外，大多数与类视黄醇相关的表型都得到了逆转。我们的数据表明，WIN 18,446可能是全身性获得性视黄酸缺乏的有用模型。鉴于我们研究中观察到的效应，抑制视黄酸生物合成可能与肥胖治疗及新型男性避孕药的开发有关。
