Dimethoate inhibits steroidogenesis by disrupting transcription of the steroidogenic acute regulatory (StAR) gene.
Dimethoate inhibits steroidogenesis by disrupting transcription of the steroidogenic acute regulatory (StAR) gene.
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DOI：
10.1677/joe.0.1670253
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发表时间：
2000-11
期刊：
影响因子：
--
通讯作者：
L. Walsh;D. R. Webster;D. Stocco
中科院分区：
文献类型：
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作者：
L. Walsh;D. R. Webster;D. Stocco
乐果是一种广泛使用的有机磷杀虫剂，已被证明会扰乱动物的生殖功能。虽然乐果生殖毒性的发病机制尚不清楚，但血清睾酮水平的降低被认为在乐果诱导的不孕症的发生中起着重要作用。由于睾丸间质细胞通过产生睾酮在男性生殖功能中起着至关重要的作用，因此利用小鼠MA-10间质细胞系来确定乐果是否能直接阻断类固醇激素的生物合成，并确定类固醇激素抑制的部位。乐果以剂量和时间依赖的方式抑制类固醇的生成，而不影响总蛋白合成或蛋白激酶A的活性。虽然它降低了P450侧链裂解(P450 SCC)酶的活性，但该酶活性的降低不能解释Bu(2)cAMP抑制孕酮产生的水平。相反，我们的结果表明，乐果主要通过阻止类固醇生成急性调节(STAR)基因的转录来抑制类固醇的生成。这一发现意义重大，因为STAR蛋白在类固醇合成中参与了限速和严格调控的步骤，即胆固醇从线粒体膜外转移到线粒体膜内。本研究表明，STAR可能是干扰类固醇合成、损害生殖功能的环境污染物的重要靶点。
Dimethoate is a widely used organophosphate insecticide that has been shown to disrupt reproductive function in animals. Although the pathogenesis of Dimethoate-induced reproductive toxicity remains to be determined, a reduction in serum testosterone levels is thought to play an important role in the development of Dimethoate-induced infertility. Since Leydig cells play a crucial role in male reproductive function by producing testosterone, the mouse MA-10 Leydig tumor cell line was used to determine if Dimethoate can directly block steroid hormone biosynthesis and to identify the site of steroidogenic inhibition. Dimethoate inhibited steroidogenesis in both a dose- and time-dependent manner without affecting total protein synthesis or protein kinase A activity. While it decreased the activity of the P450 side chain cleavage (P450 scc) enzyme, a reduction in the activity of this enzyme alone could not account for the level of Bu(2)cAMP-inhibited progesterone production. Instead, our results suggest that Dimethoate inhibited steroidogenesis primarily by blocking transcription of the steroidogenic acute regulatory (StAR) gene. This finding is significant since StAR protein mediates the rate-limiting and acutely-regulated step in steroidogenesis, the transfer of cholesterol from the outer to the inner mitochondrial membrane. This study indicates that StAR may be an important target for environmental pollutants which disrupt steroidogenesis and impair reproductive function.