Trialkyltin compounds bind retinoid X receptor to alter human placental endocrine functions
Trialkyltin compounds bind retinoid X receptor to alter human placental endocrine functions
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DOI：
10.1210/me.2004-0397
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发表时间：
2005-10-01
影响因子：
--
通讯作者：
Tanaka, K
中科院分区：
文献类型：
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作者：
Nakanishi, T;Nishikawa, J;Tanaka, K
维甲酸X受体（Retinoid X receptor，RXR）是一种在哺乳动物发育和体内平衡中起重要作用的核受体。我们以前报道，在人绒毛膜癌细胞，三丁基氯化锡和三苯基锡氢氧化物，这是典型的环境污染物，并导致雌性软体动物的雄性化，是人绒毛膜促性腺激素的生产和芳香化酶活性，发挥关键的内分泌功能，在维持妊娠和胎儿发育的有力刺激。然而，这些化合物刺激这些内分泌功能的分子机制仍不清楚。我们目前的研究表明，三烷基锡化合物，包括氯化三丁基锡和氢氧化三苯基锡，作为RXR激动剂的功能。三烷基锡以高亲和力直接结合RXR的配体结合结构域，并作为转录激活因子发挥作用。与天然RXR配体9-顺式视黄酸不同，三烷基锡的活性是RXR特异性的，并且不激活视黄酸受体途径。此外，三烷基锡激活RXR以刺激含有人胎盘启动子I的荧光素酶报告基因的表达。1序列的芳香化酶，表明三烷基锡通过RXR依赖性信号通路刺激人胎盘内分泌功能。因此，我们的研究结果表明，RXR的激活可能是一种新的机制，三烷基锡改变人类内分泌功能。
Retinoid X receptor (RXR) is a nuclear receptor that plays important and multiple roles in mammalian development and homeostasis. We previously reported that, in human choriocarcinoma cells, tributyltin chloride and triphenyltin hydroxide, which are typical environmental contaminants and cause masculinization in female mollusks, are potent stimulators of human chorionic gonadotropin production and aromatase activity, which play key endocrine functions in maintaining pregnancy and fetal development. However, the molecular mechanism through which these compounds stimulate these endocrine functions remains unclear. Our current study shows that trialkyltin compounds, including tributyltin chloride and triphenyltin hydroxide, function as RXR agonists. Trialkyltins directly bind to the ligand-binding domain of RXR with high affinity and function as transcriptional activators. Unlike the natural RXR ligand, 9-cisretinoic acid, the activity of trialkyltins is RXR specific and does not activate the retinoic acid receptor pathway. In addition, trialkyltins activate RXR to stimulate the expression of a luciferase reporter gene containing the human placental promoter I. 1 sequence of aromatase, suggesting that trialkyltins stimulate human placental endocrine functions through RXR- dependent signaling pathways. Therefore, our results suggest that activation of RXR may be a novel mechanism by which trialkyltins alter human endocrine functions.