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Effect of endocrine disruptors on nuclear receptor superfamily.

内分泌干扰物对核受体超家族的影响。

基本信息

批准号：
14370764
负责人：
NISHIKAWA Jun-ichi
金额：
$ 8.83万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Nuclear receptors play important roles in the maintenance of the endocrine system, regulation of organ differentiation and fetal development. Endocrine disruptors exert their adverse effects by disrupting the endocrine system via various mechanisms. Many naturally occurring and synthetic compounds, including DDT and its metabolites, PCBs, and some alkylphenols have hormonal activities. Although the levels of natural hormones are precisely regulated metabolically in intact organisms, synthetic chemicals elude this regulation to stimulate organs by mechanisms different from those of natural hormones. Nuclear receptors are the likely targets of endocrine disruptors, because their intrinsic ligands are fat-soluble, low-molecular weight agents, as are the environmental pollutants. To evaluate the effects of numerous synthetic chemicals on many nuclear receptors, we developed the CoA-BAP system, a high-throughput method for identifying activators of nuclear receptors. Using this system, we f … More ound that several compounds possess agonistic activities for multiple receptors simultaneously. Butyl benzyl phthalate, hexachlorocyclohexane, maneb, mancozeb, and alkylphenols were weakly agonistic for multiple receptors including estrogen receptor. One intriguing finding was that the effect of organotins (TBT and TPT) on retinoid X receptor(RXR) was as strong as that of its endogenous ligand, 9-cis retinoic acid (9-cis RA). Organotins are potent inducers of imposex (a superimposition of male genital tracts, such as penis and vas deferens, on females) in marine gastropods. Cloning of the RXR homolog from wild rock shell (Thais clavigera) revealed that the ligand-binding domain of rock shell RXR was very similar to vertebrate RXR and bound to both 9-cis RA and to organotins. Further, injection of 9-cis RA into females of Thais clavigera induced the development of imposex. These data provide strong evidence that RXR plays an important role in inducing the development of imposex, namely the differentiation and growth of male genital tracts in female gastropods. Less

核受体在维持内分泌系统、调节器官分化和胎儿发育等方面发挥着重要作用。内分泌干扰物通过多种机制干扰内分泌系统，发挥其不良作用。许多天然存在的和合成的化合物，包括滴滴涕及其代谢物、多氯联苯和一些烷基酚具有激素活性。虽然天然激素的水平在完整的生物体中受到精确的代谢调节，但合成化学物质通过与天然激素不同的机制来避开这种调节来刺激器官。核受体可能是内分泌干扰物的目标，因为它们的内在配体是脂溶性的、低分子量的物质，环境污染物也是如此。为了评估许多合成化学物质对许多核受体的影响，我们开发了CoA-BAP系统，这是一种用于鉴定核受体激活剂的高通量方法。利用该系统，我们发现几种化合物同时对多种受体具有激动作用。邻苯二甲酸丁苄酯、六氯环己烷、马麻黄、代森锰锌和烷基酚对包括雌激素受体在内的多种受体具有弱激动作用。一个有趣的发现是，有机素（TBT和TPT）对类维甲酸X受体（RXR）的作用与其内源性配体9-顺式维甲酸（9-顺式RA）的作用一样强。有机激素是海洋腹足类动物的强效诱导剂（雄性生殖道，如阴茎和输精管在雌性身上的叠加）。对野生岩壳RXR同源基因的克隆发现，岩壳RXR的配体结合域与脊椎动物RXR非常相似，并与9-顺式RA和有机蛋白结合。此外，将9-cis类风湿性关节炎注射到雌性泰国锁骨龟体内，可诱导其发生不性行为。这些数据有力地证明了RXR在诱导雌性腹足动物雄性生殖道的分化和生长中起着重要的作用。少