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

核接收器在维持内分泌系统，器官分化和胎儿发育方面起着重要作用。内分泌破坏者通过各种机制破坏内分泌系统来执行其不良影响。许多天然存在和合成化合物，包括DDT及其代谢产物，PCB和某些烷基苯酚具有激素活性。尽管天然激素的水平在完整的生物体中精确地由代谢进行调节，但合成化学物质洗脱了这种调节，以通过不同于天然马的机制来刺激器官。核受体可能是内分泌破坏者的靶标，因为它们的内在配体是脂溶性的，低分子量的剂，环境污染物也是如此。为了评估众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，这是一种用于识别核受体活化剂的高通量方法。使用该系统，我们……几种化合物仅对多种受体具有激动活动。对于包括雌激素受体在内的多种受体，邻苯二甲酸酯，六氯环己烷，Maneb，Mancozeb和烷基苯酚对多种受体的激动性弱。一个有趣的发现是，有机蛋白（TBT和TPT）对类视黄素X受体（RXR）的影响与内源性配体，9-碱基维甲酸（9-CIS RA）的作用一样强。有机素是海洋腹足类动物中Imposex（男性生殖道的叠加，例如阴茎和VAS延期的叠加）的潜在影响者。野生岩壳（Thais clavigera）的RXR同源物克隆表明，岩壳RXR的配体结合域与脊椎动物RXR非常相似，并与9-CIS RA和有机蛋白结合。此外，将9-CIS RA注射到Thais clavigera的女性中诱导了Imposex的发展。这些数据提供了有力的证据，表明RXR在诱导Imposex的发展中起着重要作用，即在女性胃足类动物中男性生殖道的分化和生长。较少的