Effect of endocrine disruptors on nuclear receptor superfamily.

核受体在维持内分泌系统、调节器官分化和胎儿发育中起重要作用。内分泌干扰物通过各种机制干扰内分泌系统，从而产生不利影响。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，都具有激素活性。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，但合成化学品避开了这种调节，通过与天然激素不同的机制刺激器官。核受体是内分泌干扰物的可能靶点，因为它们的内在配体是脂溶性的、低分子量的物质，就像环境污染物一样。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。使用这个系统，我们 ...更多信息 发现几种化合物同时对多种受体具有激动活性。邻苯二甲酸丁基苄基酯、六氯环己烷、代森锰、代森锰锌和烷基酚对多种受体（包括雌激素受体）具有弱激动作用。一个有趣的发现是，有机锡（TBT和TPT）对类维生素A X受体（RXR）的作用与其内源性配体9-顺式维甲酸（9-cis RA）的作用一样强。有机锡是海洋腹足类动物性畸变（雄性生殖道，如阴茎和输精管，在雌性上的叠加）的有效诱导剂。从野生岩壳（Thais clavigera）的RXR同源物的克隆显示，岩壳RXR的配体结合结构域是非常相似的脊椎动物RXR和绑定到9-顺式RA和有机锡。此外，9-顺式RA注射到女性的泰国clavigera诱导性畸变的发展。这些数据提供了强有力的证据表明，RXR在诱导性畸变的发展，即雌性腹足动物雄性生殖道的分化和生长中起着重要作用。少

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