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Study on the development of bioassay system for organic halogenated compounds with thyroid-disrupting activity

甲状腺干扰有机卤化物生物测定体系的建立研究

基本信息

批准号：
16310038
负责人：
YAMAUCHI Kiyoshi
金额：
$ 7.58万
依托单位：
Shizuoka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16310038/
关键词：
environmental pollutants thyroid hormone endocrine disruption bioassay 環境ホルモン受容体

项目摘要

In vertebrates, thyroid hormones are essential for post-embryonic development, such as establishing the central nervous system in mammals and metamorphosis in amphibians. The present study focused on the extra-thyroidal processes that environmental chemicals are known to or suspected to target in the thyroid hormone-signaling pathway. We developed three in vitro and one in vivo bioassays, which detect chemicals interfering with thyroid hormone binding to plasma transthyretin (TTR assay), thyroid hormone binding to nuclear receptor (TR assay), induction of thyroid hormone-dependent reporter gene expression (Luc assay, and gene expression during thyroid hormone-induced amphibian metamorphosis (metamorphosis assay). Several organohalogens affect different aspects of the extra-thyroidal thyroid-hormone-signaling pathway but hardly affect thyroid hormone binding to receptors. Amphibian tadpoles are most sensitive to the effects of environmental chemicals during specific thyroid-hormone-related developmental windows. The thyroid hormone-disrupting activity of contaminants in aquatic environments in Japan and Thailand was surveyed by these bioassays. Our assays demonstrated that wastewater treatment effectively removed the TH-disrupting contaminants from wastewater in paper manufacturing plants and sewage-treatment plants. The Luc assay indicated that sewage-treatment plant effluents in Japan contained Ta-like activity whereas that in Thailand contained anti-Ta-like activity. It is likely that the three in vitro bioassays detected the same or different contaminants with TH-disrupting activity in a water sample-dependent manner. Our results indicate that a combination of several in vitro bioassays facilitates the rapid screening of environmental water samples to identify the locations of contaminants with TH-disrupting activity.

在脊椎动物中，甲状腺激素对胚胎后发育至关重要，例如哺乳动物中枢神经系统的建立和两栖动物的变态。目前的研究主要集中在甲状腺外的过程，环境化学物质是已知的或怀疑在甲状腺激素信号通路的目标。我们开发了三种体外和一种体内生物测定法，检测干扰甲状腺激素与血浆甲状腺素运载蛋白结合（TTR测定法）、甲状腺激素与核受体结合（TR测定法）、甲状腺激素依赖性报告基因表达诱导（Luc测定法）和甲状腺激素诱导两栖动物变态过程中的基因表达（变态测定法）的化学物质。几种有机卤素影响甲状腺外甲状腺激素信号通路的不同方面，但几乎不影响甲状腺激素与受体的结合。两栖动物蝌蚪在特定的甲状腺激素相关发育窗口期间对环境化学物质的影响最敏感。通过这些生物测定法对日本和泰国水生环境中污染物的甲状腺激素干扰活性进行了调查。我们的分析表明，废水处理有效地去除了造纸厂和污水处理厂废水中的TH干扰污染物。Luc分析表明，日本的污水处理厂废水含有Ta样活性，而泰国的废水含有抗Ta样活性。这是可能的，在三个体外生物测定检测到相同或不同的污染物TH破坏活动的水样依赖性的方式。我们的研究结果表明，几种体外生物测定的组合有利于快速筛选环境水样，以确定污染物的位置与TH破坏活性。