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Analysis of endocrine-disrupting activities of environmental chemicals that associate with thyroid-hormone-binding proteins

与甲状腺激素结合蛋白相关的环境化学物质的内分泌干扰活性分析

基本信息

批准号：
13559001
负责人：
YAMAUCHI Kiyoshi
金额：
$ 6.02万
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：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13559001/
关键词：
Environmental chemicals Thyroid hormone Receptor Binding protein Amphibian

项目摘要

We investigated the effects of phenolic and phenol compounds on 3,3',5-[^<125>I]triiodothyronine ([^<125>I]T_3) binding to purified Xenopus laevis transthyretin (xTTR) and to the ligand-binding domain of X. laevis thyroid hormone receptor β (xTR LBD), on T_3-induced metamorphosis in X. laevis tadpoles and on the induction of T_3-dependent reporter gene in a X. laevis cell line. Of the halogenated phenolic and phenol compounds tested, 3,3',5-trichlorobisphenol A and 2,4,6-triiodophenol, respectively, were the most potent competitors of [^<125>I]T_3 binding to both xTTR and xTR LBD. Most of the halogenated compounds had stronger interactions with xTTR than with xTR LBD. Generally, chlorinated derivatives with a greater degree of chlorination were more efficient competitors of T_3 binding to xTTR and xTR LBD. Structures with a halogen in either ortho positions or in both ortho positions, with respect to the hydroxy group, were more efficient competitors. 3,3',5-Trichlorobisphenol A and 2,4,6-triiodophenol acted as T_3 antagonists in the X laevis tadpole metamorphosis assay. Interestingly, o-t-butylphenol and 2-isopropylphenol, for which xTTR and xTR LBD had weak or no significant affinity, showed T_3 antagonist activity in the metamorphosis assay. T_3 antagonist activities of all these chemicals except for o-t-butylphenol were verified by T_3-dependent reporter gene assay. Our results suggest that some phenolic and phenol compounds target the process of T_3 binding to xTTR and xTR and/or an unknown process, and that they interfere with the intracellular T_3 signaling pathway.

我们研究了酚类和苯酚类化合物对3，3‘，5-三碘甲腺原氨酸([^&lt；125&gt；i]T_3)与纯化的非洲爪哇转甲状腺蛋白(XtR)和非洲爪哇甲状腺激素受体β(XTRLBD)配体结合区结合的影响，以及对T_3诱导非洲爪哇蝌蚪变态和诱导非洲爪哇细胞系T_3依赖报告基因表达的影响。在所测试的卤代酚类和苯酚类化合物中，3，3‘，5-三氯双酚A和2，4，6-三碘苯酚分别是[^&lt；125；gt；i]T_3与xTtr和xtr LBD结合的最强竞争者。大多数卤代化合物与xTTR的相互作用强于与xtr LBD的相互作用。一般来说，氯化程度较高的氯化衍生物是T_3与xTTR和xTRLBD结合的更有效的竞争者。与羟基相比，在邻位或两个邻位都含有卤素的结构是更有效的竞争对手。3，3‘，5-三氯双酚A和2，4，6-三碘苯酚作为T_3拮抗剂参与了斑潜蝇蝌蚪变态试验。有趣的是，邻叔丁基苯酚和2-异丙基苯酚在变态实验中显示出T_3拮抗活性，而xTTR和xTRLBD对它们的亲和力较弱或没有显著亲和力。用T_3依赖报告基因实验验证了除邻叔丁基苯酚外的所有化合物的T_3拮抗活性。我们的结果表明，某些酚类和苯酚类化合物靶向于T_3与xTtr和xtr结合的过程和/或一个未知的过程，它们干扰了细胞内的T_3信号通路。