Weiss Jana M, Andersson Patrik L, Zhang Jin, Simon Eszter, Leonards Pim E G, Hamers Timo, Lamoree Marja H
Institute for Environmental Studies (IVM), Faculty of Earth and Life Sciences, VU University, De Boelelaan 1087, 1081HV, Amsterdam, The Netherlands,
Anal Bioanal Chem. 2015 Jul;407(19):5625-34. doi: 10.1007/s00216-015-8736-9. Epub 2015 May 19.
A variety of anthropogenic compounds has been found to be capable of disrupting the endocrine systems of organisms, in laboratory studies as well as in wildlife. The most widely described endpoint is estrogenicity, but other hormonal disturbances, e.g., thyroid hormone disruption, are gaining more and more attention. Here, we present a review and chemical characterization, using principal component analysis, of organic compounds that have been tested for their capacity to bind competitively to the thyroid hormone transport protein transthyretin (TTR). The database contains 250 individual compounds and technical mixtures, of which 144 compounds are defined as TTR binders. Almost one third of these compounds (n = 52) were even more potent than the natural hormone thyroxine (T4). The database was used as a tool to assist in the identification of thyroid hormone-disrupting compounds (THDCs) in an effect-directed analysis (EDA) study of a sediment sample. Two compounds could be confirmed to contribute to the detected TTR-binding potency in the sediment sample, i.e., triclosan and nonylphenol technical mixture. They constituted less than 1% of the TTR-binding potency of the unfractionated extract. The low rate of explained activity may be attributed to the challenges related to identification of unknown contaminants in combination with the limited knowledge about THDCs in general. This study demonstrates the need for databases containing compound-specific toxicological properties. In the framework of EDA, such a database could be used to assist in the identification and confirmation of causative compounds focusing on thyroid hormone disruption.
在实验室研究以及野生动物研究中，已发现多种人为化合物能够干扰生物体的内分泌系统。描述最为广泛的终点指标是雌激素活性，但其他激素干扰，如甲状腺激素干扰，正受到越来越多的关注。在此，我们使用主成分分析对已测试其与甲状腺激素转运蛋白甲状腺素运载蛋白（TTR）竞争性结合能力的有机化合物进行综述和化学表征。该数据库包含250种单一化合物和技术混合物，其中144种化合物被定义为TTR结合剂。这些化合物中近三分之一（n = 52）甚至比天然激素甲状腺素（T4）更具活性。在对一份沉积物样本进行的效应导向分析（EDA）研究中，该数据库被用作辅助识别甲状腺激素干扰化合物（THDCs）的工具。有两种化合物被证实对沉积物样本中检测到的TTR结合活性有贡献，即三氯生和壬基酚技术混合物。它们在未分级提取物的TTR结合活性中所占比例不到1%。活性解释率较低可能归因于与识别未知污染物相关的挑战，以及总体上对THDCs的了解有限。这项研究表明需要包含化合物特定毒理学特性的数据库。在EDA框架内，这样的数据库可用于辅助识别和确认以甲状腺激素干扰为重点的致病化合物。
