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题名: Binding interactions of perfluoroalkyl substances with thyroid hormone transport proteins and potential toxicological implications
作者: Ren, Xiao-Min; Qin, Wei-Ping; Cao, Lin-Ying; Zhang, Jing; Yang, Yu; Wan, Bin; Guo, Liang-Hong
刊名: TOXICOLOGY
出版日期: 2016-07-29
卷号: 366, 期号:0, 页码:32-42
关键词: Perfluoroalkyl substances ; Transthyretin ; Thyroxine-binding globulin ; Binding interaction
DOI: 10.1016/j.tox.2016.08.011
部门归属: 环境化学与生态毒理学国家重点实验室
英文摘要: Perfluoroalkyl substances (PFASs) have been shown to cause abnormal levels of thyroid hormones (THs) in experimental animals, but the molecular mechanism is poorly understood. Here, a fluorescence displacement assay was used to determine the binding affinities of 16 PFASs with two major TH transport proteins, transthyretin (TTR) and thyroxine-binding globulin (TBG). Most of the tested PFASs bound TTR with relative potency (RP) values of 3 x 10(-4) to 0.24 when compared with that of the natural ligand thyroxine, whereas fluorotelomer alcohols did not bind. Only perfluorotridecanoic acid and perfluorotetradecanoic acid bound TBG, with RP values of 2 x 10-4 when compared with that of thyroxine. Based on these results, it was estimated that displacement of T4 from TTR by perfluorooctane sulfonate and perfluorooctanoic acids would be significant for the occupationally exposed workers but not the general population. Structure-binding analysis revealed that PFASs with a medium chain length and a sulfonate acid group are optimal for TTR binding, and PFASs with lengths longer than 12 carbons are optimal for TBG binding. Three mutant proteins were prepared to examine crucial residues involved in the binding of PFASs to TH transport proteins. TTR with a KI5G mutation and TBG with either a R378G or R381G mutation showed decreased binding affinity to PFASs, indicating that these residues play key roles in the interaction with the compounds. Molecular docking showed that the PFASs bind to TTR with their acid group forming a hydrogen bond with K15 and the hydrophobic chain towards the interior. PFASs were modeled to bind TBG with their acid group forming a hydrogen bond with R381 and the hydrophobic chain extending towards R378. The findings aid our understanding of the behavior and toxicity of PFASs on the thyroid hormone system. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
收录类别: SCI
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内容类型: 期刊论文
URI标识: http://ir.rcees.ac.cn/handle/311016/35807
Appears in Collections:环境化学与生态毒理学国家重点实验室_期刊论文

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