Binding interactions of perfluoroalkyl substances with thyroid hormone transport proteins and potential toxicological implications
Binding interactions of perfluoroalkyl substances with thyroid hormone transport proteins and potential toxicological implications
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全氟烷基物质与甲状腺激素转运蛋白的结合相互作用和潜在的毒理学意义
DOI：
10.1016/j.tox.2016.08.011
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发表时间：
2016-07-29
期刊：
影响因子：
4.5
通讯作者：
Guo, Liang-Hong
中科院分区：
文献类型：
--
作者：
Ren, Xiao-Min;Qin, Wei-Ping;Guo, Liang-Hong
全氟烷基物质（PFAS）已被证明会导致实验动物甲状腺激素（TH）水平异常，但分子机制知之甚少。在这里，使用荧光置换试验来确定16个PFAS与两个主要TH转运蛋白，甲状腺素运载蛋白（TTR）和甲状腺素结合球蛋白（TBG）的结合亲和力。与天然配体甲状腺素相比，大多数测试的PFAS结合TTR的相对效价（RP）值为3 × 10 - 4至0.24，而氟调聚物醇不结合。只有全氟十三烷酸和全氟十四烷酸结合TBG，与甲状腺素相比，RP值为2 × 10-4。根据这些结果，估计全氟辛烷磺酸和全氟辛酸从TTR中置换T4对职业接触工人来说意义重大，但对一般人群来说意义不大。结构结合分析表明，具有中等链长和磺酸基的PFAS最适合TTR结合，长度大于12个碳的PFAS最适合TBG结合。制备了三种突变蛋白，以检查PFASs与TH转运蛋白结合所涉及的关键残基。具有KI 5G突变的TTR和具有R378 G或R381 G突变的TBG显示与PFAS的结合亲和力降低，表明这些残基在与化合物的相互作用中起关键作用。分子对接表明PFASs与TTR结合时，其酸性基团与K15形成氢键，疏水链向内。PFAS被建模为结合TBG，其酸基团与R381形成氢键，疏水链向R378延伸。这些发现有助于我们了解PFASs对甲状腺激素系统的行为和毒性。(C)2016爱思唯尔爱尔兰有限公司版权所有。
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.