Institute of Pesticide and Environmental Toxicology, Zhejiang University, Hangzhou 310058, P.R. China.
State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, P.R. China.
Toxicol Sci. 2017 Dec 1;160(2):205-216. doi: 10.1093/toxsci/kfx177.
A broad range of pesticides have been reported to interfere with the normal function of the thyroid endocrine system. However, the precise mechanism(s) of action has not yet been thoroughly elucidated. In this study, 21 pesticides were assessed for their binding interactions and the potential to disrupt thyroid homeostasis. In the GH3 luciferase reporter gene assays, 5 of the pesticides tested had agonistic effects in the order of procymidone > imidacloprid > mancozeb > fluroxypyr > atrazine. 11 pesticides inhibited luciferase activity of T3 to varying degrees, demonstrating their antagonistic activity. And there are 4 pesticides showed mixed effects when treated with different concentrations. Surface plasmon resonance (SPR) biosensor technique was used to directly measure the binding interactions of these pesticides to the human thyroid hormone receptor (hTR). 13 pesticides were observed to bind directly with TR, with a KD ranging from 4.80E-08 M to 9.44E-07 M. The association and disassociation of the hTR/pesticide complex revealed 2 distinctive binding modes between the agonists and antagonists. At the same time, a different binding mode was displayed by the pesticides showed mix agonist and antagonist activity. In addition, the molecular docking simulation analyses indicated that the interaction energy calculated by CDOCKER for the agonists and antagonists correlated well with the KD values measured by the surface plasmon resonance assay. These results help to explain the differences of the TR activities of these tested pesticides.
大量的农药已被报道会干扰甲状腺内分泌系统的正常功能。然而，其确切的作用机制尚未被彻底阐明。在这项研究中，评估了 21 种农药与甲状腺激素受体的结合相互作用及其潜在的破坏甲状腺内稳态的能力。在 GH3 荧光素酶报告基因检测中，测试的 5 种农药按丙环唑>吡虫啉>代森锰锌>氟氯吡啶酯>莠去津的顺序表现出激动剂作用。11 种农药不同程度地抑制了 T3 对荧光素酶活性的作用，显示出其拮抗剂活性。还有 4 种农药在不同浓度下表现出混合效应。表面等离子体共振（SPR）生物传感器技术被用于直接测量这些农药与人类甲状腺激素受体（hTR）的结合相互作用。13 种农药被观察到直接与 TR 结合，KD 值范围为 4.80E-08 M 至 9.44E-07 M。hTR/农药复合物的缔合和解离揭示了激动剂和拮抗剂之间 2 种不同的结合模式。同时，具有混合激动剂和拮抗剂活性的农药表现出不同的结合模式。此外，分子对接模拟分析表明，通过 CDOCKER 计算的激动剂和拮抗剂的相互作用能与表面等离子体共振检测法测量的 KD 值很好地相关。这些结果有助于解释这些测试的农药对 TR 活性的差异。
