Organophosphate esters cause thyroid dysfunction via multiple signaling pathways in zebrafish brain

作     者：Zhenfei Yan Chenglian Feng Xiaowei Jin Fangkun Wang Cong Liu Na Li Yu Qiao Yingchen Bai Fengchang Wu John P.Giesy 

作者机构：State Key Laboratory of Environmental Criteria and Risk AssessmentChinese Research Academy of Environmental SciencesBeijing100012China College of EnvironmentHohai UniversityNanjing210098China China National Environmental Monitoring CentreBeijing100012China Department of Preventive Veterinary MedicineCollege of Veterinary MedicineShandong Agricultural UniversityTaian271018China Key Laboratory of Drinking Water Science and TechnologyResearch Center for Eco-Environmental SciencesChinese Academy of SciencesBeijing100085China Department of Veterinary Biomedical SciencesUniversity of SaskatchewanSaskatoonSKCanada Toxicology CentreUniversity of SaskatchewanSaskatoonSKCanada Department of Environmental SciencesBaylor UniversityWacoTXUSA 

出 版 物：《Environmental Science and Ecotechnology》 (环境科学与生态技术（英文）)

年 卷 期：2022年第12卷第4期

页      面：26-36页

核心收录：

学科分类：0830[工学-环境科学与工程（可授工学、理学、农学学位）] 07[理学] 070303[理学-有机化学] 0703[理学-化学] 

基　　金：financially supported by National Key Research and Development Program of China,China(2021YFC3200104) National Natural Science Foundation of China(41773085 and 41977364) Beijing Outstanding Talent Training Program supported by the“High Level Foreign Experts”program(#GDT20143200016)funded by the State Administration of Foreign Experts Affairs,China,to Nanjing University the Einstein Professor Programof the Chinese Academy of Sciences. 

主　　题：Organophosphate ester Molecular docking simulation Competitive inhibition assay Thyroid endocrine function Transcriptome sequencing 

摘      要：Organophosphate esters(OPEs)are widespread in various environmental media,and can disrupt thyroid endocrine signaling pathways.Mechanisms by which OPEs disrupt thyroid hormone(TH)signal transduction are not fully understood.Here,we present in vivo-in vitro-in silico evidence establishing OPEs as environmental THs competitively entering the brain to inhibit growth of zebrafish via multiple signaling pathways.OPEs can bind to transthyretin(TTR)and thyroxine-binding globulin,thereby affecting the transport of TH in the blood,and to the brain by TTR through the blood-brain barrier.When GH3 cells were exposed to OPEs,cell proliferation was significantly inhibited given that OPEs are competitive inhibitors of TH.Cresyl diphenyl phosphate was shown to be an effective antagonist of TH.Chronic exposure to OPEs significantly inhibited the growth of zebrafish by interfering with thyroperoxidase and thyroglobulin to inhibit TH synthesis.Based on comparisons of modulations of gene expression with the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases,signaling pathways related to thyroid endocrine functions,such as receptor-ligand binding and regulation of hormone levels,were identified as being affected by exposure to OPEs.Effects were also associated with the biosynthesis and metabolism of lipids,and neuroactive ligand-receptor interactions.These findings provide a comprehensive understanding of the mechanisms by which OPEs disrupt thyroid pathways in zebrafish.