title: Mechanistic study of chlordecone-induced endocrine disruption: Based on an adverse outcome pathway network.
abstract: The adverse outcome pathway (AOP) framework could be helpful for chemical risk assessment and mechanistic research. The aim of the present study was to unravel the mechanism of chlordecone-induced endocrine disruption by illustrating the main molecular initiating event (MIE)/perturbations responsible for the observed effects. In silico simulations were performed to predict the MIE(s), and the results pointed to agonistic interaction with estrogen receptors (ERα, ERβ), androgen receptor (AR), cytochrome P450 (CYP19A) by chlordecone. In vivo endocrine disruptions were evaluated in rare minnow (Gobiocypris rarus) exposed to 0.01, 0.1, 1 and 10 μg L(-1) chlordecone from 2 h post-fertilization until sexually mature. In the females, increases of vitellogenin (vtg) mRNA levels in liver and gonad, plasma estradiol (E2), testosterone (T) and E2/T, and renalsomatic index confirmed the role of agonism of ER and CYP19A as MIEs, but the decreased gonadosomatic index, degenerated ovaries as well as the feed-forward response pointed to other potential but important MIEs and corresponding AOPs. In the males, increased E2/T ratio, increased testis vtg mRNA levels and occurrence of intersex confirmed the roles of agonism of ERα and CYP19A as main MIEs in chlordecone-induced endocrine disruptions. Our results also fetches out the limit of AOPs in predicting the adverse outcomes and explaining the mechanism of chemicals at present, thus reflected a critical need for expanding AOPs and AOP network before using it in chemical risk assessment.
authors.affiliation: State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China.
authors.forename: Bingsheng
authors.initials: B
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; Beijing Key Laboratory of Industrial Wastewater Treatment and Reuse, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China. Electronic address: jinmiaozha@gmail.com.
authors.forename: Jinmiao
authors.initials: J
authors.lastname: Zha
authors.affiliation: State Key Laboratory of Environmental Aquatic Chemistry, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, Beijing, 100085, China.
authors.forename: Zijian
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism; D007631:Chlordecone / Q000633:toxicity*; D003198:Computer Simulation; D003530:Cyprinidae / Q000097:blood / Q000378:metabolism; D052244:Endocrine Disruptors / Q000633:toxicity*; D004958:Estradiol / Q000097:blood; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008962:Models, Theoretical; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000097:blood; D014819:Vitellogenins / Q000235:genetics; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D012333:RNA, Messenger; D011944:Receptors, Androgen; D014819:Vitellogenins; D014874:Water Pollutants, Chemical; D013739:Testosterone; D004958:Estradiol; D001141:Aromatase; D007631:Chlordecone
keywords: Adverse outcome pathway (AOP); Chinese rare minnow (Gobiocypris rarus); Chlordecone; Endocrine disruption