title: Identification of Molecular Targets for 4,5-Dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT) in Teleosts: New Insight into Mechanism of Toxicity.
abstract: Environmental pollutants are capable of concomitantly inducing diverse toxic effects. However, it is largely unknown which effects are directly induced and which effects are secondary, thus calling for definitive identification of the initiating molecular event for a pollutant to elucidate the mechanism of toxicity. In the present study, affinity pull-down assays were used to identify target proteins for 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT), a costal pollutant of emerging concern, in various tissues (e.g., brain, liver, plasma, and gonad) from marine medaka (Oryzias melastigma) and zebrafish (Danio rerio). Pull-down results showed that, in male and female brains from medaka and zebrafish, DCOIT had a consistently high affinity for G protein alpha subunits (Gα), suggesting the targeted effects of DCOIT on signaling transduction from G protein-coupled receptors (GPCRs) and an extrapolatable mode of action in teleost brains. Validation using recombinant proteins and molecular docking analysis confirmed that binding of DCOIT to Gα protein competitively inhibited its activation by substrate. Considering the involvement of GPCRs in the regulation of myriad biological processes, including the hypothalamus-pituitary-gonadal-liver axis, binding of DCOIT to upstream Gα proteins in the brain may provide a plausible explanation for the diversity of toxic effects resulting from DCOIT challenge, especially abnormal hormonal production through the mitogen-activated protein kinase pathway. A new mechanism of action based on GPCR signaling is thus hypothesized for endocrine disrupting chemicals and warrants further research to clearly elucidate the link between GPCR signaling and endocrine disruption.
authors.affiliation: Division of Life Science, Hong Kong University of Science and Technology , Clear Water Bay, Hong Kong SAR, China.|State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences , Wuhan 430072, China.
authors.forename: Lianguo
authors.identifier: 0000-0003-3730-7842
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Laboratory in Marine Pollution, Department of Biology and Chemistry, City University of Hong Kong , Kowloon, Hong Kong SAR, China.
authors.forename: Doris W T
authors.initials: DW
authors.lastname: Au
authors.affiliation: School of Chemistry and Environmental Engineering, Wuhan Institute of Technology , Wuhan 430072, China.
authors.forename: Chenyan
authors.initials: C
authors.lastname: Hu
authors.affiliation: State Key Laboratory in Marine Pollution, Department of Biology and Chemistry, City University of Hong Kong , Kowloon, Hong Kong SAR, China.
authors.forename: Drew R
authors.initials: DR
authors.lastname: Peterson
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: Division of Life Science, Hong Kong University of Science and Technology , Clear Water Bay, Hong Kong SAR, China.
authors.forename: Pei-Yuan
authors.initials: PY
authors.lastname: Qian
mesh_terms: D000818:Animals; D052244:Endocrine Disruptors / Q000633:toxicity; D004703:Endocrine System / Q000187:drug effects; D006066:Gonads / Q000187:drug effects; D062105:Molecular Docking Simulation; D009990:Oryzias; D013844:Thiazoles / Q000633:toxicity*
chemical_list: D052244:Endocrine Disruptors; D013844:Thiazoles; C080469:Kathon 930