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Identification of Molecular Targets for 4,5-Dichloro-2‑n‑octyl-4-isothiazolin-3-one (DCOIT) in Teleosts: New Insight into Mechanism of Toxicity
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 mecha...
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Published in: | Environmental science & technology 2017-02, Vol.51 (3), p.1840-1847 |
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description | 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. |
doi_str_mv | 10.1021/acs.est.6b05523 |
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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.</description><identifier>ISSN: 0013-936X</identifier><identifier>EISSN: 1520-5851</identifier><identifier>DOI: 10.1021/acs.est.6b05523</identifier><identifier>PMID: 28026967</identifier><identifier>CODEN: ESTHAG</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Danio rerio ; Endocrine Disruptors - toxicity ; Endocrine system ; Endocrine System - drug effects ; Gonads - drug effects ; Kinases ; Molecular Docking Simulation ; Molecules ; Oryzias ; Oryzias latipes ; Oryzias melastigma ; Pollutants ; Proteins ; Signal transduction ; Teleostei ; Thiazoles - toxicity ; Toxicity ; Zebrafish</subject><ispartof>Environmental science & technology, 2017-02, Vol.51 (3), p.1840-1847</ispartof><rights>Copyright © 2016 American Chemical Society</rights><rights>Copyright American Chemical Society Feb 7, 2017</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a394t-d70d3ab9f5540f29efce6557f1677e96ef25949a018925aa3c2841a92af9ba723</citedby><cites>FETCH-LOGICAL-a394t-d70d3ab9f5540f29efce6557f1677e96ef25949a018925aa3c2841a92af9ba723</cites><orcidid>0000-0003-3730-7842</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28026967$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Lianguo</creatorcontrib><creatorcontrib>Au, Doris W. 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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.</description><subject>Animals</subject><subject>Danio rerio</subject><subject>Endocrine Disruptors - toxicity</subject><subject>Endocrine system</subject><subject>Endocrine System - drug effects</subject><subject>Gonads - drug effects</subject><subject>Kinases</subject><subject>Molecular Docking Simulation</subject><subject>Molecules</subject><subject>Oryzias</subject><subject>Oryzias latipes</subject><subject>Oryzias melastigma</subject><subject>Pollutants</subject><subject>Proteins</subject><subject>Signal transduction</subject><subject>Teleostei</subject><subject>Thiazoles - toxicity</subject><subject>Toxicity</subject><subject>Zebrafish</subject><issn>0013-936X</issn><issn>1520-5851</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNp1kc9uEzEQxi0EoqFw5oYscSkqTv1nvV5zQynQSC29LBK3lePYjSvHbm2vIJx4BdQ35ElwmgASEofRHOb3fTOaD4DnBE8JpuRE6Tw1uUzbBeacsgdgQjjFiHecPAQTjAlDkrWfD8CTnK8xxpTh7jE4oB2mrWzFBNzNlyYUZ51WxcUAo4UX0Rs9epVgr9KVKRnamGDzmqNTp1c-pojoz-8_Qq2oy8ajBrkcy8qpb9G7gBiKwcCj09nlvH8FXYC98Sbmkt_Aj-YLnIfsrlalDkqEF0avVHB5vV3cx69Ou7J5Ch5Z5bN5tu-H4NP7d_3sDJ1ffpjP3p4jxWRT0FLgJVMLaTlvsKXSWG1azoUlrRBGtsZSLhupMOkk5UoxTbuGKEmVlQslKDsERzvfmxRvx_rGYe2yNt6rYOKYB9IJ0REpJK7oy3_Q6zimUK-rVCsIkfSeOtlROsWck7HDTXJrlTYDwcM2r6HmNWzV-7yq4sXed1yszfIP_zugChzvgK3y787_2P0CmwSh4A</recordid><startdate>20170207</startdate><enddate>20170207</enddate><creator>Chen, Lianguo</creator><creator>Au, Doris W. 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subjects | Animals Danio rerio Endocrine Disruptors - toxicity Endocrine system Endocrine System - drug effects Gonads - drug effects Kinases Molecular Docking Simulation Molecules Oryzias Oryzias latipes Oryzias melastigma Pollutants Proteins Signal transduction Teleostei Thiazoles - toxicity Toxicity Zebrafish |
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 |
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