title: Characterization of zebrafish Abcc4 as an efflux transporter of organochlorine pesticides.
abstract: DDT and lindane are highly toxic organochlorine pesticides and posing adverse effects on the environment and public health due to their frequent usage in developing countries. ABCC4/MRP4 is an organic anion transporter that mediates cellular efflux of a wide range of exogenous and endogenous compounds such as cyclic nucleotides and anti-cancer drugs; however, it remains unclear whether ABCC4 and its orthologs function in the detoxification of organochlorine pesticides. Here, we demonstrated the roles of zebrafish Abcc4 in cellular efflux of DDT and lindane. Zebrafish abcc4 was maternally expressed in the oocytes and its transcripts were detected in the lens, pancreas, gills, liver, intestine and bladder of developing embryos and in adult tissues examined. DDT and lindane were able to induce the expression of abcc4 gene and overexpression of Abcc4 significantly decreased the cytotoxicity and accumulation of DDT and lindane in LLC-PK1 cells and developing embryos. In contrast, overexpression of an Abcc4-G1188D mutant abolished its transporter function without effects on its substrate binding activity, and sensitized LLC-PK1 cells and developing embryos to toxic pesticides. Moreover, glutathione (GSH) was involved in the efflux of cellular pesticides and ATPase activity in developing embryos can be induced by DDT or lindane. Thus, zebrafish Abcc4 plays crucial roles in cellular efflux of organochlorine pesticides and can be used a potential molecular marker for the monitor of DDT and lindane contamination in the aquatic environment.
authors.affiliation: Department of Genetics, School of Basic Medical Science, Wuhan University, Wuhan, Hubei, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Lu
authors.affiliation: The Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Long
authors.affiliation: Department of Genetics, School of Basic Medical Science, Wuhan University, Wuhan, Hubei, China.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Genetics, School of Basic Medical Science, Wuhan University, Wuhan, Hubei, China.
authors.forename: Rongze
authors.initials: R
authors.lastname: Sun
authors.affiliation: Department of Genetics, School of Basic Medical Science, Wuhan University, Wuhan, Hubei, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhong
authors.affiliation: The Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China.
authors.forename: Zongbin
authors.initials: Z
authors.lastname: Cui
mesh_terms: D000818:Animals; D003634:DDT / Q000633:toxicity; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D001556:Hexachlorocyclohexane / Q000633:toxicity; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity; D018374:LLC-PK1 Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis* / Q000235:genetics; D009865:Oocytes / Q000187:drug effects*; D010575:Pesticides / Q000633:toxicity; D013552:Swine; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development; D029961:Zebrafish Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D003634:DDT; D001556:Hexachlorocyclohexane; D006843:Hydrocarbons, Chlorinated; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010575:Pesticides; D029961:Zebrafish Proteins; C000592651:Abcc4 protein, zebrafish