title: Mechanism of synergistic DNA damage induced by the hydroquinone metabolite of brominated phenolic environmental pollutants and Cu(II): Formation of DNA-Cu complex and site-specific production of hydroxyl radicals.
abstract: 2,6-Dibromohydroquinone (2,6-DBrHQ) has been identified as an reactive metabolite of many brominated phenolic environmental pollutants such as tetrabromobisphenol-A (TBBPA), bromoxynil and 2,4,6-tribromophenol, and was also found as one of disinfection byproducts in drinking water. In this study, we found that the combination of 2,6-DBrHQ and Cu(II) together could induce synergistic DNA damage as measured by double strand breakage in plasmid DNA and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation, while either of them alone has no effect. 2,6-DBrHQ/Cu(II)-induced DNA damage could be inhibited by the Cu(I)-specific chelating agent bathocuproine disulfonate and catalase, but not by superoxide dismutase, nor by the typical hydroxyl radical (•OH) scavengers such as DMSO and mannitol. Interestingly, we found that Cu(II)/Cu(I) could be combined with DNA to form DNA-Cu(II)/Cu(I) complex by complementary application of low temperature direct ESR, circular dichroism, cyclic voltammetry and oxygen consumption methods; and the highly reactive •OH were produced synergistically by DNA-bound-Cu(I) with H2O2produced by the redox reactions between 2,6-DBrHQ and Cu(II), which then immediately attack DNA in a site-specific manner as demonstrated by both fluorescent method and by ESR spin-trapping studies. Further DNA sequencing investigations provided more direct evidence that 2,6-DBrHQ/Cu(II) caused preferential cleavage at guanine, thymine and cytosine residues. Based on these data, we proposed that the synergistic DNA damage induced by 2,6-DBrHQ/Cu(II) might be due to the synergistic and site-specific production of •OH near the binding site of copper and DNA. Our findings may have broad biological and environmental implications for future research on the carcinogenic polyhalogenated phenolic compounds.
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing 100085, PR China; School of Public Health, Jining Medical University, Jining, Shandong 272067, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Shao
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing 100085, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Mao
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing 100085, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Qu
authors.affiliation: College of Chemistry and Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education, Wuhan University, Wuhan, Hubei 430072, PR China.
authors.forename: Ya-Fen
authors.initials: YF
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing 100085, PR China.
authors.forename: Hui-Ying
authors.initials: HY
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing 100085, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing 100085, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing 100085, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shao
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing 100085, PR China.
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing 100085, PR China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing 100085, PR China.
authors.forename: Lin-Na
authors.initials: LN
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing 100085, PR China.
authors.forename: Chen
authors.initials: C
authors.lastname: Shen
authors.affiliation: College of Chemistry and Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education, Wuhan University, Wuhan, Hubei 430072, PR China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences and University of Chinese Academy of Sciences, The Chinese Academy of Sciences, Beijing 100085, PR China. Electronic address: bzhu@rcees.ac.cn.
authors.forename: Ben-Zhan
authors.initials: BZ
authors.lastname: Zhu
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000633:toxicity*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D060766:Drinking Water; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism / Q000633:toxicity; D017665:Hydroxyl Radical / Q000378:metabolism / Q000633:toxicity; D009570:Nitriles / Q000378:metabolism / Q000633:toxicity; D010084:Oxidation-Reduction; D010618:Phenanthrolines / Q000494:pharmacology; D010636:Phenols / Q000378:metabolism / Q000633:toxicity; D011075:Polybrominated Biphenyls / Q000378:metabolism / Q000633:toxicity; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase / Q000737:chemistry
chemical_list: D002614:Chelating Agents; D060766:Drinking Water; D004785:Environmental Pollutants; D006873:Hydroquinones; D009570:Nitriles; D010618:Phenanthrolines; D010636:Phenols; D011075:Polybrominated Biphenyls; D017382:Reactive Oxygen Species; D017665:Hydroxyl Radical; C028559:bathocuproine sulfonate; D003300:Copper; D000080242:8-Hydroxy-2'-Deoxyguanosine; D013482:Superoxide Dismutase; C020806:tetrabromobisphenol A; D003849:Deoxyguanosine; C006826:bromoxynil; C031927:hydroquinone; C004554:2,4,6-tribromophenol
keywords: 2,6-dibromohydroquinone; Cu(II); DNA strand breakage 8-oxo-7,8-dihydro-2'-deoxyguanosine formation; Hydroxyl radical; Site-specific mechanism