title: Hydroxyl metabolite of PCB 180 induces DNA damage signaling and enhances the DNA damaging effect of benzo[a]pyrene.
abstract: Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) and their hydroxyl metabolites (OH-PCBs) are ubiquitous environmental contaminants in human tissues and blood. The toxicological impact of these metabolites is poorly understood. In this study rats were exposed to ultrapure PCB180 (10-1000mg/kgbw) for 28days and induction of genotoxic stress in liver was investigated. DNA damage signaling proteins (pChk1Ser317 and γH2AXSer319) were increased dose dependently in female rats. This increase was paralleled by increasing levels of the metabolite 3'-OH-PCB180. pChk1 was the most sensitive marker. In in vitro studies HepG2 cells were exposed to 1μM of PCB180 and 3'-OH-PCB180 or the positive control benzo[a]pyrene (BaP, 5μM). 3'-OH-PCB180, but not PCB180, induced CYP1A1 mRNA and γH2AX. CYP1A1 mRNA induction was seen at 1h, and γH2AX at 3h. The anti-oxidant N-Acetyl-l-Cysteine (NAC) completely prevented, and 17β-estradiol amplified the γH2AX induction by 3'-OH-PCB180. As 3'-OH-PCB180 induced CYP1A1, a major BaP-metabolizing and activating enzyme, interactions between 3'-OH-PCB180 and BaP was also studied. The metabolite amplified the DNA damage signaling response to BaP. In conclusion, metabolism of PCB180 to its hydroxyl metabolite and the subsequent induction of CYP1A1 seem important for DNA damage induced by PCB180 in vivo. Amplification of the response with estradiol may explain why DNA damage was only seen in female rats.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Lauy
authors.initials: L
authors.lastname: Al-Anati
authors.affiliation: Chemicals and Health Unit, National Institute for Health and Welfare (THL), P.O. Box 95, FI-70701 Kuopio, Finland; Department of Environmental Science, University of Eastern Finland, FI-70211 Kuopio, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Viluksela
authors.affiliation: Analytical and Toxicological Chemistry Unit, Department of Environmental Science and Analytical Chemistry, Stockholm University, SE 106-91 Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Strid
authors.affiliation: Analytical and Toxicological Chemistry Unit, Department of Environmental Science and Analytical Chemistry, Stockholm University, SE 106-91 Stockholm, Sweden; Swedish Toxicology Sciences Research Center (Swetox), Forskargatan 20, 151 36 Södertälje, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Bergman
authors.affiliation: Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: Patrik L
authors.initials: PL
authors.lastname: Andersson
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Ulla
authors.initials: U
authors.lastname: Stenius
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: johan.hogberg@ki.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Högberg
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D000071877:Checkpoint Kinase 1; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects*; D004357:Drug Synergism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D056945:Hep G2 Cells / Q000187:drug effects; D006657:Histones; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity*; D011494:Protein Kinases / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C000602900:2,2',3,4,4',5,5'-heptachloro-3'-hydroxybiphenyl; C468783:H2AX protein, human; D006657:Histones; D017382:Reactive Oxygen Species; D017665:Hydroxyl Radical; D001564:Benzo(a)pyrene; D004958:Estradiol; C410127:PCB 180; D011078:Polychlorinated Biphenyls; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; D000111:Acetylcysteine
keywords: Benzo(a)pyrene; CYP1A1mRNA induction; DNA damage; Hydroxy-PCBs; NDL-PCBs; Oxidative stress