title: Oxoguanine glycosylase 1 (OGG1) protects cells from DNA double-strand break damage following methylmercury (MeHg) exposure.
abstract: Methylmercury (MeHg) is a potent neurotoxin, teratogen, and probable carcinogen, but the underlying mechanisms of its actions remain unclear. Although MeHg causes several types of DNA damage, the toxicological consequences of this macromolecular damage are unknown. MeHg enhances oxidative stress, which can cause various oxidative DNA lesions that are primarily repaired by oxoguanine glycosylase 1 (OGG1). Herein, we compared the response of wild-type and OGG1 null (Ogg1(-/-)) murine embryonic fibroblasts to environmentally relevant, low micromolar concentrations of MeHg by measuring clonogenic efficiency, cell cycle arrest, DNA double-strand breaks (DSBs), and activation of the DNA damage response pathway.Ogg1(-/-) cells exhibited greater sensitivity to MeHg than wild-type controls, as measured by the clonogenic assay, and showed a greater propensity for MeHg-initiated apoptosis. Both wild-type and Ogg1(-/-) cells underwent cell cycle arrest when exposed to micromolar concentrations of MeHg; however, the extent of DSBs was exacerbated in Ogg1(-/-) cells compared with that in wild-type controls. Pretreatment with the antioxidative enzyme catalase reduced levels of DSBs in both wild-type and Ogg1(-/-) cells but failed to block MeHg-initiated apoptosis at micromolar concentrations. Our findings implicate reactive oxygen species mediated DNA damage in the mechanism of MeHg toxicity; and demonstrate for the first time that impaired DNA repair capacity enhances cellular sensitivity to MeHg. Accordingly, the genotoxic properties of MeHg may contribute to its neurotoxic and teratogenic effects, and an individual's response to oxidative stress and DNA damage may constitute an important determinant of risk.
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Ondovcik
authors.forename: Laura
authors.initials: L
authors.lastname: Tamblyn
authors.forename: John Peter
authors.initials: JP
authors.lastname: McPherson
authors.forename: Peter G
authors.initials: PG
authors.lastname: Wells
mesh_terms: D000818:Animals; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D008767:Methylmercury Compounds / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D008767:Methylmercury Compounds; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse