title: Reduced cellular DNA repair capacity after environmentally relevant arsenic exposure. Influence of Ogg1 deficiency.
abstract: Inorganic arsenic (i-As) is a genotoxic and carcinogenic environmental contaminant known to affect millions of people worldwide. Our previous work demonstrated that chronic sub-toxic i-As concentrations were able to induce biologically significant levels of genotoxic and oxidative DNA damage that were strongly influenced by the Ogg1 genotype. In order to study the nature of the observed levels of damage and the observed differences between MEF Ogg1(+/+) and Ogg1(-/-) genetic backgrounds, the genotoxic and oxidative DNA repair kinetics of 18-weeks exposed MEF cells were evaluated by the comet assay. Results indicate that MEF Ogg1(+/+) and Ogg1(-/-) cells chronically exposed to i-As repair the DNA damage induced by arsenite, potassium bromide and UVC radiation less efficiently than control cells, being that observation clearly more pronounced in MEF Ogg1(-/-) cells. Consequently, exposed cells accumulate a higher percentage of unrepaired DNA damage at the end of the repair period. As an attempt to eliminate i-As associated toxicity, chronically exposed MEF Ogg1(-/-) cells overexpress the arsenic metabolizing enzyme As3mt. This adaptive response confers cells a significant resistance to i-As-induced cell death, but at expenses of accumulating high levels of DNA damage due to their repair impairment. Overall, the work presented here evidences that i-As chronic exposure disrupts the normal cellular repair function, and that oxidative DNA damage-and Ogg1 deficiency-exacerbates this phenomenon. The observed cell death resistance under a chronic scenario of genotoxic and oxidative stress may in turn contribute to the carcinogenic effects of i-As.
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Bach
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain.
authors.forename: Jana
authors.initials: J
authors.lastname: Peremartí
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain.
authors.forename: Balasubramnayam
authors.initials: B
authors.lastname: Annangi
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain; CIBER Epidemiología y Salud Pública, ISCIII, Madrid, Spain. Electronic address: ricard.marcos@uab.es.
authors.forename: Ricard
authors.initials: R
authors.lastname: Marcos
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain; CIBER Epidemiología y Salud Pública, ISCIII, Madrid, Spain. Electronic address: alba.hernandez@uab.es.
authors.forename: Alba
authors.initials: A
authors.lastname: Hernández
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D004249:DNA Damage / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D004781:Environmental Exposure; D005347:Fibroblasts; D005786:Gene Expression Regulation / Q000187:drug effects; D008780:Methyltransferases / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018384:Oxidative Stress / Q000235:genetics; D014466:Ultraviolet Rays
chemical_list: D008780:Methyltransferases; C532135:AS3MT protein, mouse; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D001151:Arsenic
keywords: Arsenic; As3mt; Chronic exposure; DNA repair kinetics; Ogg1; Oxidative DNA damage