title: Oxidative DNA damage enhances the carcinogenic potential of in vitro chronic arsenic exposures.
abstract: Chronic exposure to arsenic is known to increase the incidence of cancer in humans. Our previous work demonstrated that environmentally relevant arsenic exposures generate an accelerated accumulation of pre-carcinogen 8-OH-dG DNA lesions under Ogg1-deficient backgrounds, but it remains unproved whether this observed arsenic-induced oxidative DNA damage (ODD) is certainly important in terms of cancer. Here, isogenic MEF Ogg1 (+/+) cells and MEF Ogg1 (-/-) cells-unable to properly eliminate 8-OH-dG from DNA-were exposed to 0.5, 1 and 2 µM of sodium arsenite for 40 weeks. The acquisition of an in vitro cancer-like phenotype was assessed throughout the exposure; matrix metalloproteinase (MMP) activities were measured by zymography, colony formation and promotion were evaluated by soft agar assay, and cellular invasiveness was measured by the transwell assay. Alterations in cellular morphology, growth and differentiation status were also included as complementary measures of transformation. MEF Ogg1 (-/-) cells showed a cancer-associated phenotype after 30 weeks of exposure, as indicated by morphological changes, increased proliferation, deregulated differentiation status, increased MMPs secretion, anchorage-independent cell growth and enhancement of tumor growth and invasiveness. Conversely, MEF Ogg1 (+/+) cells did not present changes in morphology or proliferation, exhibited a milder degree of gene deregulation and needed 10 weeks of additional exposure to the highest arsenite doses to show tumor enhancing effects. Thus, Ogg1 genetic background and arsenic-induced 8-OH-dG proved relevant for arsenic-mediated carcinogenic effects. To our knowledge, this is the first study directly linking ODD with arsenic carcinogenesis.
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, 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, Bellaterra, 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, Bellaterra, Spain.
authors.forename: Balasubramanyam
authors.initials: B
authors.lastname: Annangi
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, Spain. Ricard.marcos@uab.es.|CIBER Epidemiología y Salud Pública, ISCIII, Madrid, Spain. Ricard.marcos@uab.es.|Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Edifici Cn, Campus de Bellaterra, 08193, Cerdanyola del Vallès, Barcelona, Spain. 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, Bellaterra, Spain.|CIBER Epidemiología y Salud Pública, ISCIII, Madrid, Spain.|Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Edifici Cn, Campus de Bellaterra, 08193, Cerdanyola del Vallès, Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Hernández
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D015153:Blotting, Western; D002274:Carcinogens, Environmental / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017670:Sodium Compounds / Q000633:toxicity*
chemical_list: D018053:Arsenites; D002274:Carcinogens, Environmental; D004785:Environmental Pollutants; D017670:Sodium Compounds; C017947:sodium arsenite; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse
keywords: 8-OH-dG; Arsenic; Carcinogenesis; Chronic exposure; Fibroblasts; Ogg1; Oxidative DNA damage