title: Arsenicals affect base excision repair by several mechanisms.
abstract: Inorganic arsenic is a strong, widespread human carcinogen. How exactly inorganic arsenic exerts carcinogenicity in humans is as yet unclear, but it is thought to be closely related to its metabolism. At exposure-relevant concentrations arsenic is neither directly DNA reactive nor mutagenic. Thus, more likely epigenetic and indirect genotoxic effects, among others a modulation of the cellular DNA damage response and DNA repair, are important molecular mechanisms contributing to its carcinogenicity. In the present study, we investigated the impact of arsenic on several base excision repair (BER) key players in cultured human lung cells. For the first time gene expression, protein level and in case of human 8-oxoguanine DNA glycosylase 1 (hOGG1) protein function was examined in one study, comparing inorganic arsenite and its trivalent and pentavalent mono- and dimethylated metabolites, also taking into account their cellular bioavailability. Our data clearly show that arsenite and its metabolites can affect several cellular endpoints related to DNA repair. Thus, cellular OGG activity was most sensitively affected by dimethylarsinic acid (DMA(V)), DNA ligase IIIα (LIGIIIα) protein level by arsenite and X-ray cross complementing protein 1 (XRCC1 protein) content by monomethylarsonic acid (MMA(V)), with significant effects starting at ≥3.2μM cellular arsenic. With respect to MMA(V), to our knowledge these effects are the most sensitive endpoints, related to DNA damage response, that have been identified so far. In contrast to earlier nucleotide excision repair related studies, the trivalent methylated metabolites exerted strong effects on the investigated BER key players only at cytotoxic concentrations. In summary, our data point out that after mixed arsenic species exposure, a realistic scenario after oral inorganic arsenic intake in humans, DNA repair might be affected by different mechanisms and therefore very effectively, which might facilitate the carcinogenic process of inorganic arsenic.
authors.affiliation: Institute of Food Chemistry, University of Münster, Corrensstrasse 45, 48149 Münster, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Ebert
authors.forename: André
authors.initials: A
authors.lastname: Weiss
authors.forename: Milena
authors.initials: M
authors.lastname: Bültemeyer
authors.forename: Ingrit
authors.initials: I
authors.lastname: Hamann
authors.forename: Andrea
authors.initials: A
authors.lastname: Hartwig
authors.forename: Tanja
authors.initials: T
authors.lastname: Schwerdtle
mesh_terms: D001151:Arsenic / Q000633:toxicity*; D001152:Arsenicals; D018053:Arsenites / Q000633:toxicity; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival; D045647:DNA Glycosylases / Q000378:metabolism; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D009153:Mutagens / Q000633:toxicity*; D000075223:Poly-ADP-Ribose Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; D029867:Xenopus Proteins
chemical_list: D001152:Arsenicals; D018053:Arsenites; D004268:DNA-Binding Proteins; D009153:Mutagens; D000075223:Poly-ADP-Ribose Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D029867:Xenopus Proteins; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus; C015001:arsenite; D001151:Arsenic