title: Oxidative DNA damage after acute exposure to arsenite and monomethylarsonous acid in biomethylation-deficient human cells.
abstract: The carcinogen inorganic arsenic (iAs) undergoes biomethylation (BMT) in some cells. The methylated metabolite, monomethylarsonous (MMA(3+)), may cause oxidative DNA damage (ODD). With chronic iAs exposure, BMT-competent cells show ODD while BMT-deficient do not. To further define these events, we studied ODD produced by acute iAs or MMA(3+) in the BMT-deficient human prostate cell line, RWPE-1. ODD, measured by the immuno-spin trapping method, was assessed after exposure to iAs or MMA(3+) alone, with the arsenic BMT inhibitor selenite or after glutathione (GSH) depletion. The expression of oxidative stress-related genes (HO-1, SOD-1, SOD-2, Nrf2 and Keap-1) was also assessed. Exposure to iAs at 24 h (0-20 µM), stimulated ODD only at levels above the LC50 of a 48 h exposure (17 µM). If iAs induced ODD, it also activated oxidative stress-related genes. Selenium did not alter iAs-induced ODD. MMA(3+) at 24 h (0-0.5 µM) caused ODD at levels below the LC50 of a 48 h exposure (1.5 µM), which were greatly increased by GSH depletion but not selenite. MMA(3+) induced ODD at levels not activating oxidant stress response genes. Overall, iAs induced ODD in BMT-deficient cells only at toxic levels. MMA(3+) caused ODD at non-toxic levels, independently of cellular BMT capacity and in a fashion not requiring further BMT.
authors.affiliation: Inorganic Toxicology Group, National Toxicology Program Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Orihuela
authors.forename: Chikara
authors.initials: C
authors.lastname: Kojima
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Tokar
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Person
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Qu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Waalkes
mesh_terms: D018053:Arsenites / Q000378:metabolism / Q000633:toxicity*; D018929:Cell Culture Techniques; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008745:Methylation; D009942:Organometallic Compounds / Q000378:metabolism / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D017670:Sodium Compounds / Q000378:metabolism / Q000633:toxicity*; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D014874:Water Pollutants, Chemical / Q000378:metabolism / Q000633:toxicity*
chemical_list: D018053:Arsenites; D009942:Organometallic Compounds; D017670:Sodium Compounds; D014874:Water Pollutants, Chemical; C406082:monomethylarsonous acid; C017947:sodium arsenite; D005978:Glutathione