Carcinogenicity of dimethylarsinic acid in Ogg1‐deficient mice
Open Access
- 18 April 2007
- journal article
- carcinogenesis
- Published by Wiley in Cancer Science
- Vol. 98 (6), 803-814
- https://doi.org/10.1111/j.1349-7006.2007.00475.x
Abstract
Oxidative stress to DNA is recognized as a mechanism underlying carcinogenic effects of some environmental agents. Here, we hypothesized that dimethylarsinic acid (DMAV), an organic metabolite of inorganic arsenic in humans, might exert carcinogenic potential in a mouse line carrying a mutant Mmh allele of the Mmh/OGG1 gene encoding the enzyme 8-hydroxyguanine DNA glycosylase 1 (OGG1). Ogg1 mutant and wild type mice were treated with DMAV in their drinking water at a dose of 200 p.p.m. for up to 72 weeks. All DMAV-treated Ogg1−/–animals developed tumors, with a tendency for lower total incidences in the Ogg1+/+ cases. Lung tumors in particular were induced as compared to the lack in non-carcinogen controls and were significantly more frequent in the homozygotes. At week 4, the levels of DNA 8-OH-dG and cell proliferation were significantly elevated in the lungs of non-treated Ogg1−/– as compared to Ogg1+/+ mice and were strongly enhanced by DMAV treatment. Marked induction of Pola1, Cyp7b1, Ndfua3, Mmp13 and other genes specific to cell proliferation, cell signaling and xenobiotic metabolism in the lungs of DMAV-treated Ogg1−/– mice was found. Electron microscopic examination revealed the growth of microvilli, with increased numbers of mitochondria only in lungs and lung tumors of DMAV-exposed Ogg1−/– mice. Therefore, we strongly suggest that DMAV exerts carcinogenicity in the lungs of Ogg1−/– mutant mice, with a possible role for persistent accumulation of DNA oxidative adducts. (Cancer Sci 2007; 98: 803–814)This publication has 42 references indexed in Scilit:
- 8-Oxoguanine Formation Induced by Chronic UVB Exposure Makes Ogg1 Knockout Mice Susceptible to Skin CarcinogenesisCancer Research, 2005
- Cloning of a human homolog of the yeast OGG1 gene that is involved in the repair of oxidative DNA damageOncogene, 1997
- Dimethylarsinic acid treatment alters six different rat biochemical parameters: Relevance to arsenic carcinogenesisTeratogenesis, Carcinogenesis, and Mutagenesis, 1997
- Involvement of Preferential Formation of Apurinic/Apyrimidinic Sites in Dimethylarsenic-Induced DNA Strand Breaks and DNA-Protein Crosslinks in Cultured Alveolar Epithelial CellsBiochemical and Biophysical Research Communications, 1995
- Induction of lung-specific DNA damage by metabolically methylated arsenics via the production of free radicals.Environmental Health Perspectives, 1994
- Induction of Lung-Specific DNA Damage by Metabolically Methylated Arsenics via the Production of Free RadicalsEnvironmental Health Perspectives, 1994
- Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodGNature, 1991
- Induction of DNA damage by dimethylarsine, a metabolite of inorganic arsenics, is for the major part likely due to its peroxyl radicalBiochemical and Biophysical Research Communications, 1990
- Dimethylated arsenics induce DNA strand breaks in lung via the production of active oxygen in miceBiochemical and Biophysical Research Communications, 1989
- Tissue distribution and retention of74As-dimethylarsinic acid in mice and ratsArchives of Environmental Contamination and Toxicology, 1984