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Subchronic effects of arsenic,arsenate,MMA and DMA in drinking water in Tg.AC mice

Kevin Trouba;Michael P.Waalkes;Dori R.Germolec

  Previous research indicates that 12_O-tetradecanoylphorbol—13-acetate(TPA) increased the number of skin papillomas in Tg.AC transgenic mice that received sodium arsenite in drinking water, indicating that this model is useful for studying the toxic effects of arsenic in vivo.In the present study,we examined the pathophysiological and molecular effects of inorganic and organic arsenical exposure on Tg.AC mouse liver.Tg.AC mice were exposed to sodium arsenite(As~Ⅲ),sodium arsenate(As~Ⅴ),monomethylarsonic acid(MMA~Ⅴ) and dimethylarsinic acid(DMA~Ⅴ),at the dosages of 150,200,1500 and 1000 ppm arsenic, respectively,in the drinking water for 17weeks.Control mice received unaltered water.Arsenic exposure reduced body weight gain by 8—15%at the end of the exposure as compared to controls.Mortality(including moribundity) incidence in mice treated with As~Ⅲ,MMA~Ⅴ,and DMA~Ⅴwas 20%,40%,and 15%respectively. Arsenic exposure resulted in a dose-dependent,but chemical species-independent accumulation of arsenic in the liver,and produced hepatic global DNA hypomethylation as assessed by the methyl-acceptance assay. CDNA micro array analysis revealed that all arsenicals induced similar yet distinct alterations in the expression of genes related to glutathione metabolism,stress,apoptosis and cell proliferation,and those associated with preneoplastic changes.Organic arsenicals(MMA~Ⅴand DMA~Ⅴ) induced a dissimilar pattern of gene expression than in organic arsenicals.Real-time RT-PCR was used to corroborate the findings of our micro array analyses for numerous genes proposed to be involved in toxicity and cancer.In summary,subchronic exposure to inorganic or organic arsenicals resulted in to toxic manifestations,hepatic arsenic accumulation,global DNA hypomethylation,and numerous gene expression changes.These effects in combination or alone may well play a role in arsenic toxicity and arsenic carcinogenesis.……