Previous research demonstrated that 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment increased the number of skin
papillomas in v-Ha-ras transgenic (Tg.AC) mice that had received
sodium arsenite [(As(III)] in
drinking water, indicating that this model is useful for studying the toxic effects of
arsenic in vivo. Because the liver is a known target of
arsenic, we examined the pathophysiologic and molecular effects of inorganic and organic arsenical exposure on Tg.AC mouse liver in this study. Tg.AC mice were provided
drinking water containing As(III),
sodium arsenate [As(V)],
monomethylarsonic acid [(MMA(V)], and 1,000 ppm
dimethylarsinic acid [DMA(V)] at dosages of 150, 200, 1,500, or 1,000 ppm as
arsenic, respectively, for 17 weeks. Control mice received unaltered water. Four weeks after initiation of
arsenic treatment, TPA at a dose of 1.25 microg/200 microL
acetone was applied twice a week for 2 weeks to the shaved dorsal skin of all mice, including the controls not receiving
arsenic. In some cases
arsenic exposure reduced
body weight gain and caused mortality (including moribundity). Arsenical exposure resulted in a dose-dependent accumulation of
arsenic in the liver that was unexpectedly independent of chemical species and produced hepatic global
DNA hypomethylation.
cDNA microarray and
reverse transcriptase-polymerase chain reaction analysis revealed that all
arsenicals altered the expression of numerous genes associated with toxicity and
cancer. However, organic
arsenicals [MMA(V) and DMA(V)] induced a pattern of gene expression dissimilar to that of inorganic
arsenicals. In summary, subchronic exposure of Tg.AC mice to inorganic or organic
arsenicals resulted in toxic manifestations, hepatic
arsenic accumulation, global
DNA hypomethylation, and numerous gene expression changes. These effects may play a role in
arsenic-induced hepatotoxicity and
carcinogenesis and may be of particular toxicologic relevance.