Biokinetics and Subchronic Toxic Effects of Oral Arsenite, Arsenate, Monomethylarsonic Acid, and Dimethylarsinic Acid in v-Ha-ras Transgenic (Tg.AC) Mice

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 μg/200 μL 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

Biokinetics and Subchronic Toxic Effects of Oral Arsenite, Arsenate, Monomethylarsonic Acid, and Dimethylarsinic Acid in v-Ha- Transgenic (Tg.AC) Mice-2

<p><b>Copyright information:</b></p><p>Taken from "Biokinetics and Subchronic Toxic Effects of Oral Arsenite, Arsenate, Monomethylarsonic Acid, and Dimethylarsinic Acid in v-Ha- Transgenic (Tg.AC) Mice"</p><p>Environmental Health Perspectives 2004;112(12):1255-1263.</p><p>Published online 18 Jun 2004</p><p>PMCID:PMC1277119.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p

Biokinetics and Subchronic Toxic Effects of Oral Arsenite, Arsenate, Monomethylarsonic Acid, and Dimethylarsinic Acid in v-Ha- Transgenic (Tg.AC) Mice-5

<p><b>Copyright information:</b></p><p>Taken from "Biokinetics and Subchronic Toxic Effects of Oral Arsenite, Arsenate, Monomethylarsonic Acid, and Dimethylarsinic Acid in v-Ha- Transgenic (Tg.AC) Mice"</p><p>Environmental Health Perspectives 2004;112(12):1255-1263.</p><p>Published online 18 Jun 2004</p><p>PMCID:PMC1277119.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p

Biokinetics and Subchronic Toxic Effects of Oral Arsenite, Arsenate, Monomethylarsonic Acid, and Dimethylarsinic Acid in v-Ha- Transgenic (Tg.AC) Mice-3

<p><b>Copyright information:</b></p><p>Taken from "Biokinetics and Subchronic Toxic Effects of Oral Arsenite, Arsenate, Monomethylarsonic Acid, and Dimethylarsinic Acid in v-Ha- Transgenic (Tg.AC) Mice"</p><p>Environmental Health Perspectives 2004;112(12):1255-1263.</p><p>Published online 18 Jun 2004</p><p>PMCID:PMC1277119.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p

Biokinetics and Subchronic Toxic Effects of Oral Arsenite, Arsenate, Monomethylarsonic Acid, and Dimethylarsinic Acid in v-Ha- Transgenic (Tg.AC) Mice-0

<p><b>Copyright information:</b></p><p>Taken from "Biokinetics and Subchronic Toxic Effects of Oral Arsenite, Arsenate, Monomethylarsonic Acid, and Dimethylarsinic Acid in v-Ha- Transgenic (Tg.AC) Mice"</p><p>Environmental Health Perspectives 2004;112(12):1255-1263.</p><p>Published online 18 Jun 2004</p><p>PMCID:PMC1277119.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p

Biokinetics and Subchronic Toxic Effects of Oral Arsenite, Arsenate, Monomethylarsonic Acid, and Dimethylarsinic Acid in v-Ha- Transgenic (Tg.AC) Mice-4

<p><b>Copyright information:</b></p><p>Taken from "Biokinetics and Subchronic Toxic Effects of Oral Arsenite, Arsenate, Monomethylarsonic Acid, and Dimethylarsinic Acid in v-Ha- Transgenic (Tg.AC) Mice"</p><p>Environmental Health Perspectives 2004;112(12):1255-1263.</p><p>Published online 18 Jun 2004</p><p>PMCID:PMC1277119.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p