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Comparative Distribution and Retention of Arsenic in Arsenic (+3 Oxidation State) Methyltransferase Knockout and Wild Type Mice
Citation:
HUGHES, M. F., B. C. EDWARDS, K. HERBIN-DAVIS, AND D. J. THOMAS. Comparative Distribution and Retention of Arsenic in Arsenic (+3 Oxidation State) Methyltransferase Knockout and Wild Type Mice. Presented at 2009 Annual Society of Toxicology meeting, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
This abstract describes the retention and distribution of radioactive arsenic in wild type mice and mice lacking the gene that codes for an arsenic methylating enzyme. The mice without this gene retain arsenic longer than mice with the gene, indicating the methylation of arsenic facilitates its excretion.
Description:
The mouse arsenic (+3 oxidation state) methyltransferase (As3mt) gene encodes a ~ 43 kDa protein that catalyzes conversion of inorganic arsenic into methylated products. Heterologous expression of AS3MT or its silencing by RNA interference controls arsenic methylation phenotypes in cultured human cells, suggesting a critical role for the enzyme in arsenic metabolism. Because methylated arsenicals mediate some of the toxic or carcinogenic effects associated with exposure to inorganic arsenic, studies of the fate and effects of arsenicals in mice which cannot methylate arsenic could be a valuable experimental tool. The mouse As3mt gene was disrupted by homologous recombination and transferred into the C57BL/6 mouse strain. Homozygous As3mt-/- mice are viable and fertile. This study compared retention and distribution of arsenic in As3mt knockout mice and C57BL/6 mice in which expression of the As3mt gene is normal. Male and female mice of either genotype received an oral dose of 0.5 mg of arsenic as arsenate per kg containing [73As]-arsenate as a label. Mice were radioassayed for up to 24 or 96 hours post dosing and tissues were collected at term. Whole body clearance of [73As] in As3mt knockouts is substantially slower than in C57BL/6 mice. At 24 hours post dosing, As3mt knockouts retain about 90% of the dose; C57BL/6 mice retain about 6%. After 96 hours, As3mt knockouts still retain 20% and C57BL/6 mice retain less than 2% of the dose. At 24 hours post dosing, As3mt knockout mice retain significantly higher percentages of arsenic dose in liver, kidney, urinary bladder, lungs, heart, and carcass than do C57BL/6 mice. These data confirm a central role for As3mt in metabolism of inorganic arsenic and indicate that phenotypes for arsenic retention and distribution are markedly affected by the null genotype for arsenic methylation. (This abstract does not reflect US EPA policy.)