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Severe systemic toxicity and urinary bladder cytotoxicity and regenerative hyperplasia induced by arsenite in arsenic (+3 oxidation state) methyltransferase knockout mice. A preliminary report
Citation:
Yokohira, M., N. L. Arnold, K. L. Pennington, S. Suzuki, S. Kakiuchi-Kiyota, S. M. Cohen, K. HERBIN-DAVIS, AND D. J. THOMAS. Severe systemic toxicity and urinary bladder cytotoxicity and regenerative hyperplasia induced by arsenite in arsenic (+3 oxidation state) methyltransferase knockout mice. A preliminary report. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, 246(1-2):1-7, (2010).
Impact/Purpose:
This ms describes the relative sensitivity of the urinary bladder epithelial cells in wild-type and As3mt knockout mice to the cytotoxic effects of dietary exposure to inorganic arsenic. The greater response seen in As3mt knockout mice reflects the altered kinetics of metabolism and clearance of inorganic arsenic in mice with an altered Iphenotype for arsenic methylation
Description:
Arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes reactions which convert inorganic arsenic to methylated metabolites. This study determined whether the As3mt null genotype in the mouse modifies cytotoxic and proliferative effects seen in urinary bladders of wild type mice after exposure to inorganic arsenic. Female wild type C57BL/6 mice and As3mt KO mice were divided into 3 groups each (n=8) with free access to a diet containing 0, 100 or 150 ppm of arsenic as arsenite (AsIII) . During the firs tweek of AsIII exposure, As3mt KO mice exhibited severe and lethal systemic toxicity; however, AsIII-treated wild type mice were unaffected. At sacrifice, urinary bladders of both As3mt KO and wild type mice showed hyperplasia by light microscopy. As expected, arsenic-containing granules were found in the superficial urothelial layer of wild type mice. In As3mt KO mice these granules were present in all layers of the bladder epithelium and were more abundant and larger than in wild type mice. Scanning electron microscopy of the bladder urothelium of As3mt KO mice treated with 100 ppm AsIlI showed extensive superficial necrosis and hyperplastic changes. In As3mt KO mice, livers showed severe acute inflammatory changes and spleen size and lymphoid areas were decreased compared with wild type mice. Thus, diminished arsenic methylation inAs3mt KO mice exacerbates systemic toxicity and the effects of AsIII on the bladder epithelium, showing that altered kinetic and dynamic behavior of arsenic can affect its toxicity. This manuscript has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.