Severe systemic toxicity and urinary bladder cytotoxicity and regenerative hyperplasia induced by arsenite in arsenic (+3 oxidation state) methyltransferase knockout mice. A preliminary report

Masanao Yokohira, Lora L. Arnold, Karen L. Pennington, Shugo Suzuki, Satoko Kakiuchi-Kiyota, Karen Herbin-Davis, David J. Thomas, Samuel M. Cohen

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

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 150ppm of arsenic as arsenite (AsIII). During the first week of AsIII exposure, As3mt KO mice exhibited severe and lethal systemic toxicity. At termination, 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 100ppm AsIII 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 in As3mt 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.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalToxicology and Applied Pharmacology
Volume246
Issue number1-2
DOIs
StatePublished - Jul 2010

Keywords

  • Arsenic methyltransferase
  • Arsenite
  • Bladder
  • Hyperplasia
  • Mouse
  • Toxicity

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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