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

Journal Article · Thu Jul 15 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.04.013· OSTI ID:21460182

Yokohira, Masanao; Arnold, Lora L; Pennington, Karen L ^[1]; Suzuki, Shugo ^[1]; Kakiuchi-Kiyota, Satoko ^[1]; Herbin-Davis, Karen; Thomas, David J ^[2]

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1. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-3135 (United States)
2. Pharmacokinetics Branch, Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States)

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 (As{sup III}). During the first week of As{sup III} 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 100 ppm As{sup III} 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 As{sup III} on the bladder epithelium, showing that altered kinetic and dynamic behavior of arsenic can affect its toxicity.

• OSTI ID: 21460182
• Journal Information: Toxicology and Applied Pharmacology, Vol. 246, Issue 1-2; Other Information: DOI: 10.1016/j.taap.2010.04.013; PII: S0041-008X(10)00140-7; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ARSENIC
ARSENIC COMPOUNDS
BLADDER
CELL PROLIFERATION
EPITHELIUM
INFLAMMATION
LIVER
METABOLITES
METHYL TRANSFERASES
MICE
SCANNING ELECTRON MICROSCOPY
TOXICITY
ANIMAL TISSUES
ANIMALS
BODY
CARBON-GROUP TRANSFERASES
DIGESTIVE SYSTEM
ELECTRON MICROSCOPY
ELEMENTS
ENZYMES
GLANDS
MAMMALS
MICROSCOPY
ORGANIC COMPOUNDS
ORGANS
PATHOLOGICAL CHANGES
PROTEINS
RODENTS
SEMIMETALS
SYMPTOMS
TRANSFERASES
URINARY TRACT
VERTEBRATES