Dietary administration of sodium arsenite to rats: Relations between dose and urinary concentrations of methylated and thio-metabolites and effects on the rat urinary bladder epithelium

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

DOI:https://doi.org/10.1016/j.taap.2009.12.026· OSTI ID:21344911

Suzuki, Shugo; Arnold, Lora L; Pennington, Karen L ^[1]; Chen, Baowei; Naranmandura, Hua; Le, X Chris ^[2]

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1. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135 (United States)
2. Analytical and Environmental Toxicology Division, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, T6G 2G3 (Canada)

Based on epidemiological data, chronic exposure to high levels of inorganic arsenic in drinking water is carcinogenic to humans, inducing skin, urinary bladder and lung tumors. In vivo, inorganic arsenic is metabolized to organic methylated arsenicals including the highly toxic dimethylarsinous acid (DMA{sup III}) and monomethylarsonous acid (MMA{sup III}). Short-term treatment of rats with 100 mug/g trivalent arsenic (As{sup III}) as sodium arsenite in the diet or in drinking water induced cytotoxicity and necrosis of the urothelial superficial layer, with increased cell proliferation and hyperplasia. The objectives of this study were to determine if these arsenic-induced urothelial effects are dose responsive, the dose of arsenic at which urothelial effects are not detected, and the urinary concentrations of the arsenical metabolites. We treated female F344 rats for 5 weeks with sodium arsenite at dietary doses of 0, 1, 10, 25, 50, and 100 ppm. Cytotoxicity, cell proliferation and hyperplasia of urothelial superficial cells were increased in a dose-responsive manner, with maximum effects found at 50 ppm As{sup III}. There were no effects at 1 ppm As{sup III}. The main urinary arsenical in As{sup III}-treated rats was the organic arsenical dimethylarsinic acid (DMA{sup V}). The thio-metabolites dimethylmonothioarsinic acid (DMMTA{sup V}) and monomethylmonothioarsinic acid (MMMTA{sup V}) were also found in the urine of As{sup III}-treated rats. The LC{sub 50} concentrations of DMMTA{sup V} for rat and human urothelial cells in vitro were similar to trivalent oxygen-containing arsenicals. These data suggest that dietary As{sup III}-induced urothelial cytotoxicity and proliferation are dose responsive, and the urothelial effects have a threshold corresponding to the urinary excretion of measurable reactive metabolites.

• OSTI ID: 21344911
• Journal Information: Toxicology and Applied Pharmacology, Vol. 244, Issue 2; Other Information: DOI: 10.1016/j.taap.2009.12.026; PII: S0041-008X(09)00533-X; Copyright (c) 2009 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 COMPOUNDS
BLADDER
CARCINOGENS
CELL PROLIFERATION
CHRONIC EXPOSURE
DOSES
DRINKING WATER
EPITHELIUM
LUNGS
MEN
METABOLITES
NECROSIS
NEOPLASMS
OXYGEN
RATS
SKIN
SODIUM COMPOUNDS
TOXICITY
URINE
ALKALI METAL COMPOUNDS
ANIMAL TISSUES
ANIMALS
BIOLOGICAL MATERIALS
BIOLOGICAL WASTES
BODY
BODY FLUIDS
DISEASES
ELEMENTS
HYDROGEN COMPOUNDS
MALES
MAMMALS
MAN
MATERIALS
NONMETALS
ORGANS
OXYGEN COMPOUNDS
PATHOLOGICAL CHANGES
PRIMATES
RESPIRATORY SYSTEM
RODENTS
URINARY TRACT
VERTEBRATES
WASTES
WATER