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

Shugo Suzuki, Lora L Arnold, Karen L. Pennington, Baowei Chen, Hua Naranmandura, X. Chris Le, Samuel Monroe Cohen

Research output: Contribution to journalArticle

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Abstract

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 (DMAIII) and monomethylarsonous acid (MMAIII). Short-term treatment of rats with 100 μg/g trivalent arsenic (AsIII) 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 AsIII. There were no effects at 1 ppm AsIII. The main urinary arsenical in AsIII-treated rats was the organic arsenical dimethylarsinic acid (DMAV). The thio-metabolites dimethylmonothioarsinic acid (DMMTAV) and monomethylmonothioarsinic acid (MMMTAV) were also found in the urine of AsIII-treated rats. The LC50 concentrations of DMMTAV for rat and human urothelial cells in vitro were similar to trivalent oxygen-containing arsenicals. These data suggest that dietary AsIII-induced urothelial cytotoxicity and proliferation are dose responsive, and the urothelial effects have a threshold corresponding to the urinary excretion of measurable reactive metabolites.

Original languageEnglish (US)
Pages (from-to)99-105
Number of pages7
JournalToxicology and Applied Pharmacology
Volume244
Issue number2
DOIs
StatePublished - Apr 1 2010

Fingerprint

Arsenicals
Dietary Sodium
Arsenic
Metabolites
Rats
Urinary Bladder
Epithelium
Cytotoxicity
Cell proliferation
Drinking Water
Hyperplasia
Cell Proliferation
Cacodylic Acid
Poisons
Inbred F344 Rats
Nutrition
Urinary Bladder Neoplasms
Tumors
Skin
Necrosis

Keywords

  • Arsenite (As)
  • Dimethylarsinous acid (DMA)
  • Monomethylmonothioarsonic acid (MMMTA)
  • Urinary bladder, urothelial cell cytotoxicity, hyperplasia, dimethylmonothioarsinic acid (DMMTA)

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

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. / Suzuki, Shugo; Arnold, Lora L; Pennington, Karen L.; Chen, Baowei; Naranmandura, Hua; Le, X. Chris; Cohen, Samuel Monroe.

In: Toxicology and Applied Pharmacology, Vol. 244, No. 2, 01.04.2010, p. 99-105.

Research output: Contribution to journalArticle

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