Cytotoxicity and Regenerative Proliferation as the Mode of Action for Diuron-Induced Urothelial Carcinogenesis in the Rat

• DOI: 10.1093/toxsci/kfp241
• Publication Date: 2009-10-08T02:13:30Z
• Authors: Mitscheli S. da R...; Merielen G. Nasci...; Ana Paula F. Cardoso; Patrícia L. A. de...; Edneia A. Zelandi; João Lauro V. de ...; Maria Luiza C. S....
• Keywords: Comet Assay; Urothelial Cell

Diuron, a substituted urea herbicide, is carcinogenic to the urinary bladder of rats at high dietary levels. Its proposed mode action (MOA) includes urothelial cytotoxicity and necrosis followed by regenerative cell proliferation sustained hyperplasia. Cytotoxicity could be induced either solids or chemical toxicity diuron and/or metabolites excreted in urine. Diuron was not genotoxic previous single-cell gel (comet) assay, but possible cross-linking activity remained evaluated. The present study explored MOA effect acidification on development lesions. Male Wistar were fed (2500 ppm, about 130 mg/kg body weight) with without NH(4)Cl 10,000 ppm acidify Reversibility changes also examined. animals euthanized after 15, 25, 30 weeks. Diuron-fed had amorphous precipitate magnesium ammonium phosphate crystals similar control animals. Groups treated + showed decreased pH reduced amounts precipitate. Urothelial simple hyperplasia observed light microscopy scanning electron both diuron- NH(4)Cl-treated groups. proliferative mostly reversible. A modified comet assay developed vitro Chinese hamster ovary cells that did induce DNA cross-links. These data suggest consequent predominant for rat carcinogenesis, being chemically due solids.