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ToxSci Advance Access published online on October 7, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp241
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

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

Mitscheli Sanches da Rocha*, Merielen Garcia do Nascimento*, Ana Paula Ferragut Cardoso*, Patrícia Lepage Alves de Lima*, Edneia Aparecida Zelandi*, João Lauro Viana de Camargo* and Maria Luiza Cotrim Sartor de Oliveira*

* Center for the Evaluation of the Environmental Impact on Human Health (TOXICAM)

Department of Pathology, Botucatu Medical School, UNESP - São Paulo State University, Botucatu, 18618-000, São Paulo, Brazil., João Lauro Viana de Camargo, Departamento de Patologia, Faculdade de Medicina, UNESP, 18618-000, Botucatu, São Paulo, Brasil, Tel: +55 14 38116238; Fax: +55 14 38152348, Email: decam{at}fmb.unesp.br

Received June 10, 2009; revision received September 23, 2009; accepted September 28, 2009


  Abstract

Diuron, a substituted urea herbicide, is carcinogenic to the urinary bladder of rats at high dietary levels. Its proposed carcinogenic mode of action (MOA) includes urothelial cytotoxicity and necrosis followed by regenerative cell proliferation and sustained urothelial hyperplasia. Cytotoxicity could be induced either by urinary solids or by chemical toxicity by diuron and/or metabolites excreted in the urine. Diuron was not genotoxic in a previous single cell gel (comet) assay, but possible cross-linking activity remained to be evaluated. The present study explored the MOA of diuron and the effect of urinary acidification on the development of urothelial lesions. Male Wistar rats were fed diuron (2,500 ppm, about 130 mg/kg of body weight) either with or without NH4Cl 10,000 ppm to acidify the urine. Reversibility of urothelial changes was also examined. The animals were euthanized after 15, 25 or 30 weeks. Diuron-fed rats had urinary amorphous precipitate and magnesium ammonium phosphate crystals similar to control animals. Groups treated with diuron+NH4Cl showed decreased urinary pH and reduced amounts of urinary crystals and precipitate. Urothelial necrosis and simple hyperplasia were observed by light microscopy and scanning electron microscopy both in diuron and in diuron+NH4Cl treated groups. Cytotoxicity and proliferative changes were mostly reversible. A modified comet assay developed in vitro with CHO cells showed that diuron did not induce DNA cross-links. These data suggest that cytotoxicity with consequent regenerative cell proliferation is the predominant MOA for diuron rat urothelial carcinogenesis, the cytotoxicity being chemically induced and not due to urinary solids.

Key Words: Urinary bladder; urinary pH; urothelial hyperplasia; urinary crystals and precipitates; DNA cross-link; cytotoxicity.

mitscheli{at}gmail.com, merielen{at}fmb.unesp.br, anapaulafc1{at}hotmail.com, patilepage{at}hotmail.com, ezelandi{at}hotmail.com, decam{at}fmb.unesp.br, mdeolive{at}fmb.unesp.br


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