Diuron carcinogenicity study: morfological and transcriptional changes induced in the urothelium of rats

Abstract

Diuron (3-(3,4- Dichloropenyl)- 1,1- dimethylurea) is an urea-derived herbicide used in several crops types that induces urothelial tumors in Wistar rats fed 2500ppm during 2 years. The suggested non-genotoxic carcinogenic mode of action involves: metabolic activation mainly N- (3,4- dichlorophenyl) urea (DCPU) and 4,5-dichloro-2-hydroxyphenyl) urea (2-OHDCPU), cytotoxicity, necrosis, exfoliation, regenerative cell proliferation and eventually urinary bladder tumors. The dose-response relationship of diuron occurs both: in the induction of transcriptional alterations and in the incidence of morphological changes. Although the induction of urothelial carcinogenicity by exposure to high concentrations (1.250ppm and 2.500ppm) of diuron is well established, successive studies performed in our laboratory suggest that the intermediate concentration of 500 ppm in the diet may also be cytotoxic and carcinogenic of the urothelium rats. Carcinogenicity evidence for this concentration would cause direct impact on the risk assessment of this substance, since the concentration of 500ppm is five times smaller than the currently described in the literature as carcinogenic (2.500ppm) and very close to the currently accepted NOAEL (125ppm). The purpose of this study will be to evaluate the development of lesions in a long exposure time and compare them with changes in gene expression that are relevant to the development of urothelial lesions chemically induced. Wistar rats will be allocated in control or diuron 500ppm group and evaluated at the 20th and 104th week. The urinary bladders will be submitted to scanning electron microscopy, histological or qRT-PCR analysis to for identification and classification of citotoxicity changes and gene expression alterations in the urothelium (AU)