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Cytotoxicity of diuron and its metabolites: mitochondrial dysfunction, cell death, genotoxicity and mutagenicity

Abstract

The worldwide use of high amounts of pesticides is a matter of constant concern due to potential adverse effects on human health. Herbicides belongs to one of the most widely class of pesticides used in agriculture, being diuron, a compound derived from urea, the fifth most used in Brazil, despite its classification by the U.S. Environmental Protection Agency (USEPA) as "probably carcinogenic to the human species". This classification was based in the development of urinary bladder tumors in rats exposed during several months to high concentrations of diuron through diet. Our research group (TOXICAM) has published abroad several studies on the carcinogenic potential and mode of action (MOA) of diuron in highly ranked peer-reviewed journals. However, it remains unknown which diuron metabolite exerts direct cytotoxicity, and which is the intimate mechanism of toxicity. Xenobiotic-induced cytotoxicity occurs through different adverse pathways that may act individually or jointly leading to cell degeneration and death. Understanding mechanisms of cytotoxicity may support measures for preventing and or mitigation of potential adverse effects caused by chemicals in humans. This study aims to elucidate the effects of diuron in the urinary bladder urothelial cells and in liver cells, where most of its biotransformation occurs. Experimental test systems will be mitochondria isolated from the urinary bladder and the liver of Wistar rats, and bladder (1T1) and liver (HepG2) cell lines, both systems exposed in vitro individually to diuron or to each of its major metabolites, 3,4-dichlorophenylurea (DCPU) and 3,4-dichloroaniline (DCA). This project is a proposal for cooperation between the TOXICAM/Medical School and the Dr. Lilian Cristina Pereira, Dept. of Bioprocesses and Biotechnology/Faculty of Agronomic Sciences, who has consolidated expertise with in vitro tests of toxicological evaluation. Also, will have support from Dr. Samuel M. Cohen, University of Nebraska Medical Center (UNMC), USA, who will provide one of the cells lineages to be studied and will be involved in the interpretation and discussion of the results. The establishment of in vitro assays for high yield toxicological evaluation, such as cell-based screening, in this laboratory is a great qualitative and quantitative opportunity for our research group to advance its research on the cytotoxicity of diuron and others environmental contaminants. (AU)