3,4-DICHLOROANILINE NEPHROTOXICITY

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DESCRIPTION: (Adapted from the Investigator's Abstract) 3,4-Dichloroaniline, an aromatic amine, is an ingredient in the production of several herbicides widely used in the U.S. 3, 4-Dichloroaniline is detectable in soil, groundwater and fresh water lakes throughout the world. The goal of this project is to investigate the renal toxicity of 3,4-dichloroaniline. The proposed studies will test the hypothesis that: a) 3,4-dichloroaniline nephrotoxicity is due to the parent compound as well as its metabolites, b) 3,4 dichloroaniline and its major metabolites are directly toxic to the renal cortex, c) 3,4 dichloroaniline decreases renal glutathione levels and d) glutathione is needed in the sequence of toxicity. This project will establish the potential renal toxicity for two major metabolites of 3,4-dichloroaniline: 3,4-dichlorophenylhydroxylamine (3,4CPHA) and 2-amino-4,5-dichlorophenol (2A4,5CP). Toxicity will be evaluated following in vivo administration to F344 rats by monitoring kidney weight, BUN, urine profile and renal cortical slice accumulation of organic ions. In vitro toxicity will be determined by direct exposure of renal cortical slices to the parent compound and major metabolites. Toxicity in vitro will be monitored by direct or indirect measurement of cellular enzyme activity. Renal glutathione levels will be measured following in vivo and in vitro exposure to 3,4-dichloroaniline as well as 3,4 dichlorophenylhydroxylamine and 2-amino-4,5-dichlorophenol. The data provided by this AREA grant will provide a foundation of knowledge that will first characterize the potential nephrotoxicity of 3,4-dichloroaniline and 2 major metabolites. These results will then begin a foundation of information regarding the cellular mechanism of 3,4 dichloroaniline toxicity. These findings will also evaluate whether glutathione is involved as a detoxification pathway of in generation of a reactive component.