University of California-San Diego

Project Summary (2000-2005)

Of the 30 most common toxicants detected at Superfund sites, five are nephrotoxic vicinal haloalkenes, such as TCE. Unlike other halogenated hydrocarbons, vicinal haloalkenes uniquely damage the kidney by destroying proximal tubule cells and inducing renal carcinomas. It is believed the nephrotoxic and nephrocarcinogenic effects of vicinal haloalkenes stem from their conversion by hepatic microsomal glutathione transferase to GSH-conjugates. The objective of this project is to determine the roles of individual MGSTs in modulating the hepatotoxicity and nephrotoxicity of vicinal haloalkenes, which are common Superfund site toxicants. This is being accomplished by isolating the three different MGST genes and producing "knock-out" or overexpressing transgenic animals. The sensitivity of these animals to the vicinal haloalkenes can then be determined. Using cDNA microarray technology, researchers are identifying genes whose expression is dramatically altered upon exposure to low levels of these vicinal haloalkenes. This information is being used to develop novel biomarkers and animal models capable of detecting subtle halogenated and aromatic hydrocarbon damage. Current models only detect damage arising from frank tissue damage and repair, or subsequent development of tumors, which normally require exposure to high doses. The models developed in this project, in contrast, are able to detect alteration in cellular homeostasis arising from exposure to low levels of the vicinal haloalkenes and any other toxin capable of producing liver or renal damage.