Project Summary (2000-2005)

Lung disease is a significant cause of morbidity and mortality in the US; lung cancer is the leading cause of cancer related deaths in both males and females. Although a portion of the disease incidence has been linked to tobacco use, exposure to chemicals in the air, water and food also may play a role. This project focuses on the development of molecular markers that are tightly linked to the mechanisms for cytotoxicity of two chemicals--naphthalene and 1-nitronaphthalene. Both are combustion by-products present in Superfund hazardous waste sites, and nitronaphthalene and close structural congeners have been shown to contribute significantly to mutagenic activity of airborne particulates. Both chemicals undergo metabolic activation to electrophilic intermediates, which become bound covalently to proteins in target cells. Project investigators are expanding previous observations showing that actin is a target protein for electrophilic naphthalene and 1-nitronaphthalene metabolites, and that naphthalene metabolites alter actin polymerization and the cytoskeletal changes observed are consistent with the cytotoxic effects of naphthalene in the lung. Researchers are identifying the remaining adducted proteins, and defining the time course and concentration/dose relationships for formation and disappearance of adducts in vitro and in vivo. Understanding the generation and disappearance of adducts will provide information needed to follow adducted proteins or their degradation products in blood, lavage samples and/or urine. The overall goal is to develop markers capable of indicating not only that an exposure has occurred but that the exposure has resulted in a deleterious effect.