Lung disease are 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. A number of chemicals undergo bioactivation to produce highly selective lung injury in rodent models. However, there are significant uncertainties in assessing the risks to humans from these chemicals including high variability in sensitivity of rodent models and in displaying apparent does thresholds. This application focuses on the development of molecular markers which are tightly linked to the mechanisms for cytotoxicity for two chemicals-naphthalene and 1- nitroaphthalene. Both are combustion byproducts 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. The proposed work will expand previous observations showing that: actin is a target protein for electrophilic naphthalene and 1- nitroaphthalene metabolites, naphthalene in the lung. The goals are: to identify the remaining adducted proteins, to define the time course and concentration/dose relationships for formation and disappearance of adducts in vitro and in vivo and relate these changes to cellular homeostasis in susceptible and non-susceptible species and in the Rhesus macaque, a species whose lungs are similar structurally and biochemically to the human. The understanding of 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 induction not only than an exposure has occurred but that the exposure has resulted in a deleterious effect. This work will be extended to include real chemical mixtures generated by the thermal remediation project where bioavailability and metabolism of the target PAH and nitroPAH will be examined. Finally, cDNA arrays and subtractive hybridization experiments will be utilized to determine changes that occur at the gene level in response to lung toxicants.
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