This Program seeks to discover if the mutations, especially oncomutations, in the bronchial cells of human lungs from nonsmokers are principally caused by exposure to air-borne chemicals in urban outdoor and environments. To achieve this goal, we propose to study the expression of lung cell xenometabolic genes associated with mutagen activation in bronchial brush biopsies of males and females, smokers and nonsmokers, Afro- and Euro Americans. Because we measure the amount of protein and DNA adducts and mutations in each of these biopsies we expect to define xenometabolic patterns associated with high risk of lung genetic damage. These patterns we will engineer into human diploid cells for use in determining the chemicals principally responsible for the mutagenicity of environmental air samples from four American cities; Washington D.C., Los Angeles, CA, Rochester NY, and Woburn, MA. These research goals require a carefully managed cross-disciplinary team of combustion and environmental engineers, analytical chemistry, lung physiologists and genetic toxicologists. We further propose to measure certain oncomutations associated with human lung cancer (K-ras, P53 genes) as function of anatomical position in the bronchial tree and to observe the amount chemical adducts and mitochondrial mutations in these same dissection samples. The results of this study will determine if oncomutations arise as developmental jackpots, if mutations are associated with bronchiolar bifurcations having high air-borne chemical deposition and if the kinds of mitochondrial mutations observed are those induced in human cell studies in which air- borne chemicals are known to be the responsible mutagens. The program is a combination of original analytical and synthetic approaches in the fields of analytical chemistry and analytical genetics. The strengths of three research universities are combined: lung physiology at the University of Rochester Medical School; area-grid air sampling and source attribution at the California Institute of Technology combustion engineering, complex mixture analysis and genetic toxicology at M.I.T.
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