This application proposes to build on studies conducted during the past 5 years which have focused on two pulmonary cytotoxicants, naphthalene (NA) and 1-nitronaphthalene (NN). This work has: 1) demonstrated lung injury for NA at vapor concentrations well below the current occupational standard, 2) shown that the nasal epithelium is a susceptible target for both compounds, 3) identified many of the proteins adducted by reactive metabolites from NA and NN, and 4) demonstrated substantial quantitative differences in rodent vs nonhuman primate lung metabolism of these substrates. Overall, this work has contributed important data for current assessments of the potential human health hazards of these compounds. New methods have been developed which: 1) allow preservation of the lung for transcriptome analysis in well defined subcompartments, 2) allow selective sampling of proteins from airway epithelium facilitating analysis of changes in the airway proteome in response to toxicants and 3) improve analysis of alterations in protein expression by incorporation of a fluorescent internal standard. The foci of the studies proposed are to: 1) delineate differences in cytotoxic injury associated administration of respirable particle/chemical mixtures, 2) understand the importance of protein/nonprotein thiol oxidation in injury, 3) determine whether proteins which are adducted in the lung by reactive NA and NN metabolites are also adducted in susceptible nasal epithelium, 4) determine whether protein profiles and alterations in the metabolome present in nasal and bronchiolar lavage samples reflect injury to nasal and airway epithelium, 5) determine whether the nasal epithelium (and associated lavage sampling) can act as a legitimate surrogate for more distal parts of the lung and 6) delineate the importance of adducts with antioxidant enzymes and proteins involved in protein folding in cytotoxicity. These studies will provide important baseline data for work on the toxicology of 'real world'combustion mixtures. These particulars samples, many of which contain heavy metals, will be evaluated using nasal epithelium in vitro and in respiratory and renal tissue using proteomics approaches in vivo. The project depends upon close collaboration with the Thermal remediation project and will rely on the Analytical core for metabolomic, accelerator and protein mass spectrometry, and on the 'Omics and biostatistics core for proteome and transcriptome analysis.
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