This work proposes to study two lung toxicants, ozone (O3) and 1-nitronaphthalene (1-NN) using a metabolomics approach. Specifically, mechanisms causing lung tolerance to repeated O3 exposure and the synergistic effects on 1-NN toxicity will be investigated. It is hypothesized that a metabolomics approach will detect changes in the metabolome corresponding to modulation of lung susceptibility to repeated O3 exposure with and without 1-NN. Analysis of these changes in metabolic phenotype will contribute to the understanding of underlying mechanisms leading to ozone tolerance and the corresponding higher lung susceptibility to 1-NN.
In specific aim (SA) 1, a time course study of O3 exposure using rats will be performed to analyze metabolic changes associated with acute O3 toxicity, repair and tolerance development. In SA 2, changes in metabolic phenotype caused by co-exposure to 1-NN will be studied at the three stages of O3 exposure; acute inflammation, resolution of initial inflammation and O3 tolerance. It is hypothesized that metabolic changes will be reflected in bronchiolar alveolar lavage fluid (BALF), as well as circulating and excreted biofluids. It is further hypothesized that metabolic markers detected in the rodent model will be indicative for O3 toxicity in non-human primates, providing a basis for a biomarker approach extendable to humans. In SA 3, BALF and plasma from O3 exposure experiments with non-human primates, obtained from a collaborator, will be analyzed and compared to the rodent model. SA 4 focuses on data analysis, interpretation and integration. The metabolomics approach includes both metabolic fingerprinting to identify novel biomarkers of toxin exposure as well as a hypothesis-driven metabolic profiling. This includes profiling of oxylipins and antioxidant levels to investigate inflammatory response and oxidative stress, phospholipid speciation in BALF to reflect compositional changes in epithelial lining fluid, and screening for common Phase II metabolites to investigate metabolite excretion.
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