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Serum Metabolomic Profiling and Liver Transcriptomic Analysis Provide Mechanistic Evidence of Ozone (O3)- Induced Systemic Metabolic Impairment
Citation:
Miller, D., E. Karoly, W. Ward, D. Andrews, V. Bass, M. Schladweiler, A. Ledbetter, AND U. Kodavanti. Serum Metabolomic Profiling and Liver Transcriptomic Analysis Provide Mechanistic Evidence of Ozone (O3)- Induced Systemic Metabolic Impairment. Presented at Society of Toxicology, Phoenix, AZ, March 23 - 27, 2014.
Impact/Purpose:
Systemic response to air pollution is linked to metabolic syndrome. In this study we show that ozone induces acute systemic alterations in circulating metabolites reflective of changes in glucose, lipid, and amino acid metabolism which upon chronic exposure might contribute to insulin resistance and obesity.
Description:
Recently, air pollution has been linked to insulin resistance and obesity but the mechanisms remain to be elucidated. We have recently shown that acute O3 exposure induces glucose intolerance, hyperglycemia and increases in leptin and epinephrine in rats. Here, we hypothesized that the metabolic effects of O3 are associated with global changes in liver fatty acid and amino acid metabolism and that global metabolomic and transcriptomic approaches will provide insights into the mechanisms by which O3 might contribute to increased insulin resistance and/or obesity. Male Wistar Kyoto (WKY) rats were exposed to air or 1 ppm O3, 6 hrs/day for 1 or 2 days and liver gene expression and serum metabolomic analysis were performed immediately after. Metabolomic analysis identified O3 effects on numerous small metabolite biomarkers. O3 increased blood glucose; long chain free fatty acids, cholesterol and decreased 1,5-anhydroglucitol (AG); biomarkers of insulin resistance. Metabolites of glycolysis were increased however; intermediates of the TCA cycle and bile acids were decreased in the serum by O3. Branched chain amino acids were increased, suggesting muscle amino acid catabolism. Of particular interest, metabolites that are associated with gut microbiome (e.g. phenylacetylglycine) were also markedly affected by O3. Liver gene expression profile after O3 exposure correlated with the serum metabolite changes. For example, elevated serum fatty acids coincided with decreased expression of lipid biosynthetic genes, suggesting that the liver might have initiated homeostatic control for metabolic changes. In conclusion, our metabolomic and genomic analyses show that O3 induces acute systemic alterations reflective of changes in glucose, lipid, and amino acid metabolism which upon chronic exposure might contribute to insulin resistance and obesity. (Does not reflect EPA Policy).