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Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver
Johnson, D., W. Ward, V. Bass, M. Schladweiler, A. Ledbetter, D. Andrews, AND U. Kodavanti. Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver. Presented at American Thoracic Society, May 17 - 22, 2013.
This study shows that acute ozone exposure can induce marked metabolic changes in glucose and lipid metabolism and also alter insulin signaling. These might contribute to metabolic syndrome later in life.
Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver D.B. Johnson, 1 W.O. Ward, 2 V.L. Bass, 2 M.C.J. Schladweiler, 2A.D. Ledbetter, 2 D. Andrews, and U.P. Kodavanti 2 1 Curriculum in Toxicology, UNC School of Medicine, Chapel Hill, NC 27599, USA 2 NHEERL, U.S. EPA, Research Triangle Park, NC 27711, USA Chronic manifestation of metabolic syndrome is associated with the development of cardiovascular abnormalities and diabetes long-term. It has been postulated that air pollutants contribute to the development of metabolic syndrome through liver endoplasmic reticulum (ER) stress but the mechanisms still remain to be elucidated. We hypothesized that ozone exposure will induce glucose intolerance in Wistar Kyoto Rats (WKY) by initiating ER stress and altering liver glucose and fatty acid metabolic pathways. WKY rats were exposed to filtered air (FA) or 1ppm ozone, 6hr/day for one or two days. Glucose tolerance tests were conducted immediately following each day or one day after 2-day exposure. The serum biomarkers of inflammation and metabolic syndrome, and liver global transcriptome were analyzed at each time point following ozone exposure. Interestingly, rats exposed to ozone presented with marked hyperglycemia and glucose intolerance compared to FA group. Serum leptin levels increased sharply concurrent with hyperglycemia at day 1 but acute phase proteins increased maximally at day 2 after ozone exposure. Ozone significantly altered 2335 genes in the liver at day 1 with fewer genes at subsequent time points. Among these genes were those involved in glucose and fatty acid metabolism, insulin signaling and ER stress. Inhibition of cyclin D1, X-box binding gene and increases in Na+,K+-ATPase B1 suggested ER stress but other ER stress markers were minimally affected. The upregulation of many hypoxia response genes might be a result of adaptive hypothermic response following acute ozone exposure. Inhibition of glucokinase and pyruvate kinase after ozone exposure suggests inhibition of glycolysis. Several Krebs cycle genes however, were significantly induced following ozone exposure. These changes coincided with decreased gene expression of key enzymes involved fatty acid synthesis and increased expression of those involved in oxidation. Specifically, there was a decrease in the ATP citrate lyase gene while an upregulation of carnitine palmitoyltransferase 1/2 (CPT1/2) enzymes. These changes suggested that activation of Krebs cycle was likely mediated through increased beta oxidation of fatty acids but not increased glycolysis. In conclusion, ozone induced hyperglycemia and glucose intolerance are associated with metabolic and growth inhibitory changes in the liver in an attempt to maintain homeostatic control in response to hypoxia and stress, which during chronic exposures may contribute to metabolic impairments. (This abstract does not reflect USEPA policy).
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
ENVIRONMENTAL PUBLIC HEALTH DIVISION
CARDIOPULMONARY AND IMMUNOTOXICOLOGY BRANCH