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Ozone (O3): A Potential Contributor to Metabolic Syndrome through Altered Insulin Signaling
Johnson, D., D. Andrews, V. Bass, M. Schladweiler, A. Ledbetter, AND U. Kodavanti. Ozone (O3): A Potential Contributor to Metabolic Syndrome through Altered Insulin Signaling. Presented at Society of Toxicology, March 09 - 14, 2013.
Air pollution has been linked to diabetes and metabolic syndrome. This is the first animal study which shows a causal link between ozone exposure and impaired metabolism and glucose tolerance.
Air pollutants have been associated with diabetes and metabolic syndrome, but the mechanisms remain to be elucidated. We hypothesized that acute O3 exposure will produce metabolic impairments through endoplasmic reticular stress (ER) stress and altered insulin signaling in liver, muscle and adipose tissues in the Wistar Kyoto rats. Rats were exposed to air or O3 (1ppm), 6hr/day for 1 or 2 days. Glucose tolerance tests were conducted immediately following each day or one day after 2-day exposure. Tissues were analyzed for insulin and ER stress signaling mediators and serum for inflammation and metabolic syndrome biomarkers. O3 produced severe hyperglycemia and glucose intolerance that was reversible following 1 day recovery. Phosphorylation of insulin receptor substrate (pIRS) decreased after 2nd day O3 in all three organs. Downstream mediators of insulin signaling, phospho-serine/threonine kinase and phospho-glycogen synthase kinase also decreased but only in adipose tissue. Serum insulin changes were correlated with tissue levels of pIRS. Serum IL-6, thought to link ozone-induced inflammation and metabolic alterations, did not increase at any time; however lipocalin and acute phase proteins increased after O3. Serum leptin was also increased sharply after 1-day O3 exposure and this increase was correlated with O3-induced hyperglycemia, but not glucose intolerance. Genes downstream of unfolded protein response were changed in the liver indicating ER stress. To examine the role of liver ER stress in O3 induced impairment of metabolism, we treated rats with ER-stress inhibitor, salubrinal prior to air or 1ppm O3. Salubrinal did not diminish O3 induced hyperglycemia and glucose intolerance, suggesting that hyperglycemia likely did not result from ER stress. In conclusion, acute O3 exposure alters insulin signaling in metabolic organs causing hyperglycemia and glucose intolerance, which might contribute to increased incidences of diabetes and metabolic syndrome. (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