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Acute ozone (O3) -induced impairment of glucose regulation: Age-related and temporal changes
Citation:
Bass, V., R. Macphail, D. Andrews, B. Vallanat, W. Ward, M. Schladweiler, A. Ledbetter, D. Johnson, K. Jarema, C. Gordon, AND U. Kodavanti. Acute ozone (O3) -induced impairment of glucose regulation: Age-related and temporal changes. Presented at Society of Toxicology, March 10 - 14, 2013.
Impact/Purpose:
The research in this abstract shows that ozone can cause glucose glucose intolerance as a result of metabolic changes. These findings raise concerns about ambient O3’s potential to cause predisposition towards metabolic impairment.
Description:
O3 is associated with adverse cardiopulmonary health effects in humans and is thought to produce metabolic effects, such as insulin resistance. Recently, we showed that episodic O3 exposure increased insulin levels in aged rats. We hypothesized that O3 exposure could impair glucose homeostasis by altering insulin signaling and/or causing unfolded protein response (UPR) in the liver. Brown Norway rats of ages 1, 4, 12, 21, and 24mo (a model of non-obese aging) were exposed to O3 at 0, 0.25 or 1ppm, 6h/day for 2 days. As a follow-up study, 4mo old rats were exposed to 0 or 1ppm O3 over 2 days to examine the time course of response. Glucose tolerance tests (GTT) directly followed exposure in all studies. An additional GTT was done 24h post-exposure in the time-course experiment. Gene expression was examined with RT-PCR in the liver and adipose tissue for metabolic, UPR, and acute phase response (APR) markers and with an Affy array in the liver. Phospho-protein analysis to assess insulin signaling was done in the liver, adipose tissue, and muscle. GTT showed a marked impairment of glucose clearance among 1ppm O3 exposed rats of all ages. The reduction in glucose regulation after O3 exposure was most apparent in 1mo rats, who exhibited no baseline glucose intolerance. Senescent rats exhibited glucose intolerance at baseline. Analyses of metabolic and APR biomarkers show that the insulin signaling pathway is altered by O3 in all three tissues and serum APR proteins were increased. Selected UPR genes were upregulated in the liver. In the time-course study, serum leptin increased acutely following 1 day (6h) O3 exposure. Maximum effects of O3 on insulin signaling and APR were seen directly following the second day of exposure. Our results suggest that glucose intolerance is a result of metabolic changes in response to O3. These findings raise concerns about ambient O3’s potential to cause predisposition towards metabolic impairment. (Does not reflect US EPA policy)