ABSTRACT: Long-term exposure to particulate air pollutants has been linked to increased incidence of Type 2 Diabetes (T2DM). Recently, we showed that the gaseous pollutant, O3, induced glucose intolerance, and increased serum leptin and epinephrine in Brown Norway rats. In this study, we hypothesized that O3 exposure will cause broad scale changes in metabolic homeostasis involving liver, muscle and adipose tissues, and that serum metabolomic and liver transcriptomic profiling will provide mechanistic insights into pollutant-induced metabolic alterations. In the first experiment, male Wistar Kyoto (WKY) rats were exposed to filtered air (FA) or O3 at 0.25, 0.50, or 1.00 ppm, 6h/day for two consecutive days to establish concentration-related effects on glucose tolerance and lung injury. In a second experiment, rats were exposed to FA or 1.0 ppm O3, 6h/day for either one day or two consecutive days and systemic metabolic responses were determined immediately after each exposure or after an 18h recovery period. In WKY rats, O3 increased serum fasting glucose and leptin on day 1. Glucose intolerance persisted through two days of exposure but reversed 18h post second exposure. O3 exposure increased circulating metabolites of glycolysis, long-chain free fatty acids, branched chain amino acids (BCAA) and cholesterol while 1,5- anhydroglucitol, bile acids and metabolites of TCA cycle were decreased, indicating impaired glycemic control, muscle proteolysis and adipose lipolysis. Liver gene expression profile after O3 exposure reflected a response to the serum metabolite changes, as evidenced by increased expression of genes for glycolysis, TCA cycle and gluconeogenesis, and decreased expression of genes involved in steroid and fat biosynthesis. In conclusion, short-term O3 exposure induced hormonal changes and global metabolic disorder reflective of changes in peripheral glucose, lipid, and amino acid metabolism, representative of a stress-response. It remains to be examined if these metabolic alterations contribute to insulin resistance upon chronic exposure.
