Inhaled ozone (O3)-induces changes in serum metabolomic and liver transcriptomic profiles in rats

Abstract

Air pollution has been linked to increased incidence of diabetes. Recently, we showed that ozone (O3) induces glucose intolerance, and increases serum leptin and epinephrine in Brown Norway rats. In this study, we hypothesized that O3 exposure will cause systemic changes in metabolic homeostasis and that serum metabolomic and liver transcriptomic profiling will provide mechanistic insights. In the first experiment, male Wistar Kyoto (WKY) rats were exposed to filtered air (FA) or O3 at 0.25, 0.50, or 1.0 ppm, 6 h/day for two 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, 6 h/day for either one or two consecutive days, and systemic metabolic responses were determined immediately after or 18 h post-exposure. O3 increased serum glucose and leptin on day 1. Glucose intolerance persisted through two days of exposure but reversed 18 h-post second exposure. O3 increased circulating metabolites of glycolysis, long-chain free fatty acids, branched-chain amino acids and cholesterol, while 1,5-anhydroglucitol, bile acids and metabolites of TCA cycle were decreased, indicating impaired glycemic control, proteolysis and lipolysis. Liver gene expression increased for markers of glycolysis, TCA cycle and gluconeogenesis, and decreased for markers of steroid and fat biosynthesis. Genes involved in apoptosis and mitochondrial function were also impacted by O3. In conclusion, short-term O3 exposure induces global metabolic derangement involving glucose, lipid, and amino acid metabolism, typical of a stress–response. It remains to be examined if these alterations contribute to insulin resistance upon chronic exposure.

Ozone Exposure Increases Circulating Stress Hormones and Lipid Metabolites in Humans

“…pathways (19,20). The goal of the current study was to determine if metabolomic assessment of serum samples obtained from a prior clinical study where humans were acutely exposed to ozone show similar systemic metabolic alterations as rodents.…”

“…Chronic elevations of these metabolites in the circulation might contribute to metabolic diseases and systemic inflammation (30,31). In nonexercising rats, acute ozone exposure induces glucose intolerance and increases circulating leptin and epinephrine (19,20). Both leptin and epinephrine changes are associated with a reversible decrease in body temperature (23), suggesting involvement of the sympathetic axis and changes in hypothalamic thermoregulation.…”

“…Specifically, exposure to ozone activates the nucleus tractus solitarius and stress responsive regions of the hypothalamus through stimulation of pulmonary vagal C fibers (18). Acute ozone exposure can increase levels of circulating stress hormones, such as epinephrine and corticosterone, in rats (19)(20)(21). Ozone exposure also induces cardiac autonomic effects in humans (22); hypothermia and bradycardia in rats (23); and leptinemia, hyperglycemia, glucose intolerance, and global changes in circulating metabolites involved in peripheral glucose, lipid, and amino acid metabolism in rats (20).…”

“…Acute ozone exposure can increase levels of circulating stress hormones, such as epinephrine and corticosterone, in rats (19)(20)(21). Ozone exposure also induces cardiac autonomic effects in humans (22); hypothermia and bradycardia in rats (23); and leptinemia, hyperglycemia, glucose intolerance, and global changes in circulating metabolites involved in peripheral glucose, lipid, and amino acid metabolism in rats (20). These changes are reflective of classical stress response-mediated homeostatic alterations involving activation of sympathetic neurons and hypothalamus-pituitary-adrenal (HPA) axis (20).…”

“…We have previously performed global metabolomic assessment of serum to characterize the metabolic responses to ozone and to gain mechanistic insights in rats (20). The goal of this exploratory study was to perform a global metabolomic assessment of archived human serum samples from a prior clinical study involving ozone exposure, and determine ozone-induced metabolic changes in humans, establish rodent-to-human coherence, and identify novel nonprotein biomarkers of ozone exposure.…”