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Ozone Exposure Increases Circulating Stress Hormones and Lipid Metabolites in Humans
Miller, D., Andy Ghio, E. Karoly, L. Bell, S. Snow, M. Madden, J. Soukup, W. Cascio, Ian Gilmour, AND U. Kodavanti. Ozone Exposure Increases Circulating Stress Hormones and Lipid Metabolites in Humans. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE. American Thoracic Society, New York, NY, 193(12):1382-91, (2016).
This study is the first to characterize the global metabolic derangement in humans after ozone exposure using metabolomic assessment. Acute ozone exposure in humans is associated with marked increases a variety of fatty acids in the circulation together with increases in cortisol/corticosterone suggesting the activation of neurohormonal stress response pathway and subsequent changes in peripheral metabolic homeostasis. This study establishes the coherence between humans and rodents in ozone-induced metabolic effects. Through this approach, novel biomarkers such as cortisol, free fatty acids, and monoacylglycerols, are identified.
RATIONALE: Air pollution has been associated with increased prevalence of type 2 diabetes; however, the mechanisms remain unknown. We have shown that acute ozone exposure in rats induces release of stress hormones, hyperglycemia, leptinemia, and gluoose intolerance that are associated with global changes in peripheral glucose, lipid, and amino acid metabolism.OBJECTIVES: To examine ozone-induced metabolic derangement in humans using serum metabolomic assessment, establish human-to-rodent coherence, and identify novel nonprotein biomarkers.METHODS: Serum samples were obtained from a crossover clinical study that included two clinic visits (n = 24 each) where each subject was blindly exposed in the morning to either filtered air or 0.3 parts per million ozone for 2 hours during 15-minute on-off exercise. Serum samples collected within 1 hour after exposure were assessed for changes in metabolites using a metabolomic approach.MEASUREMENTS AND MAIN RESULTS: Metabolomic analysis revealed that ozone exposure markedly increased serum cortisol and corticosterone together wth increases in monoacylglycerol, glycerol, and medium- and long-chain free fatty acids, reflective of lipid mobilization and catabolism. Additionally, ozone exposure increased serum lysolipids, potentially originating from membrane lipid breakdown. Ozone exposure also increased circulating mitochondrial B-oxidation-derived metabolites, such as acylcarnitines, together with increases in the ketone body 3-hydroxybutyrate. These changes suggested saturation ofB-oxidation by ozone in exercising humans.CONCLUSIONS: As in rodents, acute ozone exposure increased stress hormones and globally altered peripheral lipid metabolism in humans, likely through activation of a neurohormonally mediated stress response pathway. The metabolomic assessment revealed new biomarkers and allowed for establishment of rodent-to-human coherence. Clinical trial registered with www.clinicaltrials.gov (NCT 01492517)..