title: Ozone Inhalation Provokes Glucocorticoid-Dependent and -Independent Effects on Inflammatory and Metabolic Pathways.
abstract: Growing evidence implicates air pollutants in adverse health effects beyond respiratory and cardiovascular disease, including metabolic impacts (diabetes, metabolic syndrome, obesity) and neurological/neurobehavioral outcomes (neurodegenerative disease, cognitive decline, perceived stress, depression, suicide). We have shown that inhalation of particulate matter or ozone activates the hypothalamic-pituitary-adrenal axis in rats and increases plasma levels of the glucocorticoid corticosterone. To investigate the role of corticosterone in mediating inflammatory and metabolic effects of pollutant exposure, in this study male Fischer-344 rats were administered the 11β-hydroxylase inhibitor metyrapone (0, 50, 150 mg/kg body weight) and exposed by nose-only inhalation for 4 h to air or 0.8 ppm ozone. Ozone inhalation provoked a 2-fold increase in plasma corticosterone, an effect blocked by metyrapone, but did not alter epinephrine levels. Inhibition of corticosterone production was associated with increased inflammatory signaling in the lungs and plasma in response to ozone, consistent with a role for glucocorticoids in limiting local and systemic inflammatory responses. Effects of ozone on insulin and glucagon, but not ghrelin or plasminogen activator inhibitor-1, were modified by metyrapone, revealing glucocorticoid-dependent and -independent effects on circulating metabolic and hemostatic factors. Several immunosuppressive and metabolic impacts of ozone in the lungs, heart, liver, kidney, and spleen were blocked by metyrapone and reproduced through exogenous administration of corticosterone (10 mg/kg body weight), demonstrating glucocorticoid-dependent effects in target tissues. Our results support involvement of endogenous glucocorticoids in ozone-induced inflammatory and metabolic effects, providing insight into potential biological mechanisms underlying health impacts and susceptibility.
authors.affiliation: *Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, K1A 0K9, Canada and errol.thomson@hc-sc.gc.ca.
authors.forename: Errol M
authors.initials: EM
authors.lastname: Thomson
authors.affiliation: *Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, K1A 0K9, Canada and.
authors.forename: Shinjini
authors.initials: S
authors.lastname: Pal
authors.affiliation: *Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, K1A 0K9, Canada and.
authors.forename: Josée
authors.initials: J
authors.lastname: Guénette
authors.affiliation: *Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, K1A 0K9, Canada and.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Wade
authors.affiliation: *Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, K1A 0K9, Canada and.
authors.forename: Ella
authors.initials: E
authors.lastname: Atlas
authors.affiliation: Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, L8N 3Z5, Canada.
authors.forename: Alison C
authors.initials: AC
authors.lastname: Holloway
authors.affiliation: *Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, K1A 0K9, Canada and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.affiliation: *Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, K1A 0K9, Canada and.
authors.forename: Renaud
authors.initials: R
authors.lastname: Vincent
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects* / Q000378:metabolism; D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D015415:Biomarkers / Q000097:blood; D003345:Corticosterone / Q000097:blood*; D016207:Cytokines / Q000097:blood; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018836:Inflammation Mediators / Q000097:blood; D019570:Inhalation Exposure / Q000009:adverse effects*; D008297:Male; D010126:Ozone / Q000633:toxicity*; D011014:Pneumonia / Q000097:blood / Q000139:chemically induced*; D011725:Pyridines / Q000494:pharmacology; D011916:Rats, Inbred F344; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000393:Air Pollutants; D015415:Biomarkers; D016207:Cytokines; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D011725:Pyridines; C013109:metapyrone; D010126:Ozone; D013252:Steroid 11-beta-Hydroxylase; D003345:Corticosterone
keywords: air pollution; glucocorticoid; hypothalamic–pituitary–adrenal (HPA) axis; inflammation; metabolic effects.; ozone; stress response; systemic effects