title: Systemic metabolic derangement, pulmonary effects, and insulin insufficiency following subchronic ozone exposure in rats.
abstract: Acute ozone exposure induces a classical stress response with elevated circulating stress hormones along with changes in glucose, protein and lipid metabolism in rats, with similar alterations in ozone-exposed humans. These stress-mediated changes over time have been linked to insulin resistance. We hypothesized that acute ozone-induced stress response and metabolic impairment would persist during subchronic episodic exposure and induce peripheral insulin resistance. Male Wistar Kyoto rats were exposed to air or 0.25ppm or 1.00ppm ozone, 5h/day, 3 consecutive days/week (wk) for 13wks. Pulmonary, metabolic, insulin signaling and stress endpoints were determined immediately after 13wk or following a 1wk recovery period (13wk+1wk recovery). We show that episodic ozone exposure is associated with persistent pulmonary injury and inflammation, fasting hyperglycemia, glucose intolerance, as well as, elevated circulating adrenaline and cholesterol when measured at 13wk, however, these responses were largely reversible following a 1wk recovery. Moreover, the increases noted acutely after ozone exposure in non-esterified fatty acids and branched chain amino acid levels were not apparent following a subchronic exposure. Neither peripheral or tissue specific insulin resistance nor increased hepatic gluconeogenesis were present after subchronic ozone exposure. Instead, long-term ozone exposure lowered circulating insulin and severely impaired glucose-stimulated beta-cell insulin secretion. Thus, our findings in young-adult rats provide potential insights into epidemiological studies that show a positive association between ozone exposures and type 1 diabetes. Ozone-induced beta-cell dysfunction may secondarily contribute to other tissue-specific metabolic alterations following chronic exposure due to impaired regulation of glucose, lipid, and protein metabolism.
authors.affiliation: Curriculum in Toxicology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, United States.
authors.forename: Desinia B
authors.initials: DB
authors.lastname: Miller
authors.affiliation: Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Snow
authors.affiliation: Curriculum in Toxicology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, United States.
authors.forename: Andres
authors.initials: A
authors.lastname: Henriquez
authors.affiliation: Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States.
authors.forename: Mette C
authors.initials: MC
authors.lastname: Schladweiler
authors.affiliation: Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States.
authors.forename: Allen D
authors.initials: AD
authors.lastname: Ledbetter
authors.affiliation: Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States.
authors.forename: Judy E
authors.initials: JE
authors.lastname: Richards
authors.affiliation: Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States.
authors.forename: Debora L
authors.initials: DL
authors.lastname: Andrews
authors.affiliation: Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. Electronic address: kodavanti.urmila@epa.gov.
authors.forename: Urmila P
authors.initials: UP
authors.lastname: Kodavanti
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D002784:Cholesterol / Q000097:blood; D004837:Epinephrine / Q000097:blood; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010126:Ozone / Q000633:toxicity*; D011921:Rats, Inbred WKY
chemical_list: D000393:Air Pollutants; D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D010126:Ozone; D002784:Cholesterol; D005947:Glucose; D004837:Epinephrine
keywords: Insulin resistance; Metabolism; Ozone; Pancreatic beta cells; Stress response