title: 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 1.0ppm, 6h/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 1.0ppm O3, 6h/day for either one or two consecutive days, and systemic metabolic responses were determined immediately after or 18h post-exposure. O3 increased serum glucose and leptin on day 1. Glucose intolerance persisted through two days of exposure but reversed 18h-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.
authors.affiliation: Curriculum in Toxicology, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Desinia B
authors.initials: DB
authors.lastname: Miller
authors.affiliation: Metabolon Incorporation, Durham, NC, USA.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Karoly
authors.affiliation: Metabolon Incorporation, Durham, NC, USA.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Jones
authors.affiliation: Research Cores Unit, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: William O
authors.initials: WO
authors.lastname: Ward
authors.affiliation: Research Cores Unit, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Beena D
authors.initials: BD
authors.lastname: Vallanat
authors.affiliation: Research Cores Unit, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
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, USA.
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, USA.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Snow
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Bass
authors.affiliation: Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
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, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ghio
authors.affiliation: Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Wayne E
authors.initials: WE
authors.lastname: Cascio
authors.affiliation: Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
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, USA. Electronic address: kodavanti.urmila@epa.gov.
authors.forename: Urmila P
authors.initials: UP
authors.lastname: Kodavanti
mesh_terms: D000280:Administration, Inhalation; D000393:Air Pollutants / Q000633:toxicity*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000097:blood; D015870:Gene Expression / Q000187:drug effects; D005951:Glucose Tolerance Test; D006019:Glycolysis / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D055432:Metabolomics; D010126:Ozone / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011921:Rats, Inbred WKY; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D000393:Air Pollutants; D000596:Amino Acids; D005230:Fatty Acids, Nonesterified; D010126:Ozone
keywords: Air pollution; Metabolic syndrome; Ozone; Serum metabolomic; Stress response
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