Ozone induces glucose intolerance and systemic metabolic effects in young and aged Brown Norway rats

Toxicol Appl Pharmacol. 2013 Dec 15;273(3):551-60. doi: 10.1016/j.taap.2013.09.029. Epub 2013 Oct 6.


Air pollutants have been associated with increased diabetes in humans. We hypothesized that ozone would impair glucose homeostasis by altering insulin signaling and/or endoplasmic reticular (ER) stress in young and aged rats. One, 4, 12, and 24 month old Brown Norway (BN) rats were exposed to air or ozone, 0.25 or 1.0 ppm, 6 h/day for 2 days (acute) or 2 d/week for 13 weeks (subchronic). Additionally, 4 month old rats were exposed to air or 1.0 ppm ozone, 6 h/day for 1 or 2 days (time-course). Glucose tolerance tests (GTT) were performed immediately after exposure. Serum and tissue biomarkers were analyzed 18 h after final ozone for acute and subchronic studies, and immediately after each day of exposure in the time-course study. Age-related glucose intolerance and increases in metabolic biomarkers were apparent at baseline. Acute ozone caused hyperglycemia and glucose intolerance in rats of all ages. Ozone-induced glucose intolerance was reduced in rats exposed for 13 weeks. Acute, but not subchronic ozone increased α2-macroglobulin, adiponectin and osteopontin. Time-course analysis indicated glucose intolerance at days 1 and 2 (2>1), and a recovery 18 h post ozone. Leptin increased day 1 and epinephrine at all times after ozone. Ozone tended to decrease phosphorylated insulin receptor substrate-1 in liver and adipose tissues. ER stress appeared to be the consequence of ozone induced acute metabolic impairment since transcriptional markers of ER stress increased only after 2 days of ozone. In conclusion, acute ozone exposure induces marked systemic metabolic impairments in BN rats of all ages, likely through sympathetic stimulation.

Keywords: Aging; Air pollution; Epinephrine; Metabolic syndrome; Ozone; Serum biomarkers.

MeSH terms

  • Adiponectin / blood
  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Age Factors
  • Animals
  • Biomarkers / metabolism
  • Diabetes Mellitus / chemically induced
  • Diabetes Mellitus / pathology
  • Endoplasmic Reticulum Stress / drug effects
  • Glucose Intolerance / chemically induced
  • Glucose Intolerance / pathology*
  • Glucose Tolerance Test
  • Insulin / blood
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance
  • Leptin / blood
  • Lipoproteins, HDL / blood
  • Lipoproteins, IDL / blood
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Metabolic Diseases / chemically induced
  • Metabolic Diseases / pathology*
  • Osteopontin / blood
  • Ozone / toxicity*
  • Phosphorylation
  • Rats
  • Rats, Inbred BN
  • Reverse Transcriptase Polymerase Chain Reaction
  • Risk Factors
  • Triglycerides / blood
  • alpha-Macroglobulins / metabolism


  • Adiponectin
  • Biomarkers
  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Leptin
  • Lipoproteins, HDL
  • Lipoproteins, IDL
  • Triglycerides
  • alpha-Macroglobulins
  • Osteopontin
  • Ozone