Repeated Ozone Exposure Exacerbates Insulin Resistance and Activates Innate Immune Response in Genetically Susceptible Mice

Inhal Toxicol. 2016 Aug;28(9):383-92. doi: 10.1080/08958378.2016.1179373. Epub 2016 May 31.


Background: Inhaled ozone (O3) has been demonstrated as a harmful pollutant and associated with chronic inflammatory diseases such as diabetes and vascular disorders. However, the underlying mechanisms by which O3 mediates harmful effects are poorly understood.

Objectives: To investigate the effect of O3 exposure on glucose intolerance, immune activation and underlying mechanisms in a genetically susceptible mouse model.

Methods: Diabetes-prone KK mice were exposed to filtered air (FA), or O3 (0.5 ppm) for 13 consecutive weekdays (4 h/day). Insulin tolerance test (ITT) was performed following the last exposure. Plasma insulin, adiponectin, and leptin were measured by ELISA. Pathologic changes were examined by H&E and Oil-Red-O staining. Inflammatory responses were detected using flow cytometry and real-time PCR.

Results: KK mice exposed to O3 displayed an impaired insulin response. Plasma insulin and leptin levels were reduced in O3-exposed mice. Three-week exposure to O3 induced lung inflammation and increased monocytes/macrophages in both blood and visceral adipose tissue. Inflammatory monocytes/macrophages increased both systemically and locally. CD4 + T cell activation was also enhanced by the exposure of O3 although the relative percentage of CD4 + T cell decreased in blood and adipose tissue. Multiple inflammatory genes including CXCL-11, IFN-γ, TNFα, IL-12, and iNOS were up-regulated in visceral adipose tissue. Furthermore, the expression of oxidative stress-related genes such as Cox4, Cox5a, Scd1, Nrf1, and Nrf2, increased in visceral adipose tissue of O3-exposed mice.

Conclusions: Repeated O3 inhalation induces oxidative stress, adipose inflammation and insulin resistance.

Keywords: Air pollution; inflammation; insulin resistance; oxidative stress; ozone exposure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Air Pollutants / toxicity*
  • Animals
  • Gene Expression / drug effects
  • Immunity, Innate / drug effects*
  • Immunity, Innate / genetics
  • Inhalation Exposure / adverse effects*
  • Insulin / blood
  • Insulin Resistance / genetics*
  • Leptin / blood
  • Lung / drug effects
  • Lung / pathology
  • Mice, Inbred Strains
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Ozone / toxicity*


  • Air Pollutants
  • Insulin
  • Leptin
  • Ozone