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

Abstract

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.

Ozone Exposure Increases Circulating Stress Hormones and Lipid Metabolites in Humans

“…pathways (19,20). The goal of the current study was to determine if metabolomic assessment of serum samples obtained from a prior clinical study where humans were acutely exposed to ozone show similar systemic metabolic alterations as rodents.…”

“…Chronic elevations of these metabolites in the circulation might contribute to metabolic diseases and systemic inflammation (30,31). In nonexercising rats, acute ozone exposure induces glucose intolerance and increases circulating leptin and epinephrine (19,20). Both leptin and epinephrine changes are associated with a reversible decrease in body temperature (23), suggesting involvement of the sympathetic axis and changes in hypothalamic thermoregulation.…”

“…Specifically, exposure to ozone activates the nucleus tractus solitarius and stress responsive regions of the hypothalamus through stimulation of pulmonary vagal C fibers (18). Acute ozone exposure can increase levels of circulating stress hormones, such as epinephrine and corticosterone, in rats (19)(20)(21). Ozone exposure also induces cardiac autonomic effects in humans (22); hypothermia and bradycardia in rats (23); and leptinemia, hyperglycemia, glucose intolerance, and global changes in circulating metabolites involved in peripheral glucose, lipid, and amino acid metabolism in rats (20).…”

Air Pollution and Insulin Resistance: Do All Roads Lead to Rome?

“…This is associated with impaired glucose homeostasis (8) and mobilization of energy sources during stress responses, an observation that might coincide with the adaptive insulin resistance in peripheral tissues (9) that was observed in the new work by Vella et al (5). A growing body of evidence supports the hypothesis that ozone exposure induces a neuronal response that activates stress-sensitive centers in the nucleus tractus solitarius (10,11).…”

“…However, highconcentration ozone exposure, especially during the night and in experiments of exceedingly long duration (16 h), which has been shown to cause remarkable lung injury in rats, is not likely to occur in a real-world scenario for humans. Moreover, we are still far from understanding if transient insulin resistance can be exacerbated or if adaptation is likely over extended periods, as noted with other biological end points on repeated chronic episodic ozone exposure (7,8). Considering the magnitude of the health burden of air pollution on chronic neurological and cardiovascular disease, lipidemia, ectopic lipid accumulation, nonalcoholic steatohepatitis, and diabetes in healthy and genetically compromised individuals, more studies like that by Vella et al (5) are needed to fully understand the impact of this exposure on chronic disease.…”