Susceptibility to Ozone-Induced Metabolic and Immunological Alterations in Rat Models of Social Isolation and Mild Chronic Stress
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Underserved vulnerable communities are disproportionally impacted by psychosocial stressors and poor living conditions. Epidemiological studies have shown an interaction between psychologically stressed individuals and air pollution exposure. Our lab and others have recently demonstrated that ozone exposure activates neuroendocrine stress response pathways leading to systemic metabolic and inflammatory responses. The purpose of this study was to identify whether community level stressors (i.e. noise, uncomfortable living conditions, confinement, fear) can interact with ozone to increase susceptibility for immunological and metabolic diseases. Male, 4-week-old Wistar-Kyoto rats were randomized into 3 stress groups: No Stress (NS) – control group; Social Isolation (SI) – single-housed; Chronic Stress (CS) – single-housed and subjected to mild randomized stressors (i.e. restraint, tilted cage, shaking, intermittent noise, and predator odor) 5 days/week for 8 weeks. Animals were then exposed acutely to filtered air or ozone (0.8 ppm) for 4h followed by necropsy. After 3 weeks on the stress protocol through the end of the study, the CS group had significantly decreased body weight compared to the NS and SI groups. This corresponded with increased adrenal weight and urine corticosterone and metanephrine levels measured in the CS group, suggesting the chronic stress protocol was successful. SI and CS tended to deplete circulating thyroid stimulating hormone, luteinizing hormone, prolactin, follicle stimulating hormone, and brain-derived natriuretic factor, but not adrenocorticotrophic hormone in air-exposed rats (SI>CS). SI also induced more severe systemic inflammation than CS, as evidenced by increases in circulating cytokine levels (i.e. IL-1β, IL-4, IL-5, IL-6, IL-10, IL-13, and IFN-γ) regardless of exposure. Ozone exposure led to increases in plasma corticosterone levels (NS and SI), plasma epinephrine (CS), and urine corticosterone and catecholamine metabolites (all groups). Exposure to ozone also led to increases in serum glucose, leptin, and branched-chain amino acids; increases in BALF IL-6 and TNF-α; and decreases in serum thyroid stimulating hormone, prolactin, and luteinizing hormone, with small influence of CS and SI. Systemic inflammation and some pulmonary effects of ozone were exacerbated by SI. Collectively, these data suggest that the degree to which psychosocial stressors affect the neuroendocrine system will likely sway the adverse metabolic and inflammatory responses induced by ozone exposure, a challenge stressor. (Does not reflect the US EPA policy)