Influence of Mild Chronic Stress and Social Isolation on Acute Ozone-Induced Alterations in Stress Biomarkers and Brain-Region-Specific Gene Expression in Male Wistar-Kyoto Rats.

Individuals with psychosocial stress often experience an exaggerated response to air pollutants. Ozone (O) exposure has been associated with the activation of the neuroendocrine stress-response system. We hypothesized that preexistent mild chronic stress plus social isolation (CS), or social isolation (SI) alone, would exacerbate the acute effects of O exposure on the circulating adrenal-derived stress hormones, and the expression of the genes regulating glucocorticoid stress signaling via an altered stress adaptation in a brain-region-specific manner. Male Wistar-Kyoto rats (5 weeks old) were socially isolated, plus were subjected to either CS (noise, confinement, fear, uncomfortable living, hectic activity, and single housing), SI (single housing only, restricted handling and no enrichment) or no stress (NS; double housing, frequent handling and enrichment provided) for 8 weeks. The rats were then exposed to either air or O (0.8 ppm for 4 h), and the samples were collected immediately after. The indicators of sympathetic and hypothalamic-pituitary axis (HPA) activation (i.e., epinephrine, corticosterone, and lymphopenia) increased with O exposure, but there were no effects from CS or SI, except for the depletion of serum BDNF. CS and SI revealed small changes in brain-region-specific glucocorticoid-signaling-associated markers of gene expression in the air-exposed rats (hypothalamic , , and inhibition in SI; hippocampal increase in SI; and inhibition of the bed nucleus of the stria terminalis (BNST) in CS). Gene expression across all brain regions was altered by O, reflective of glucocorticoid signaling effects, such as in NS, CS and SI. The SI effects on were greatest for SI in BNST. O increased expression in the hypothalamus and olfactory bulbs of the NS and SI groups. O in all stress conditions, generally inhibited the expression of in all brain regions, in the hippocampus and hypothalamus and in the hippocampus. SI, in general, showed slightly greater O-induced changes when compared to NS and CS. Serum metabolomics revealed increased sphingomyelins in the air-exposed SI and O-exposed NS, with underlying SI dampening some of the O-induced changes. These results suggest a potential link between preexistent SI and acute O-induced increases in the circulating adrenal-derived stress hormones and brain-region-specific gene expression changes in glucocorticoid signaling, which may partly underlie the stress dynamic in those with long-term SI.