Adrenal stress hormone regulation of hepatic homeostatic function after an acute ozone exposure
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Lung injury, inflammation, pulmonary and hypothalamic gene expression, and changes in circulating neurohormones after a single 4-hr ozone exposure are diminished in adrenalectomized (AD) rats. Acute ozone exposure induces wide metabolic alterations in serum and liver, concomitantly with increases in epinephrine and corticosterone. We hypothesized that adrenal hormones are responsible for observed ozone effects, and that in AD rats with minimal circulating hormones, these changes in liver would similarly be diminished. 5 to 7 days after sham or AD surgeries, male Wistar-Kyoto rats were exposed to air or 0.8 ppm ozone for 4 hrs. Blood samples were analyzed for metabolites and liver tissues for transcriptional changes immediately post-exposure. Ozone increased circulating triglycerides, cholesterol, free fatty acids and leptin in sham but not AD rats. Ozone-induced inhibition of glucose-mediated insulin release was reversed in AD rats. Unlike previously reported modest changes in hypothalamus (~ 21 genes), AD in air-exposed rats caused ~1200 genes to be differentially expressed in liver, consistent with the role of adrenal hormones in metabolic homeostasis. Ozone-induced changes in the livers of sham rats reflected enrichment for pathways involving metabolic processes including acetyl-CoA biosynthesis, TCA-cycle, inositol phosphate, and sirtuin metabolism. The upstream predictor analysis identified significant similarity to glucocorticoid agonists and pathways involving CREBBP and TRAM24. None of these changes were identified in AD rats exposed to ozone relative to air. However, AD rats exposed to ozone had unique changes in liver mRNA expression reflecting the activation of synaptogenesis, neurovascular coupling, neuroinflammation, and insulin signaling with inhibition of senescence pathways. Unlike ozone effect in sham, in AD rats the upstream predictor identified a variety of microRNAs possibly involved in gene expression changes induced by ozone triggered under glucocorticoid insufficiency. These data demonstrate the critical role of adrenal stress hormones in ozone-induced hepatic homeostatic changes and pleads further research on how their abnormal levels may propagate environmentally driven disease. (This abstract does not reflect the U.S. EPA policy).