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Ozone-Induced Systemic Metabolic Alterations are Regulated by Circulating Stress Hormones in Rats
Citation:
Snow, S., A. Henriquez, J. House, M. Schladweiler, C. Miller, AND U. Kodavanti. Ozone-Induced Systemic Metabolic Alterations are Regulated by Circulating Stress Hormones in Rats. Experimental Biology, Orlando, Florida, April 06 - 09, 2019.
Impact/Purpose:
Several recent studies from our lab and others have demonstrated widespread metabolic effects following an acute ozone exposure. Although these effects are similar to those induced by the fight-or-flight response involving adrenal-derived stress hormones, little data are available linking these metabolic changes to activation of neuroendocrine pathways. Collectively, these data suggest adrenal-derived stress hormones play a significant role in mediating ozone-induced systemic metabolic effects.
Description:
Several recent studies from our lab and others have demonstrated widespread metabolic effects following an acute ozone exposure. Although these effects are similar to those induced by the fight-or-flight response involving adrenal-derived stress hormones, little data are available linking these metabolic changes to activation of neuroendocrine pathways. In this study, we used surgical and pharmacological interventions to understand the influence of adrenal-derived stress hormones in mediating ozone-induced metabolic alterations. Male Wistar-Kyoto (WKY) rats underwent bilateral total adrenalectomy (ADREX) or sham surgery prior to their exposure to filtered air or ozone (0.8 ppm), 4h/day for 1 day. In the sham animals, ozone exposure induced hyperglycemia and glucose intolerance as well as increased levels of circulating total cholesterol, free fatty acids (FFA), and leptin. ADREX and the resultant depletion of adrenal-derived stress hormones, adrenaline and corticosterone, significantly attenuated these ozone-induced metabolic effects. Furthermore, ozone-induced global transcriptional changes in the liver from sham and ADREX rats were assessed by total mRNA sequencing. The upstream regulator assessment within Ingenuity Pathway Analysis revealed that ozone-induced changes in gene expression were similar to those induced by corticosterone, methylprednisolone, and forskolin, suggesting glucocorticoids and adrenergic mechanisms significantly contributed to the ozone-induced changes in the liver. These same regulators were not predicted in the ADREX animals exposed to ozone. In a follow up study, we utilized a non-specific beta-adrenergic receptor antagonist (propranolol) and/or glucocorticoid receptor antagonist (mifepristone) to understand the specific contribution of these stress hormones in mediating metabolic effects following ozone exposure. Ozone-induced hyperglycemia, glucose intolerance, and increased FFA levels were significantly attenuated only by the combination of antagonists, suggesting that both adrenergic and glucocorticoid pathways were involved in the regulation these processes. However, increases in total cholesterol and leptin levels following ozone exposure were blocked by mifepristone alone and in combination with propranolol, suggesting these ozone effects are glucocorticoid-dependent. Collectively, these data suggest adrenal-derived stress hormones play a significant role in mediating ozone-induced systemic metabolic effects. (Does not reflect the US EPA policy)