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The contribution of the neuroendocrine system to adaption after repeated daily ozone exposure in rats
Citation:
Heinriquez, A., S. Snow, J. Dye, Mette C. Schladweiler, D. Alewel, C. Miller, AND U. Kodavanti. The contribution of the neuroendocrine system to adaption after repeated daily ozone exposure in rats. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, 447(116085):1, (2022). https://doi.org/10.1016/j.taap.2022.116085
Impact/Purpose:
Our recent work demonstrated the contribution of components of the neuroendocrine system (especially adrenal gland-derived stress hormones), in mediating ozone effects. Since glucocorticoids mediate feedback regulation, resiliency, and adaptation to stress through their central effects, we hypothesized that the adaptation that occurs with daily repeated exposure to ozone in rats will involve neuroendocrine system activation and the availability of glucocorticoids in the circulation. The data together indicates the role of endogenous glucocorticoid release in adaptation response, likely at tissue and central levels.
Description:
Ozone-induced lung injury/inflammation dissipates despite continued exposure for 3 or more days; however, the mechanisms of adaptation/habituation remain unclear. Since ozone effects are mediated through adrenal-derived stress hormones, which also regulate longevity of centrally-mediated stress response, we hypothesized that ozone-adaptation is linked to diminution of neuroendocrine stress-axes activation and glucocorticoid levels. Male Wistar-Kyoto-rats (12-week-old) were injected with vehicle or a therapeutically-relevant dexamethasone dose (0.01-mg/kg/day; intraperitoneal) for 1-month to determine if suppression of glucocorticoid signaling was linked to adaptation. Vehicle- and dexamethasone-treated rats were exposed to air or 0.8-ppm ozone, 4 h/day × 2 or 4 days to assess the impacts of acute exposure and adaptation, respectively. Dexamethasone reduced thymus and spleen weights, circulating lymphocytes, corticosterone and increased insulin. Ozone increased lavage-fluid protein and neutrophils and decreased circulating lymphocytes at day-2 but not day-4. Ozone-induced hyperglycemia, glucose intolerance and inhibition of beta-cell insulin release occurred at day-1 but not day-3. Ozone depleted circulating prolactin, thyroid-stimulating hormone, and luteinizing-hormone at day-2 but not day-4, suggesting central mediation of adaptation. Adrenal epinephrine biosynthesis gene, Pnmt, was up-regulated after ozone exposure at both timepoints. However, genes involved in glucocorticoid biosynthesis were up-regulated after day-2 but not day-4, suggesting that acute 1- or 2-day ozone-mediated glucocorticoid increase elicits feedback inhibition to dampen hypothalamic stimulation of ACTH release in response to repeated subsequent ozone exposures. Although dexamethasone pretreatment affected circulating insulin, lymphocytes and adrenal genes, it had modest effect on ozone adaptation. In conclusion, ozone adaptation likely involves lack of hypothalamic response due to reduced availability of circulating glucocorticoids.
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DOI: The contribution of the neuroendocrine system to adaption after repeated daily ozone exposure in rats