The contribution of the neuroendocrine system to adaption after repeated daily ozone exposure in rats

Henriquez, Andres R.; Snow, Samantha J.; Dye, Janice A.; Schladweiler, Mette C.; Alewel, Devin I.; Miller, Colette N.; Kodavanti, Urmila P.

doi:10.1016/j.taap.2022.116085

The contribution of the neuroendocrine system to adaption after repeated daily ozone exposure in rats

Journal Article · Mon May 23 00:00:00 EDT 2022 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2022.116085· OSTI ID:1981774

^[1]; ^[2]; Dye, Janice A. ^[2]; Schladweiler, Mette C. ^[2]; ^[1]; Miller, Colette N. ^[2]; ^[2]

US Environmental Protection Agency (EPA), Research Triangle Park, NC (United States). Oak Ridge Institute for Science and Education Research Participation Program
US Environmental Protection Agency (EPA), Research Triangle Park, NC (United States). Center for Public Health and Environmental Assessment

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.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States); US Environmental Protection Agency (EPA), Research Triangle Park, NC (United States)

Sponsoring Organization:: USDOE; USDOE Office of Science (SC)

Grant/Contract Number:: SC0014664

OSTI ID:: 1981774

Alternate ID(s):: OSTI ID: 1962927

Journal Information:: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: C Vol. 447; ISSN 0041-008X

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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The contribution of the neuroendocrine system to adaption after repeated daily ozone exposure in rats

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