Citation:

Kodavanti, U., S. Snow, Mette C. Schladweiler, C. Miller, AND A. Henriquez. Neuroendocrine aspect of ozone adaptation at lung and systemic level: The influence of one-month glucocorticoid pretreatment. Society of Toxicology (SOT) - Virtual, NA, Virtual, March 14 - 18, 2021.

Impact/Purpose:

The mechanisms of adaptation that occur in animal models and humans after exposure to irritant pollutants are not understood. Based on our findings that neuroendocrine system is involved in mediating ozone health effects, here we assessed its role in animal adaptation to ozone-induced injury and inflammation. We show that glucocorticoid availability and likely the lack of resultant central neuroendocrine activation after repeated ozone exposure are involved in mediating tolerance/adaptation. This is important when understanding how organisms adapt to environmental stressors and what conditions may fail them.

Description:

Ozone-induced lung injury and inflammation dissipate despite continuation of exposure for 3 or more days; however, the mechanisms of adaptation/habituation remain unclear. We have shown that ozone-induced pulmonary and systemic effects are mediated through reversible neuroendocrine activation and adrenal release of the stress hormones corticosterone and epinephrine. Here, we hypothesized that adaptation from ozone-induced pulmonary and systemic effects is associated with diminution of neuroendocrine activation and reduced glucocorticoid activity. Male Wistar Kyoto rats (12-week old) were injected daily with vehicle (VEH, saline) or a therapeutically relevant dose of dexamethasone sulfate (DEX, 0.01 mg/kg/day; i.p.) for 1-month to induce glucocorticoid resistance and to determine if reduced glucocorticoid effectiveness is associated with diminution of ozone adaptation response. Saline or DEX-treated rats were exposed to air or 0.8 ppm ozone, 4 hours/day for 2 or 4 days (D+2 or D+4) to assess impacts of acute exposure and characterize adaptation responses, respectively. Acute ozone exposure (D+2) increased lung lavage fluid protein and neutrophils, and decreased circulating lymphocytes; effects that were not evident in D+4. Likewise, ozone-induced hyperglycemia, glucose intolerance and inhibition of beta-cell insulin release in D+2 were attenuated in D+4. This adaptation was modestly attenuated in DEX pretreated rats. Ozone-induced depletion of circulating prolactin, thyroid stimulating hormone, and luteinizing hormone after 2-day exposure were not observed at D+4 suggesting central mediation of adaptation. Genes involved in epinephrine synthesis were similarly induced in adrenals after ozone exposure at D+2 and D+4, however, those involved in glucocorticoid biosynthesis were induced only after D+2 but not D+4 exposure, suggesting involvement of reduced glucocorticoid synthesis in mediating ozone adaptation. These results suggest that ozone adaptation likely involves the lack of hypothalamic-pituitary-adrenal axis activation and glucocorticoid production. (Does not reflect US EPA policy)

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