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Heat and lifestyle stressors interact with episodic wildfire smoke exposure to induce rat hypothalamic transcriptional changes, serum markers of oxidative stress, and glucocorticoid signaling
Citation:
Kodavanti, P., D. Freeborn, J. Valdez, D. Alewel, M. Schladweiler, P. Evansky, D. Davies, M. Monsees, T. Jackson, AND U. Kodavanti. Heat and lifestyle stressors interact with episodic wildfire smoke exposure to induce rat hypothalamic transcriptional changes, serum markers of oxidative stress, and glucocorticoid signaling. 63rd Annual Meeting of Society of Toxicology, Salt Lake City, UT, March 10 - 14, 2024.
Impact/Purpose:
Non-chemical factors have been shown to interfere with chemical stressors on the human and animal health outcome. We have now studied the effect of ambient temperature (high temperature, HT) and dietary condition (high cholesterol diet; HCD) on the neuronal outcome following exposure to episodic sub-chronic wildfire eucalyptus smoke exposure (WFES). We hypothesize that WFES would interact to increase tissue oxidative stress, disrupt glucocorticoid signaling in stress response brain region such as hypothalamus and interfere with stress hormones in blood. The results showed that there is interaction between WFES and temperature/dietary condition. .Even though hypothalamic effects of HT and WFES/HCD stressors on selected markers might be independent, high ambient temperature likely influences the peripheral effects of these stressors and thus, interactively increases the risk for neural and peripheral health effects of WFES, and that these effects are likely exacerbated in at risk individuals consuming high-cholesterol diets. This information is useful to the scientific community as well as risk assessors.
Description:
Climate change is associated with increased ambient temperatures, more frequent and longer-lasting heatwaves, and increased air pollution from widespread wildfires, all of which are likely to exacerbate stress-related disorders. We hypothesized that stress caused by subchronic high-temperature housing (HT), unhealthy high-cholesterol diet (HCD), and episodic subchronic wildfire eucalyptus smoke exposures (WFES) would interact to increase tissue oxidative stress, disrupt glucocorticoid signaling in stress-responsive regions of the brain, and impair the ability to appropriately respond to subsequent additional stressors. Male Wistar-Kyoto rats (4-week-old) were housed at standard housing conditions (room temperature, RT, ~22°C) or HT (~31°C), just above temperatures historically characterized as thermoneutral for rats, for 13 weeks while receiving either normal (ND) or 2% cholesterol-supplemented diet (HCD) and were exposed to either episodic filtered air or WFES (~7 mg/m3 x 1hr/d x 1d/week x 12-13 weeks). Serum and hypothalamus were collected and flash-frozen for subsequent analyses, with serum hormone levels measured and qPCR performed on RNA from hypothalamus. Subchronic WFES exposure resulted in lower basal corticosterone levels in HT-housed rats fed a normal diet and HT-housed rats fed HCD, but not in RT rats fed HCD, suggesting that WFES when combined with HT may be chronically stressing these animals and leading to depleted corticosterone. Adrenocorticotropic hormone (ACTH), which regulates cortisol and androgen production, was also lower in WFES-exposed, ND-fed rats housed at RT, but not in HT-housed ND or HCD rats. Although ACTH was unchanged by HT housing, testosterone was lower in HT-housed rats irrespective of diet or exposure. HCD also lowered ACTH in air-exposed RT-housed rats when compared to air-exposed ND. Alterations in serum levels of brain-derived neurotrophic factor (BDNF) involved in several brain disorders were noted with HT housing and HCD. HT housing resulted in lower serum BDNF regardless of diet or exposure, with mixed effects of HCD and/or WFES on BDNF levels. Conversely, thyroid-stimulating hormone (TSH) was higher in HT-housed rats regardless of diet or exposure, with WFES-exposed rats having even higher levels of TSH in the HT-housed animals. Hypothalamic expression of inflammatory and oxidative stress genes including Aif1 and Atp5a1 was increased by the interaction of HCD and WFES regardless of housing temperature. Glucocorticoid-responsive genes including Fkbp5, and Hsp90aa1 were increased by WFES or HCD, irrespective of housing temperature. Housing temperature alone did not result in significant changes in expression of stress-responsive genes in the hypothalamus. Taken together, these results demonstrate that even though hypothalamic effects of HT and WFES/HCD stressors on selected markers might be independent, high ambient temperature likely influences the peripheral effects of these stressors and thus, interactively increases the risk for neural and peripheral health effects of WFES, and that these effects are likely exacerbated in at risk individuals consuming high-cholesterol diets. (This abstract does not necessarily reflect USEPA policy).