Adrenal stress hormone regulation of hepatic homeostatic function after an acute ozone exposure in Wistar-Kyoto Male Rats

Ozone-induced lung injury and inflammation and pulmonary/hypothalamus gene expression changes are diminished in adrenalectomized (AD) rats. Acute ozone exposure induces metabolic alterations concomitant with increases in epinephrine and corticosterone. We hypothesized that adrenal hormones are responsible for observed hepatic ozone effects, and in AD rats, these changes would be diminished. 5-7 days after sham (SH) or AD surgeries, male Wistar-Kyoto rats were exposed to air or 0.8-ppm ozone for 4-hrs. Serum samples were analyzed for metabolites and liver for transcriptional changes immediately post-exposure. Ozone increased circulating triglycerides, cholesterol, free fatty-acids, and leptin in SH but not AD rats. Ozone-induced inhibition of glucose-mediated insulin release was absent in AD rats. Unlike diminution of hypothalamus and lung mRNA expression changes, AD in air-exposed rats (AD-air/SH-air) caused differential expression of ~1000 genes in liver. Likewise, ozone in AD rats caused differential expression of ~1000 genes (AD-ozone/AD-air). Ozone-induced hepatic changes in SH rats reflected enrichment for pathways involving metabolic processes, including acetyl-CoA biosynthesis, TCA cycle, and sirtuins. Upstream predictor analysis identified similarity to responses produced by glucocorticoids and pathways involving forskolin. These changes were absent in AD rats exposed to ozone. However, ozone caused unique changes in AD liver mRNA reflecting activation of synaptogenesis, neurovascular coupling, neuroinflammation, and insulin signaling with inhibition of senescence pathways. In these rats, upstream predictor analysis identified numerous microRNAs involved in glucocorticoid insufficiency. These data demonstrate the critical role of adrenal stress hormones in ozone-induced hepatic homeostasis and necessitate further research elucidating their role in propagating environmentally driven diseases.

Impact/Purpose

We demonstrate that systemic metabolic alterations after a single O3 exposure are diminished in adrenalectomized (AD) rats. However, unlike the attenuation of lung and hypothalamic transcriptional response to O3, more genes were significantly changed by O3 in the livers of AD rats compared to sham rats (SH). Bioinformatic assessment indicated expected differences of catecholamine and glucocorticoid regulated homeostatic metabolic processes in O3-exposed SH rats. Whereas, there were unique expression changes in the livers of AD rats exposed to O3. Only AD rats exposed to O3 had increased expressions of genes involved in neuronal communication, insulin signaling, and senescence pathways. In these animals, increased expression of genes involved in insulin signaling and glucose transport reflected directionally unique changes in glucose-mediated insulin release in AD rats. Upstream predictor analysis identified a variety of microRNAs as critical mediators of liver gene expression changes induced by O3 under glucocorticoid insufficiency. Liver might be susceptible to environmental stressor-induced pathological effects under adrenal insufficiency.

Citation

Jackson, T., A. Henriquez, S. Snow, M. Schladweiler, A. Astriab Fisher, D. Alewel, J. House, AND U. Kodavanti. Adrenal stress hormone regulation of hepatic homeostatic function after an acute ozone exposure in Wistar-Kyoto Male Rats. Society of Toxicology, RESTON, VA, 189(1):73-90, (2022). [DOI: 10.1093/toxsci/kfac065]

DOI: Adrenal stress hormone regulation of hepatic homeostatic function after an acute ozone exposure in Wistar-Kyoto Male Rats