Citation:

Henriquez, A., J. House, S. Snow, C. Miller, M. Schladweiler, A. Astriab Fisher, H. Ren, M. Valdez, P. Kodavanti, AND U. Kodavanti. Ozone-induced dysregulation of neuroendocrine axes requires adrenal-derived stress hormones. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 172(1):38-50, (2019). https://doi.org/10.1093/toxsci/kfz182

Impact/Purpose:

Irritant air pollutants activate neuroendocrine system. In this study, we postulated that 1) ozone exposure alters primary circulating pituitary hormones and induces changes in gene expression patterns in the brainstem and hypothalamus, and 2) circulating stress hormones are required for ozone-induced effects in the brain. We examined ozone-induced changes in global gene expression in the brainstem and hypothalamus and assessed circulating neuroendocrine hormones in Wistar-Kyoto (WKY) rats that underwent sham (SHAM) surgery or total bilateral adrenalectomy (AD).

Description:

Acute ozone inhalation increases circulating stress hormones through activation of the sympathetic-adrenal-medullary and hypothalamic-pituitary-adrenal axes. Adrenalectomized (AD) rats have attenuated ozone-induced lung responses. We hypothesized that ozone exposure will induce changes in circulating pituitary-derived hormones and global gene expression in the brainstem and hypothalamus, and that AD will ameliorate these effects.. Male Wistar-Kyoto rats (13-weeks) that underwent sham-surgery (SHAM) or AD were exposed to ozone (0.8-ppm) or filtered-air for 4-hours. In SHAM rats, ozone exposure decreased circulating thyroid-stimulating hormone (TSH), prolactin (PRL), and luteinizing hormone (LH). AD prevented reductions in TSH and PRL, but not LH. AD increased ACTH ~5-fold in both air and ozone-exposed rats. AD in air-exposed rats resulted in few significant transcriptional differences in the brainstem and hypothalamus (~20 genes per tissue).. By contrast, ozone-exposure in SHAM rats resulted in increases and decreases in expression of hundreds of genes in brainstem and hypothalamus relative to air-exposed SHAM rats (303 and 568 genes, respectively, adjusted p value<0.1). Differentially expressed genes from ozone exposure were enriched for pathways involving hedgehog signaling, responses to alpha-interferon, hypoxia, and mTORC1, among others. Gene changes in both brain areas were analogous to those altered by corticosteroids and L-dopa, suggesting a role for endogenous glucocorticoids and catecholamines. AD completely prevented this ozone-induced transcriptional response. These findings show that short-term ozone inhalation promotes a shift in brainstem and hypothalamic gene expression that is dependent on the presence of circulating adrenal-derived stress hormones. This is likely to have profound downstream influence on systemic effects of ozone.

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