Ozone-Induced Dysregulation of Neuroendocrine Axes Requires Adrenal-Derived Stress Hormones

Abstract

Acute ozone inhalation increases circulating stress hormones through activation of the sympathetic-adrenal-medullary and hypothalamic-pituitary-adrenal axes. Rats with adrenalectomy (AD) 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 h. 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 adrenocorticotropic hormone approximately 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 (approximately 20 genes per tissue). In contrast, ozone-exposure in SHAM rats resulted in either increases or decreases in expression of hundreds of genes in the brainstem and hypothalamus relative to air-exposed SHAM rats (303 and 568 genes, respectively). 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-3,4-dihydroxyphenylalanine, 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 upon the presence of circulating adrenal-derived stress hormones. This is likely to have profound downstream influence on systemic effects of ozone.

Offspring susceptibility to metabolic alterations due to maternal high-fat diet and the impact of inhaled ozone used as a stressor

“…The increases in 7-HOCA after ozone exposure might also be linked to gut microbiome changes since gut microbes are involved in production of secondary bile acids and 7-HOCA is an intermediate in this process 56 . Gut microbiome changes due to maternal diet and acute ozone exposure may underlie the marked changes in brain and neuroendocrine pathways after ozone exposure 10,57 .…”

The Metabolic Response to Ozone

“…Serum concentrations of epinephrine are also increased following O 3 (19, 21, 31) and remain elevated even 18 h after cessation of exposure (21). These changes in stress hormones are thought to arise from O 3 -induced stimulation of sensory afferents within the lungs and nose (32). These afferents have been shown to terminate in stress responsive regions of the brain (33).…”

Susceptibility Variations in Air Pollution Health Effects: Incorporating Neuroendocrine Activation

“…Our recent study has shown that acute ozone exposure induces a wide array of gene expression changes in the brain stem and hypothalamus that are similar to those induced during hypoxia (ie, interferon signaling and the activation of stress pathways). 128 These ozone-induced gene expression changes in rats are associated with increases in adrenaline and corticosterone while depleting prolactin, luteinizing hormone, and also thyroid-stimulating hormone, suggesting the concomitant inhibition of hypothalamus–pituitary–gonadal (HPG) and hypothalamus–pituitary–thyroid (HPT) axes. The activation of SAM and HPA and associated inhibition of HPG and HPT axes have been reported after application of other stressors.…”

“…Circulating stress hormones are needed to produce lung effects of ozone, and if no lung effects occur due to lack of stress hormones, no changes in brain regions are noted. 128 Glucocorticoids in conjunction with mineralocorticoids and catecholamines have been shown to interactively regulate the process of adaptation and habituation centrally. 99 The regulatory roles of adrenergic and glucocorticoid receptors systems and feedback inhibition need to be further examined in relation to health effects of acute and chronic air pollution exposures and more importantly how neuroendocrine response variations may lead to variations in human susceptibility to air pollution health effects.…”

“…138,139 Based on the role of adrenergic and glucocorticoid regulation of habituation, learning, and memory 99,130,131 and the activation of SAM and HPA axes after a single air pollution exposure, it is conceivable that the adaptation that occurs upon repeated exposure to ozone will involve the loss of neuroendocrine activation through adrenergic and glucocorticoid mechanisms. The importance of the presence of catecholamines and glucocorticoids in the peripheral circulation, their increases following stress, and in mediation of systemic, pulmonary, and even brain effects of air pollutants 120,121,124,128 emphasizes their role in regulation of adaptive, homeostatic, and pathological processes. 131,132 It has been shown that after applying psychological stress, the changes in peripheral stress hormones is necessary for inducing inflammatory changes in the brain, 135 implying the regulatory role of peripheral stress hormones in orchestrating brain response.…”