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Pulmonary exposure to respirable particulate matter alters hypothalamic gene expression and induces neuroendocrine changes
Citation:
Alewel, D., A. Henriquez, Mette C. Schladweiler, A. Fisher, R. Grindstaff, AND U. Kodavanti. Pulmonary exposure to respirable particulate matter alters hypothalamic gene expression and induces neuroendocrine changes. Society of Toxicology, San Diego, CA, March 27 - 31, 2022.
Impact/Purpose:
This abstract shows that particulate matter exposure also induces neuroendocrine system and that pulmonary airways exposure bypassing nasal airways is sufficient to induce stress related changes in the brain. The study emphesizes the contribution of enuroendocrine system in particulate matter-induced pulmonary and systemic effects.
Description:
Previous studies demonstrate that irritant air pollutant inhalation activates central hypothalamic-pituitary stress axes. While airway neural networks are known to communicate noxious stimuli to higher brain centers, it is not entirely known to what extent responses generated from either nasal or pulmonary areas contribute to neuroendocrine activation. Unlike inhalational exposures that involve the entire respiratory tract, we employed intratracheal (IT) instillations to characterize isolated pulmonary responses from either soluble metal-rich residual oil fly ash (ROFA) or compressor-generated diesel exhaust particles (C-DEP). Male Wistar-Kyoto rats (11-12 weeks) were IT instilled with either saline, C-DEP or ROFA (5 mg/kg) and necropsied 4 or 24 hr later to assess temporal effects. In addition to pulmonary endpoints, we analyzed systemic and transcriptomic neuroendocrine markers to assess the relationship between lung injury and brain effects. We observed robust pulmonary neutrophilia and lymphocytosis in a particle- (ROFA > C-DEP) and time-specific manner (24 > 4 hr), which was corroborated by increases in lavage fluid lung injury markers (protein, albumin, and LDH, GGT, and NAG activity) and pro-inflammatory cytokines (CXCL1, TNF-a, IL-6, IL-1b). Particle impacts on hallmarks of neuroendocrine activation were observed through depletion of circulating immune cells (C-DEP=ROFA), increases in adrenaline (ROFA), and alterations in hormones such as thyroid-stimulating (C-DEP=ROFA) and thyroxine-T3 and luteinizing hormone (ROFA). Moreover, we analyzed lung and hypothalamic transcriptomic alterations in genes associated with neuroendocrine, immune, glucocorticoid, and apoptotic processes. We found particle-induced alterations of multiple targets (Cxcl1, Il-6, Il-33, Areg, Tnf, and more) in the lung, and more importantly, hypothalamic transcriptomic changes in genes such as Fkbp5, a glucocorticoid-regulating gene, Il-33, Tlr2, and Bcl2. These findings indicate that isolated lung injury induces neuroendocrine mechanisms that elicit a systemic stress response, bolstering previous claims that pulmonary autonomic vagal communication activates central hypothalamic-pituitary stress axes, although the underlying mechanisms are yet to be examined. (This abstract does not reflect the U.S. EPA policy).