NEUROENDOCRINE MECHANISMS OF ACROLEIN-INDUCED HEALTH OUTCOMES

Air pollution is currently ranked as the 2nd leading risk factor of global premature mortality, contributing to death and illness from cardiopulmonary, metabolic, and neurological diseases. While current understanding of air pollution health effects has largely focused on airway irritation, oxidative stress, and inflammation outcomes, there is growing evidence for neuroendocrine-mediated processes that link to the onset of acute and chronic respiratory and multi-organ effects, as well as response habituation and adaptation. As such, a systems-based understanding of neuroendocrine stress arising from air pollutant exposure is needed to link peripheral disease susceptibility, identify mediating mechanisms, and offer evidence-based health risk assessment and more comprehensive therapeutic intervention strategies. Using a rodent model of inhalation exposure to the prototypic air pollutant acrolein, this dissertation will delineate neuroendocrine mechanisms of respiratory and systemic endocrine health effects, highlighting novel susceptibility factors, specifically sex, through multi-omics and pharmacological approaches. In Aim 1, sex-specific respiratory and systemic neuroendocrine-mediated stress effects of acute acrolein inhalation are characterized in male and female rats. In Aim 2, mechanistic insights into the role of neuroendocrine hormones and sympathetic stress pathways in acrolein-induced multi-organ health outcomes are assessed using a multi-omics approach in male and female rats. Next, the latter two studies of this work explore independent but interrelated mechanisms involving sympathetic-adrenergic and hypothalamic-pituitary-adrenal (HPA) axis mechanisms through targeted pharmacological interventions in male and female rats, respectively. In Aim 3, the contribution of sympathetically-mediated catecholamine signaling through adrenergic receptor subtypes is examined in male rats acutely exposed to acrolein. In Aim 4, the coregulatory roles of glucocorticoids and estradiol in modifying acrolein-induced respiratory and systemic effects are examined in in female rats. In sum, this dissertation will highlight: (1) the need for integrating neuroendocrine pathways and system level health effects assessment in understanding susceptibility variations, especially related to sex, resulting from air pollutant exposures, (2) identify sex-specific respiratory and systemic effects of acrolein inhalation-induced stress, as well as novel adrenergic receptor-mediated mechanisms of respiratory and system level health outcomes, and (3) highlight how centrally-regulated neuroendocrine axes, including HPA and gonadal axes, interact to modify sex-specific health outcomes from acrolein exposure.