Estrogen and glucocorticoid receptors co-regulate acrolein-induced respiratory and systemic homeostatic stress responses.

The contribution of neuroendocrine mechanisms of air pollution health effects in females and the extent to which such effects are related to estrogen signaling are unclear. To examine the interactive roles of estrogen (ER) and glucocorticoid receptors (GR) in acrolein-induced respiratory and systemic effects, female Wistar-Kyoto rats were treated daily for 9 days with corn oil (vehicle, 1 ml/kg), fulvestrant (ER-antagonist/degrader, 20 mg/kg), mifepristone (GR antagonist, 30 mg/kg) or fulvestrant + mifepristone, and on days 8 and 9 post-drug-treatment start, rats were exposed nose-only to 0 or 3.2 ppm acrolein for ∼4 h/day. Glucose-tolerance testing was performed following the first exposure. Nasal and lung lavages and blood samples were collected following the second exposure. Fulvestrant and mifepristone pretreatments decreased serum estrogen and progesterone, respectively, and each drug increased adrenocorticotropic hormone in acrolein-exposed rats. Although acrolein-induced nasal and lung protein leakage was reduced in fulvestrant-treated rats, neutrophilic inflammation and pro-inflammatory cytokine increases were exacerbated. However, acrolein-induced airway inflammation was not observed in mifepristone or co-treated rats. Regarding systemic markers of hypothalamic-pituitary-adrenal (HPA) activity, fulvestrant and mifepristone each increased circulating basal leukocytes regardless of exposure, especially total white blood cells and neutrophils. Fulvestrant-induced neutrophilia was slightly dampened in acrolein-exposed females. Fulvestrant also primed multiple adverse acrolein-induced metabolic alterations. Importantly, systemic markers of acrolein-induced HPA activity were not impacted in mifepristone or fulvestrant + mifepristone co-treated rats. These data demonstrate that neuroendocrine co-regulation by ER and GR might explain acrolein susceptibility differences, contributing novel mechanistic information to the growing recognition of gonadal hormone influence in air pollution health effects susceptibility.