Alewel Devin I, Rentschler Katherine M, Schladweiler Mette C, Miller Colette N, Gavett Stephen H, Evansky Paul A, Grindstaff Rachel, Williams Wanda C, Kodavanti Urmila P
Existing Chemicals Risk Assessment Division, Office of Chemical Safety and Pollution Prevention, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States of America.
Oak Ridge Institute for Science and Education Research Participation Program, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States of America.
Toxicol Sci. 2025 Jun 9. doi: 10.1093/toxsci/kfaf084.
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 day-8 and -9 post-drug-treatment, rats were exposed nose-only to 0 or 3.2 ppm acrolein for ∼4hours/day. Glucose-tolerance testing was performed following the first exposure. Nasal and lung lavages and blood samples were collected following 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 cytokines increases were exacerbated. However, acrolein-induced airway inflammation was not observed in mifepristone or co-treated rats. Regarding systemic markers of 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 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.
空气污染对女性健康影响的神经内分泌机制的作用以及这些影响与雌激素信号传导的相关程度尚不清楚。为了研究雌激素（ER）和糖皮质激素受体（GR）在丙烯醛诱导的呼吸道和全身效应中的相互作用，对雌性Wistar-Kyoto大鼠每天进行9天的处理，分别给予玉米油（赋形剂，1 mL/kg）、氟维司群（ER拮抗剂/降解剂，20 mg/kg）、米非司酮（GR拮抗剂，30 mg/kg）或氟维司群+米非司酮，在药物处理后的第8天和第9天，大鼠每天仅经鼻暴露于0或3.2 ppm丙烯醛中约4小时。在首次暴露后进行葡萄糖耐量测试。在第二次暴露后收集鼻腔和肺灌洗液以及血液样本。氟维司群和米非司酮预处理分别降低了血清雌激素和孕酮水平，并且每种药物在丙烯醛暴露的大鼠中均增加了促肾上腺皮质激素水平。尽管在氟维司群处理的大鼠中，丙烯醛诱导的鼻腔和肺蛋白渗漏减少，但中性粒细胞炎症和促炎细胞因子的增加却加剧了。然而，在米非司酮或联合处理的大鼠中未观察到丙烯醛诱导的气道炎症。关于HPA活性的全身标志物，无论是否暴露，氟维司群和米非司酮均增加了循环基础白细胞，尤其是总白细胞和中性粒细胞。在丙烯醛暴露的雌性大鼠中，氟维司群诱导的中性粒细胞增多略有减轻。氟维司群还引发了多种由丙烯醛诱导的不良代谢改变。重要的是，在米非司酮或氟维司群+米非司酮联合处理的大鼠中，丙烯醛诱导的HPA活性的全身标志物未受到影响。这些数据表明，ER和GR的神经内分泌共同调节可能解释丙烯醛易感性差异，为越来越多认识到性腺激素对空气污染健康影响易感性的影响提供了新的机制信息。
