Untargeted metabolomics and pathophysiological analyses of 17β-estradiol protection against house dust mite-induced allergic asthma with associated ERα/ERβ and NF-κB p65 expression changes in ovariectomized mice.

Postmenopausal women are more susceptible to allergic asthma, likely due to estrogen deficiency-associated immune dysregulation, yet the effects of 17β-estradiol (E2) in postmenopausal allergic asthma remain incompletely defined. In this study, we investigated the effect of E2 in ovariectomized (Ovx) mice subjected to chronic house dust mite (HDM) challenge. Mice were assigned to Sham, Ovx, Sham+HDM, Ovx + HDM, Ovx + E2 and Ovx + HDM + E2 groups. Airway pathology, peripheral inflammatory cells, pulmonary cytokine transcripts, ERα, ERβ, and total NF-κB p65 protein levels, and untargeted lung-tissue metabolomics were assessed. HDM exposure exacerbated allergic airway responses, particularly in Ovx mice, whereas E2 treatment attenuated the reduction in body-weight gain, nasal rubbing, circulating eosinophil and basophil counts, lung inflammation, mucus production, and Il-4, Il-5, Il-13, and Ifn-γ mRNA expression. Moreover, HDM stimulation increased pulmonary ERα, ERβ, and total NF-κB p65 expression, particularly in Ovx mice, while E2 treatment reduced the levels of these proteins. Untargeted metabolomic profiling further revealed E2-associated shifts involving tryptophan-related, glycerophospholipid, sphingolipid, riboflavin, pyrimidine, and carbohydrate metabolism. These findings indicate that E2 attenuates HDM-induced allergic airway inflammation under estrogen-deficient conditions, accompanied by lower pulmonary ERα, ERβ, and total NF-κB p65 protein levels and partial modification of lung-tissue metabolic disturbances.