44 Sexual dimorphism in E-cigarette-induced developmental lung immune adaptations

Abstract Electronic cigarette (e-cig) use during pregnancy has become a major health concern in recent years, perpetuated by perceptions that e-cigs are less harmful than traditional cigarettes. Extensive knowledge gaps persists regarding e-cig health impacts when aerosolized, especially in pregnancy. Recent reports indicate e-cig vaping leads to heightened risk of respiratory infection in nonpregnant adults, but there is limited data for the neonatal population. We hypothesized that fetal exposure to e-cig aerosols alters the developing lung’s immune environment in a sex-specific manner, resulting in deficient antiviral innate immune responses and more risk for respiratory viral infections. Using our well-established pregnant rat model, we utilized a custom-engineered e-cig system with a commercial e-cig unit and atomizer that offered a translational inhalation delivery method and generated vapor profiles comparable to human vaping. Our data indicate a major separation of immune-related genes between male and female fetal lungs, with sex-specific deficits in innate immune pathways, including the neutrophil system. Flow cytometry analysis of fetal lungs confirmed sex-specific changes in innate immune cell populations (primarily neutrophils) following e-cig exposure. RNA-seq showed that viral-sensing pathways, and type I IFN signaling pathways, including IRFs, INF receptors, and INF stimulated genes (ISGs), were downregulated in a sex-specific manner after e-cig exposure, suggesting impaired antiviral responses. Importantly, sex-specific enhanced susceptibility to neonatal viral infection in the e-cig exposed developing lung was noted. Sex-specific innate immune alterations were compounded by altered morphometrics, and e-cig altered neonatal lung development and function in a sex- specific manner. These data provide novel information on the growing area of e-cig effects on the offspring lung and on fetal/neonatal immune responses. It highlights the importance of examining sexual dimorphism in developmental adaptations. The findings emphasize the need for translational studies to better understand and manage respiratory infections with clinical differences between males and females. (Supported by NIH HL151497, AA23520, AA23035)