Impact of prenatal exposures to copper from electronic nicotine delivery system (ENDS) aerosols on the immature neonatal pulmonary immune system and IL-10-mediated asthmatic responses - PROJECT SUMMARY/ABSTRACT Fetal development is a sensitive window of vulnerability to toxicant exposures, which can lead to lifelong respiratory health consequences. Epidemiological studies suggest that maternal vaping, estimated at 5% to 15% of pregnant women in the U.S., is associated with infants born small-for-gestational-age, a clinical indicator for increased risk of severe complications in lung diseases. The long-term respiratory health effects in these offspring, however, are unclear. The overall goal of this proposal is to define the mechanisms by which prenatal exposure to electronic nicotine delivery system (ENDS) aerosol modulates the neonatal pulmonary immune system to prime the lungs for allergic asthma. Although the metals used in coils and atomizers vary across types of ENDS devices, copper (Cu) is in the top two most frequently detected metals in ENDS aerosols, and in a woman, transplacental transfer of Cu from secondhand ENDS exposures was documented. Copper has allergic sensitizing properties and its accumulation in tissue decreases DNA methylation. Our published and preliminary data demonstrate that Cu is the main metal found in our ENDS aerosols and that in mice, prenatal exposures to ENDS increased the expression of Il-10 at birth, decreased the methylation of the promoter region of Il-10ra, and increased Il-10 driven Th2 asthmatic responses following an allergen challenge. Also, IL-10 deficiency reduced serum concentrations of IgE in ENDS-exposed mice at birth, suggesting a role for IL-10 in allergic sensitization. Thus, our findings strongly indicate that prenatal ENDS exposures containing high levels of Cu lead to an immuno-pulmonary environment that may result in hypomethylation of genes within the II-10/Il-10ra axis and prime the lungs for enhanced IL-10-mediated, Th2-driven allergic asthma. Cu from ENDS aerosols may be a factor whose effect on sensitization and DNA methylation influences lung immune responses. Based on these compelling findings, our working hypothesis is that prenatal exposure to Cu from ENDS aerosols induce respiratory sensitization and epigenetically regulated IL-10-mediated pulmonary immune dysfunction in neonates, which combined with an allergen exposure, results in enhanced Th2-driven asthma. Our approach for testing this hypothesis will leverage our research team’s long-standing expertise in inhalation, metal and immunotoxicology to generate comprehensive mechanistic evidence using a combination of innovative in vitro and in vivo models and clinical sample datasets. In our first aim, we will determine the proportion of transplacental passage of Cu after ENDS aerosol exposure and exacerbation of asthma in offspring. Next, we will use in vitro and in vivo models to demonstrate the key role of IL-10 and its methylation status in this context. Lastly, we will quantify levels of Cu and IL-10 in cord blood and establish fetal T cells polarization in vaping and non-vaping mother-infant dyads. Overall, this research will determine blood-based biomarkers of prenatal ENDS exposures (e.g., increased concentration of Cu), a pivotal first step for early management of asthma for the >500,000 prenatally ENDS-exposed infants born each year in the U.S.
