Project Summary We are a current Environmental influences on Children's Health Outcomes (ECHO) Cohort awardee (Cohort Identifier “Maternal Vitamin C Supplementation to Decrease Effects of Smoking during Pregnancy on Infant Lung Function and Health” [VCSIP]) with expertise in upper and lower airway outcomes and analysis of associated epigenetic mechanisms. We have been part of the ECHO cohort since its inception in 2016. This application is to renew our participation in the ECHO Program for an additional seven years (9/2023-8/2030). The overall goal of this renewal of the ECHO program is to extend the longitudinal follow-up of existing ECHO Cohort participants and add new pregnant participants. The ECHO Cohort was successfully established by combining data and biospecimens from multiple maternal-child cohorts such that there is now data and biospecimens from up to 60,000 children and their families. This robust and ongoing data set offers a tremendous opportunity to collaboratively investigate multiple simultaneous exposures on one or more health outcomes. Multiple prenatal factors that can adversely affect lung development and place an infant on a lower lung function trajectory and increase risk of lung disease. Maternal smoking during pregnancy (MSDP) is a well- established risk factor for impaired fetal lung development, decreased airway function, and an increased risk for wheeze and asthma in the offspring. We have shown that supplemental vitamin C (500 mg/day) to pregnant cigarette smokers significantly improves their offspring's lung function through 5 years of age and decreases the occurrence of wheeze. We have also demonstrated specific and stable epigenetic changes associated with MSDP in pathways linked to lung development. The focus of this application are the effects of in utero exposure to smoking on offspring lung function and respiratory health as modified by in utero exposure to air pollution, vaping, and/or cannabis as well as the potential modulation by postnatal exposures. In specific aim 1, we will leverage ECHO Cohort Protocol 3.0 core data elements to characterize the epigenetic signatures in placenta and offspring associated with MSDP, and examine their additive predictive value relative to additional prenatal and postnatal exposures. In specific aim 2, we will leverage ECHO cohorts with airway-specialized outcomes (yearly exposure postnatal spirometry and twice-yearly respiratory questionnaires) to characterize the relationships between fetal to MSDP on airway function and wheeze during childhood as modified by multi-factorial prenatal and exposures.We hypothesize that MSDP will significantly affect clinical respiratory outcomes including wheeze and airway function trajectories up to 21 years of age. We also hypothesize that these effects will be modified by the multi-factorial exposures that ECHO will be measuring. Given our cohort's excellent track record during the initial phase of ECHO (2016-present) as outlined in sp...