Wednesday, February 5, 2025
2/5/2025
Abstract Individuals born prematurely are at increased risk for many chronic conditions, and respiratory disease represents a significant portion of the morbidity and mortality in this population. Better understanding of the etiology of chronic respiratory disease among those born preterm has the potential to improve diagnosis, treatment, and prevention. Asthma occurs more frequently and severely among those born preterm. The etiology of asthma is known to be multifactorial, involving innate inflammatory tendencies, potentiated by prenatal and early life exposures. Asthma exhibits differences in presentation, and pathophysiology, based on biologic sex, a phenomenon known as sexual dimorphism. Epigenetics represents a powerful tool for understanding early-life origins of chronic disease. Research from our group in the Extremely Low Gestational Age Newborn (ELGAN) cohort has illustrated the critical role of epigenetic and gene expression changes in the placenta as they relate to later development of a host of chronic conditions. As a temporary organ during gestation, the placenta forms a barrier between the developing fetus, the mother, and by extension, the outside world. It is a critical conduit through which the effects of environmental exposures are filtered. The placenta also plays critical roles in directing fetal growth and development, and establishing the neonatal immune system, while also protecting the fetus from rejection by the maternal immune response. The placenta is also highly sexually dimorphic, responding differently to prenatal exposures, and conferring risk differently for chronic disease, based on the biologic sex of the infant. Prior work from other groups has shown epigenetic changes in immune-related genes from cord blood cells in association with the later development of childhood asthma among children born at term. Preliminary analyses from EGLAN have shown differential epigenetic changes to immune-related genes in the placenta that are associated with asthma development in a largely sex-dependent manner. No other published studies have examined placental epigenetic factors as antecedents of asthma. We propose to further examine placental epigenetic mechanism and gene expression and their association with development of asthma at age 10 years. Our study would be the first to provide a comprehensive examination of epigenetic mechanisms and gene expression in the placenta, as well as epigenetic changes in neonatal blood on day of life 1 as they relate to later development of asthma among ELGANs. The examination of the role of differences based on biologic sex is also novel. These investigations will elucidate important general and sex-specific genetic pathways that form the basis of the developmental origins of asthma. Enhanced understanding of these will allow for improved diagnosis, treatment, and perhaps even prevention of asthma in a particularly vulnerable population.
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