Molecular and Neurodevelopmental Alterations Associated with Prenatal Wildfire Exposures - More frequent and intense wildfires in recent years have increased concerns about potential health impacts of wildfire exposures and the need to understand how to mitigate their effects, especially in vulnerable populations like pregnant people and their children. Prenatal ambient air pollution and particulate matter (PM) exposures are linked to adverse pregnancy and child neurodevelopmental outcomes. Epidemiologic evidence supports similar impacts of wildfire smoke events on pregnancy outcomes, but little is known about the potential mechanisms or their association with downstream child neurodevelopmental and behavioral outcomes. Pregnancy is a period vulnerable to environmental exposures like air pollution that can disrupt immune regulation and induce inflammatory responses. Further, given strong neuro-immune connections, maternal immune dysregulation and changes in cytokines and chemokines can disrupt fetal brain development. Non-human primate studies linked early gestational wildfire exposure to increased pregnancy loss, and greater inflammation, blunted cortisol, memory impairment and behavioral differences in offspring. Early-life wildfire smoke exposure also led to longterm changes in macaque nasal epithelium methylome over genes impacting the immune and nervous systems, including synaptogenesis, with related expression differences. As the closest animal model of human neurodevelopment and function, these macaque studies suggest developmental impacts of wildfires, with an early critical exposure period, immune and neuro-biologic pathways impacted, and cognitive and behavioral consequences. Preliminary findings from the B-SAFE cohort suggest similar impacts of prenatal wildfire PM2.5 on differentially methylated regions (DMRs) in baby nasal epithelium enriched for neuronal and immune related pathways and associated with bivalent chromatin marks of developmental genes, as well as novel evidence that prenatal wildfire PM2.5 is linked to significantly increased child behavioral problems. We also show associations with maternal inflammation. Wildfires can induce emotional and psychological distress. Combined exposure to contaminants and maternal stress could impact overlapping biologic pathways, including inflammatory responses, and induce serious long-term developmental consequences. We propose to be among the first to assess these links in a prospective cohort of 544 women and their children who were exposed perinatally to some of the highest PM ever recorded in Northern California wildfires from 2017 through 2021. The goals of this R01 are to examine whether wildfire PM2.5 exposure during pregnancy increases maternal immune dysregulation and altered epigenetic programming in children, whether these modifications mediate downstream increases in risk for adverse child neurodevelopmental and behavioral outcomes, and whether maternal stress modulates these responses. Enhanced understanding of immunologic and epigenetic pathways associated with prenatal wildfire exposures and their relevance to child neurodevelopmental outcomes could highlight strategies to minimize the adverse health effects of future wildfires and other environmental exposures.
