The early life exposome, emerging chemical exposures, and structural and functional brain development in childhood

/ABSTRACT Rapid brain growth and development throughout the first years of life and the fragility of the blood brain barrier cerebrovasculature render the early childhood brain (birth-age five) uniquely susceptible to chemical exposures. Children are exposed to pesticides, flame retardants, and other suspected and known neurotoxicants in air, water, and dietary sources through exposure opportunities that are either uniquely high in early life (e.g., fruit and vegetable consumption, air intake) or specific to this developmental window (e.g., breastfeeding, hand to mouth behaviors, crawling exposure to house dust, and sustained contact with baby products). Despite evidence linking prenatal chemical exposures to neurodevelopmental deficits, insufficient biomonitoring in early childhood limits our understanding of the early life chemical exposure landscape, and few studies have assessed changes in underlying neural substrates. My objective is to characterize the early life chemical exposome and its impact on structural and functional brain development during this critical period of brain growth. I propose to leverage the University of North Carolina Baby Connectome Project (BCP), a longitudinal study that maps brain growth and development in early life using serial structural and resting-state functional magnetic resonance imaging (MRI), paired with developmental assessments and repeated child urine specimens to measure environmental exposures. During the K99 phase, I will characterize longitudinal patterns in the untargeted early life urine exposome and their associations with structural brain growth (among 250 children contributing 540 scan-urine pairs between 0-5 years). During the R00 period, I will generate novel exposure data by launching a targeted investigation measuring biomarker levels of high priority contaminants identified in the K99 period, as well as emerging fungicides and organophosphate esters that have been prioritized for early life biomonitoring based on toxicologic evidence of neurotoxicity and uncertain exposure burden. I will use innovative mixture methods to estimate associations between these emerging exposure biomarkers, brain anthropometry, functional network connectivity, and developmental assessments. The proposed work combines omics technology, longitudinal neuroimaging, and innovative dimension reduction methods to establish mechanisms of chemical neurotoxicity. To be successful in the proposed work and launch my independent research career, I need to gain: (1) statistical skills for analyzing high dimensional exposomic data, (2) proficiency in interpreting neuroimaging data, and (3) professional skills to establish and maintain an independent research program. The K99 structured training plan and exceptional team of mentors and scientific advisors will help address each of these dimensions. This award will provide a critical foundation for me to launch an independent research career investigating the impacts of environmental exposures on child health and development. This study has significant public health impact because it can causally link chemical exposures with adverse effects, leading to earlier interventions and improved neurodevelopmental outcomes. Project Number: 4R00ES035123-02 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Emily Werder | Institution: UNIV OF NORTH CAROLINA CHAPEL HILL, CHAPEL HILL, NC | Award Amount: $249,000 | Activity Code: R00 | Study Section: NSS View on NIH RePORTER: https://reporter.nih.gov/project-details/11360902