PROJECT SUMMARY/ABSTRACT Chronic conditions, such as obesity, asthma, depression, and developmental disabilities, are increasing among children worldwide. Further, the age at diagnosis for many such conditions is decreasing, pointing to early-life origins. The developmental origins of health and disease (DOHaD) paradigm posits that exposures and experiences in utero and during early life influence phenotype and physiology as well as behaviors that shape lifelong health. Epidemiologic studies of DOHaD phenomena have historically focused on single exposure-health outcome associations, despite calls for more holistic approaches to capture the totality of exposures and their causal pathways. Other important limitations of prior work include homogenous study samples that diminish generalizability and limit opportunities to identify disparities and infrequent or lack of granularity in assessment of exposures and health outcomes across ontogeny. Together, these limitations hamper identification of when and how risk factors and combinations of risk factors across early life culminate in chronic disease. This proposal addresses the above gaps by leveraging the Environmental influences on Child Health Outcomes (ECHO) Program to investigate a broad range of early-life exposures, from society to biology, in relation to pediatric health outcomes among ~50,000 caregiver-offspring pairs. The Colorado team will implement ECHO’s Core and Specialized Protocols in the Healthy Start Study, a Colorado pre-birth cohort that recruited and followed 1,250 mother-child dyads. In this cohort, exposures, and outcomes relevant to ECHO were collected during pregnancy, at birth, during infancy and the toddler years, and in early childhood (4-5 years). In the first ECHO Cycle, the Colorado team followed 765 children, to date, through middle childhood (8-12 years) and transferred extant data from pregnancy onward to the ECHO platform. In response to RFA-OD-22-019 and in collaboration with other ECHO components, our team will implement the ECHO Cohort Data and Biospecimen Collection Protocol with high fidelity and use community-engaged retention strategies to follow 900 diverse participants aged 11-19 years to achieve two scientific objectives: (1) characterize patterns of structural, chemical, and physical exposures during the in utero period and early childhood that predict co-occurring clusters of major ECHO outcomes through adolescence; and (2) examine joint effects of exposure to in utero overnutrition and childhood psychosocial adversity on the Specialized Outcome of pediatric obesity. The work proposed will facilitate a holistic understanding of how the totality of early-life exposures and experiences shape chronic disease risk in children; examine the involvement of a potentially modifiable biological mechanism (DNA methylation); and provide insights into multi-level targets for preventive action, including family- and individual-level factors that build resiliency in the...