Environmental interactions with genes, co-occurring environmental factors, sex, and life stage define normal variation and adverse neurodevelopment over the life course. Beginning in utero, the central nervous system (CNS) develops sequentially with network components of distinct functional domains (e.g., attention, memory, etc.) developing at different times. Thus, toxin effects depend both on timing of exposure and dose. The developing fetus and infant are most vulnerable. Moreover, pregnant women and children are not exposed to a single chemical but to complex chemical mixtures. Complex interactions between chemical and non-chemical stressors as well as sex can also influence outcomes. We propose a new ECHO Consortium of 5,000 prenatally enrolled and prospectively followed ethnically diverse mothers and their children to better address these complexities. Our UG3 mission will be to measure environmental exposures across pregnancy and childhood to determine how pro-oxidant environmental factors affect neurodevelopment. We will leverage methodological advances developed by our team including 1) a novel tooth-based biomarker that can objectively ; 2) satellite remote sensing based air pollution models that can reconstruct ; 3) mixtures statistics; and 4) data-driven statistical reconstruct past exposure timing and dose past exposure timing and dose methods to identify vulnerable windows. The Mount Sinai Consortium will also be part of the larger national ECHO synthetic cohort to study the health impacts of chemicals, nutrition, social factors, the biological response to these exposures, and the gene-environment interactions that underlie childhood disease more broadly. We can both meet our UG3 aims and the goals of the ECHO UH3, as our cohorts have extensive biobanking to facilitate expanded exposure assessment and mechanistic studies and our team has the requisite expertise in phenotyping in the four ECHO focus areas, in exposure science, and in cohort management. In this application, we will establish the infrastructure to coordinate, plan, and communicate with the four cohorts that make up our consortium, while performing similar functions within the greater NIH ECHO program, working with the Coordinating Center, the ECHO Data Center, the Pediatric Research Outcomes (PRO) Core, the future Genomics Core, and the CHEAR Exposure Core. Our Consortium will harmonize the databases of our four established cohorts to achieve these goals in tandem with experts in data science from the CHEAR Network Data Center. This proposal links highly experienced environmental health scientists with, statisticians, social epidemiologists, stress researchers, child psychologists, chemists, pediatricians, toxicologists, geneticists, and epigeneticists to build the infrastructure and scientific capacity to create a highly functional, state of the art longitudinal birth cohort consortium that objectively measures human environments that program child health and integrates with the greater NIH ECHO program.
Findings from the proposed UG3 ECHO consortium may identify prevalent pro-oxidant exposures (air pollution, metal mixtures) and mechanisms operating through the placenta and in early childhood that increase our understanding of the developmental origins of maladaptive neurodevelopment, so that interventions may be applied early to promote optimal child development. Our assembled ethnically diverse cohort consortium and collective multidisciplinary research expertise will also contribute more broadly to elucidating environmental determinants of perinatal, respiratory health and obesity in the UH3 effort.
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