PROJECT SUMMARY Telomere attrition starts in early life, tracks into adulthood, and is associated with increased risk for aging-related chronic diseases, such as cardiovascular disease. Because genetic factors explain only a small proportion of telomere length variability, it is critical to determine prenatal environmental exposures that affect telomere length dynamics in early life. Recent evidence shows that prenatal exposures to endocrine-disrupting chemicals (EDCs) may promote telomere attrition in young children. However, existing data are limited, and the potential interplay of EDC mixtures with other environmental stressors and the implicated mechanisms remain unknown. For example, dietary factors and obesity also have been associated with shorter telomere length, potentially by altering oxidative stress, inflammation, and metabolic pathways that are also disrupted by EDCs. Thus, EDC exposures may act synergistically with diet and obesity to influence telomere length dynamics in childhood and beyond. However, no previous study has examined the potential impacts and interactions of prenatal EDC exposures with other factors on telomere lenght dynamics during the sensitive period of accelerated growth in the transition from childhood to adolescence. Therefore, we propose the first and largest longitudinal investigation on the prenatal exposome and telomere attrition, with extended follow-up through adolescence. We will use an innovative multi-omics analytical framework to advance the knowledge about the joint impacts of prenatal EDC exposures and their interplay with diet, obesity, and inflammatory and metabolic pathways on telomere lenght dynamics and adolescent health. Our central hypothesis, supported by strong preliminary results, is that prenatal exposures to EDC mixtures and their interactions promote telomere attrition in childhood and through adolescence by dysregulating inflammatory and metabolism-regulating pathways. To test this hypothesis, we will leverage the unique existing resources of the population-based Human Early Life Exposome (HELIX) project. HELIX provides an unparalleled early-life exposome characterization (>200 environmental exposures) with completely harmonized biomonitoring data on ~80 known EDCs and repeated telomere lenght measurements in 700 mothers and their children followed longitudinally from pregnancy to age ~16 years in six European countries. We will measure high-throughput proteomics covering >700 inflammation and metabolic proteins in archived plasma from children collected at age ~8 years to comprehensively characterize biological pathways promoting telomere attrition due to early-life EDC exposures, as well as their interplay with telomere lenght tracking from childhood to adolescence. Findings will advance our understanding of the impacts of early-life exposures to exogenous chemicals and their interplay with diet, obesity, and inflammatory and metabolic pathways on telomere attrition during sensitive...