Phthalates and perfluoroalkyl substances (PFAS) are synthetic chemicals with widespread human exposures that lower bone density in animals. Our preliminary data and limited epidemiologic studies report associations of these chemicals with shorter stature in children as well as lower bone density and altered vitamin D metabolism in adults. Low peak bone mass in adolescence is a strong modifiable risk factor for osteoporosis, a bone disease impacting millions of older Americans. Although early life is a critical period of skeletal growth and bone mass accrual, there are currently no longitudinal studies of phthalate or PFAS exposures in relation to childhood bone density. Therefore, our goal is to test the novel hypothesis that early life phthalate and PFAS exposures adversely impact skeletal growth, bone strength, and vitamin D metabolism in children. Our highly efficient proposal leverages the Health Outcomes and Measures of the Environment (HOME) Study, a prospective, racially-diverse pregnancy cohort study enrolled in Cincinnati, Ohio with existing exposure biomarker, confounder, and height measures from gestation through 8 years of age. Dual-energy X-ray absorptiometry measurements of bone density are currently being collected at an ongoing 12-year follow-up visit. We will additionally measure validated vitamin D and phthalate exposure biomarkers to investigate whether phthalate or PFAS exposures are associated with height trajectories from birth to age 12 years (Aim 1), bone density at age 12 years (Aim 2), and vitamin D biomarker concentrations at ages 8 and 12 years (Aim 3). Further, we will explore the role of chemical and nutritional co-exposures by examining whether height or bone density associations are modified or mediated by vitamin D biomarker concentrations or calcium intake (Aim 4). Using rich longitudinal data and a sophisticated Bayesian modeling approach, we will investigate potential windows of susceptibility (prenatal, early childhood, mid childhood, and early adolescence) as well as effects of cumulative exposures and exposure mixtures. This research will constitute the first systematic assessment of the role of phthalates and PFAS in altering bone health, a significant but understudied component of child well-being with critical importance for life-long risk of fractures and osteoporosis. In addition, this NIEHS ONES Award will support an exceptional Early Stage Investigator to establish an innovative research program specializing in children's environmental health. Finally, our findings will catalyze future research examining environmental impacts on bone health in later adolescence, elucidating biological mechanisms, investigating other environmental bone toxicants, and developing chemical or nutritional interventions with the goal of setting children on a path to healthier, stronger bones throughout life. ExpandCollapse Abstract