PROJECT ABSTRACT Obesity and osteoporosis are public health epidemics with costly comorbidities and limited treatment options. Rates of these disorders globally remain unacceptably high, and this is particularly true in the US where 1 in 3 adults are obese and 1 in 25 has osteoporosis. Adiposity and low bone mineral density (BMD) are precursors to these debilitating disorders and track closely from childhood to adulthood. Identifying preventive measures and intervening in early life is critical to curb these epidemics. There are suggestive animal data that chemicals in the environment, per- and polyfluoroalkyl substances (PFASs) and phthalates, may disrupt common mechanistic pathways to concomitantly increase risk of both adiposity and low BMD. Our preliminary data within the prospective Project Viva cohort (~900 children) suggest that children with higher PFAS plasma concentrations in mid-childhood have greater central adiposity and lower BMD by early adolescence. In this proposal, we will expand this prior work. We will extend evaluation through late adolescence, when body composition more strongly predicts adult body composition and related disease risks. We will additionally examine phthalates which act through similar mechanistic pathways as PFASs. We will also employ the novel step of accounting for diet, which has not been comprehensively done in studies of these chemicals, despite the fact that the same Western-style foods that may be a source of chemical exposure also predict risk for adiposity and low BMD. We will accomplish these objectives by first identifying dietary predictors of PFASs and phthlalates in mid-childhood, then examining associations of PFASs and phthalates independent of diet on central adiposity and BMD in late adolescence. Based on our preliminary data suggesting that central adiposity is associated with lower BMD, we will also evaluate the extent to which central adiposity may mediate associations of chemical exposures on BMD. We expect this to be the most comprehensive population-based study to date testing the role of childhood exposures to PFASs and phthalates on development of adiposity and low BMD through adolescence. By examining longitudinal associations across adolescence, we will overcome limitations of many of the existing epidemiologic studies of these chemicals and adiposity, and this will be the first large study to examine the role of these chemicals on BMD in adolescence. Diet, physical activity, and genetics do not explain all of the variability in adiposity and low BMD, and moreover can be difficult to modify. Identifying remediable factors that increase risk of both adiposity and low BMD is a public health priority because this will enable development of preventive strategies to target both conditions. Furthermore, this proposal will advance Dr. Fleisch's career investigating the impact of the toxic environment on endocrine development in childhood with a focus on peripubertal health.

PROJECT NARRATIVE Obesity and osteoporosis are global epidemics marked by costly associated health problems, and identifying preventable childhood determinants and intervening in early life is a public health imperative. This study will investigate the role of childhood exposures to the environmental chemicals per- and polyfluoroalkyl substances and phthalates on adolescent markers of obesity and osteoporosis risk. Our findings will influence policies to limit chemical production and individual behaviors to minimize exposures.