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.

Childhood obesity is a global epidemic with costly comorbidities. In the US, the rate of obesity has tripled over the past 40 years. Diet, physical activity, and genetics do not explain all of the variability in weight, and moreover can be difficut to modify. Identifying environmental triggers and feasible public health interventions is therefore a policy imperative. Prior data from this team has suggested an association of prenatal exposure to air pollution with maternal hyperglycemia and reduced fetal growth. Paradoxically we have also demonstrated an association between greater prenatal traffic-related pollution and excess infant weight gain after birth, leading to higher risk for obesity in infancy. With the guidance of my mentoring team, during this 5 year K23 career development award, the Candidate will leverage data from two prospective longitudinal cohorts of mothers and children (Project Viva, n=2,128 and the New Hampshire Birth Cohort Study (NHBCS), n=1,500) to extend this prior work through three inter-related projects. The Principal Investigator will: (1) examine prenatal exposure to ambient air pollution as a risk factor for rapid weight trajectories throughout childhood and central fat accrual in mid-childhood. (2) consider the relationship of prenatal air pollution exposure with obesity-associated hormonal biomarkers, including leptin, adiponectin, and insulin resistance in childhood. (3) characterize exposures and habits related to indoor sources of air pollution in rural New England and estimate the extent to which indoor wood burning during pregnancy is associated with maternal hyperglycemia, fetal growth, and offspring weight gain in early childhood. The training plan proposed will build upon my clinical training in pediatric endocrinology and basic knowledge of biostatistics and epidemiology to provide formal training in (1) environmental exposure assessment, (2) statistical techniques necessary to analyze complex exposure-response relationships, and (3) the practical skills necessary to lead a research team. The Candidate will leverage the wealth of resources available at Boston Children's Hospital, the Department of Population Medicine (Harvard Medical School and Harvard Pilgrim Health Care), the Harvard School of Public Health, and the Dartmouth Children's Environmental Health and Disease Prevention Research Center to conduct the proposed analyses. These studies and training will lay the necessary scientific framework to launch her career as an independent physician researcher studying the impact of environmental toxicants on children's health, with a focus on obesity and insulin resistance.

PFCs are synthetic chemicals used as surfactants and in surface protection, including stain-resistant products (e.g., carpets and fabrics), nonstick coatings, and food packaging. PFCs are ubiquitous and persistent in the environment and in human tissue. Though present in the environment for decades, PFCs are relatively new compounds of interest with respect to health outcomes and there is mounting evidence from animal and human studies suggesting that they may be developmental toxicants. The primary aim of the proposed research is to investigate the association of prenatal PFC exposure with growth and development in children. We will measure levels of four perfluorinated compounds - perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA) - in prenatal maternal plasma collected in early gestation and estimate associations with fetal and infant somatic growth, childhood adiposity and metabolic outcomes such as serum cholesterol and insulin resistance, and neurodevelopment, including cognition and behavior. We will examine associations of PFCs with prenatal maternal and neonatal thyroid hormone levels and explore thyroid function as an underlying pathway for PFC-related associations with growth and neurodevelopment. We will also measure postnatal PFCs in offspring at age 7 to explore their contribution to these outcomes independent of prenatal exposure. We will investigate these aims in Project Viva, a large, well-characterized longitudinal pre-birth cohort of mothers recruited 1999-2002 during pregnancy (approximately 1,700 have archived early pregnancy plasma samples available for PFC analysis) and their offspring (approximately 610 have archived postnatal blood samples available for PFC analysis) followed from birth through age 7 years. We will estimate associations using multivariable regression, controlling for a wide range of covariates. This will be the largest study to date to assess the effect of prenatal PFCs on childhood growth and development the first study to account for prenatal and postnatal PFCs. This highly cost-effective investigation will benefit from the use of a well-characterized population assessed longitudinally since early pregnancy for whom a wealth of information on risk factors for adverse child development has already been collected. Recruitment of pregnant mothers during 1999-2002 coincides with the period of peak PFC emissions, enhancing our power to detect exposure effects. Results will further our understanding of the impact of prenatal and postnatal exposure to PFCs on growth and development during the prenatal and early childhood period. This is a major public health concern given the ubiquity and persistence of these chemicals in the environment and in humans and their potential role as developmental toxicants.

Fish and other seafood may contain beneficial nutrients, as well as harmful contaminants. The prenatal period is a time of particular susceptibility to the adverse effects of organic mercury as well as to the beneficial influence of nutrients such as elongated n-3 fatty acids and selenium. However, little is known about the balance of risk and benefit from maternal fish intake during pregnancy on child development. The small number of previous studies regarding fish intake and child development are limited by lack of detailed nutrient measures, short duration of follow-up, and few outcome measures. In the proposed study, we will use information on maternal fish intake and biomarkers of mercury and nutrient exposure to examine the combined influence of the risks and benefits of maternal diet during pregnancy on child development. This project build upon the established infrastructure of Project Viva, an ongoing pre-birth US cohort study with stored maternal blood samples, validated prenatal dietary assessment, and detailed information on a number of covariates including home environment and other important predictors of child development. Study aims will be to assess associations of levels of mercury and n-3 fatty acids from maternal blood collected during pregnancy with child cognition and behavior at age 7 years. In addition, we will examine the influence of maternal prenatal fish intake on child cognition and behavior, with and without additional adjustment for mercury and n-3 fatty acids. We will explore the role of nutrients as modifiers of the effect of prenatal mercury exposure, by determining whether mercury has a stronger adverse effect among participants with lower levels of elongated n-3 fatty acids or selenium. Funds from this grant will support wide-ranging cognitive and behavioral assessments added to the already-funded cohort follow-up visit at age 7 years, as well as assays of exposure biomarkers and data analysis. This project is both cost- and time-efficient compared to the initiation of a new cohort, and offers many advantages over previous studies. The study team brings internationally recognized expertise in establishing, maintaining, and analyzing data from a longitudinal cohort, in performing and interpreting assays of nutrient and toxicant exposure, and in interpreting cognitive test results. The proposed study will provide information important to helping mothers and their health advisors make the best decisions about diet during pregnancy to optimize child development. The proposed study will provide timely and high quality data to inform the ongoing national policy discussion regarding the nutritional benefits as well as the contaminant risks from fish intake during pregnancy, and how these competing effects may balance out. Getting the message right is crucial, since pregnant women act upon recommendations regarding the safety of dietary fish intake. The right kind of message could improve children's developmental potential, but the wrong message could do the opposite.