Prospective associations of childhood PFAS with metabolomic profiles, pubertal timing, and bone health - PROJECT ABSTRACT Per- and polyfluoroalkyl substances (PFAS) are ubiquitous oil- and water-resistant ‘forever chemicals’ that contaminate over 9,000 U.S. communities and have been linked to adverse health outcomes. U.S. clinical practice guidelines for PFAS lack data on reproductive and bone health, particularly in the setting of pediatric exposure. PFAS exposure reduces sex hormone concentrations, which may delay pubertal timing and impair bone accrual, thereby increasing the risk of chronic health conditions. In our highly productive first funding cycle in the Project Viva cohort, we reported that children with higher blood PFAS had later pubertal timing and lower bone mineral density (BMD) accrual across puberty. We found the strongest associations in females, who are at highest risk for osteoporosis, a biological susceptibility that may be exacerbated by PFAS. However, the field remains hampered by a lack of data on molecular pathways of action that can become targets for clinical intervention. Also, prospective cohorts with data from childhood to adulthood are needed to quantify the impact of childhood PFAS exposure on bone structure, strength, and peak bone mass. In this renewal R01, we will expand our prior work by leveraging the larger Avon Longitudinal Study of Parents and Children (ALSPAC) to identify (among N=1,000) sustained changes in blood metabolites related to PFAS exposure and the impact of PFAS on pubertal timing and peak bone mass, as well as on bone accrual, structure, and strength. To our knowledge, the UK ALSPAC cohort is unique in having blood samples across childhood, multiple markers of pubertal timing, peripheral quantitative computed tomography (pQCT) measures of bone structure and strength, and repeated dual energy X-ray absorptiometry (DXA) scans from adolescence to peak bone mass in early adulthood. ALSPAC has previously contributed to the evidence base informing U.S. clinical guidance, and our findings will similarly have direct relevance to U.S. children given the comparable relative exposures and absolute PFAS concentrations in the U.S. and UK. Further, we will validate metabolomic results in the U.S. Project Viva cohort. We will use sophisticated statistical methods to assess associations of individual PFAS and PFAS mixtures with health outcomes, examining effect modification by sex. In Aim 1, we will identify sustained changes in metabolites related to childhood PFAS exposure. In Aim 2, we will examine associations of childhood PFAS and PFAS-related metabolites with pubertal timing. In Aim 3, we will examine associations of childhood PFAS with DXA measures of peak bone mass and bone accrual, as well as pQCT measures of bone structure and strength; we will also explore the extent to which pubertal timing and PFAS-related metabolites mediate associations of PFAS with peak bone mass. The proposed project provides a rare opportunity to draw on 20 years of data to inform current clinical decision-making and improve care for children in the U.S. affected by PFAS exposure, with implications for risk reduction of long-term chronic health sequelae.
