Interaction Between Folate and Per- and Polyfluoroalkyl Substances on Birth Outcomes and Immune Health in Children

Abstract

Per- and polyfluoroalkyl substances (PFAS) are a large class of high-production volume synthetic water- and stain-resistant chemicals used in countless consumer products including nonstick cookware, textiles, and food packaging. The chemical properties that make PFAS useful in applications also cause persistence in the environment and accumulation in the body (half-lives ~2 to 8 years). Indeed, PFAS have been labelled “forever chemicals.” As a result, PFAS are ubiquitously detected in the general populations worldwide. Several adverse health outcomes have been linked to PFAS exposure, including adverse birth outcomes and immune dysregulation in children. Despite significant health effects associated with PFAS exposure, and their universal and long-term persistence in human populations worldwide, few studies have assessed potential mitigation measures to reduce their deleterious health effects. Folate plays an essential role in the one-carbon metabolism, which is a fundamental molecular pathway to human health. Folate has been shown to counteract the health effects of several environmental pollutant exposures. Observational studies have reported that higher intake of vegetables, fruits, grains, and beans – major sources of dietary folate – were negatively associated with serum/plasma PFAS concentrations. However, no study directly assessed the relationships between folate biomarkers and PFAS concentrations, and if folate could further mitigate PFAS-related adverse health effects. In this dissertation, we aimed to leverage large-scale U.S. population data to examine the associations between folate status and serum PFAS concentrations, and to further evaluate if folate status could modify PFAS-related adverse health outcomes in vulnerable populations, specifically birth outcomes among mother-singleton pairs and the antibody levels in children. Chapter 1 examined the associations of folate concentrations in serum and red blood cell (RBC) with PFAS concentrations in a large U.S. representative sample of adolescents and adults. We found that folate concentrations in both serum and RBC were associated with lower concentrations of select PFAS compounds in both adolescents and adults. Associations were stronger in magnitudes for RBC folate than serum folate concentrations. Chapter 2 further evaluated if early pregnancy folate status, measured by dietary folate equivalent intake or plasma folate concentrations, modifies the associations between early pregnancy plasma PFAS concentrations and adverse birth outcomes among mother-singleton pairs in a large birth cohort in U.S. We found that early pregnancy plasma concentrations of select PFAS compounds were associated with lower birthweight and birthweight to gestational age and sex z-score, shorter gestational age, and increased risk of low birthweight, but only among mothers whose early pregnancy folate levels were below the 25th percentiles (dietary folate equivalent intake: 660 mcg/day; plasma folate concentrations: 14 ng/mL) while not among mothers with higher folate status. Chapter 3 evaluated whether RBC folate concentrations modify associations between serum PFAS concentrations and antibody levels to rubella, mumps, and measles among adolescents of a U.S. representative sample. We found that serum concentrations of select PFAS compounds and the total PFAS mixture were associated with lower antibody levels to rubella and mumps, only among adolescents whose RBC folate levels were below the 66th percentile while no associations were found among adolescents with higher RBC folate levels. In summary, this dissertation found that higher folate was associated with lower serum PFAS concentrations among adolescents and adults, and that populations with lower folate status are more vulnerable to PFAS-related adverse birth outcomes and immune antibody levels among children. This dissertation highlights the importance of studying nutrition-pollutant interactions and the potential of using nutrients as a primary or/and secondary prevention measure for chemical exposure reduction and disease prevention. Future studies are needed to validate our findings in other populations with diverse socio-demographic background and folate and PFAS levels. Mechanistic and experimental studies are needed to explore causal relationships between folate, PFAS, and health outcomes. This would help provide additional evidence of using folate supplements – a low-cost measure - to potentially reduce PFAS burden and their related adverse health impacts.