Metabolic Perturbation Associated with Per- and Polyfluoroalkyl Substances (PFAS) in an African American Pregnancy Cohort

Abstract

Background. Per- and polyfluoroalkyl substances (PFASs) are suspected developmental toxicants that are ubiquitous and persistent in the environment. Exposures to PFASs during the prenatal period have been linked to adverse pregnancy and birth outcomes. Notably, communities of color and those affected by socioeconomic disadvantage, particularly African American (AA) pregnant women, disproportionately experience high levels of PFAS exposure and adverse health outcomes. Mechanisms underlying these relationships are complex and largely unknown. Methods. We used metabolomics, a high-throughput analytical method involving the identification and quantification of thousands of metabolic features associated with exogenous exposure and endogenous processes, to address these knowledge gaps. We measured serum levels of 12 PFAS and conducted high-resolution metabolic profiling on 320 maternal serum samples collected during the first trimester of pregnancy from Atlanta African American Maternal-Child cohort participants. We conducted untargeted Metabolome Wide Association Study (MWAS) to detect metabolic perturbations associated with PFAS exposures and explore underlying molecular mechanisms. Results. The average serum levels of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) were 0.94±0.57 and 3.28±1.67 ng/mL, respectively. In total, 29,524 metabolic features have been reliably extracted from two technical columns. Using multivariate linear regression models, we found 125 metabolic features were significantly associated with one or more PFAS, when controlling for covariates and false positive discovery rate. Pathway analysis indicated several oxidative stress and inflammatory pathways associated with PFAS exposures, including aspartate, arginine, and glycosphingolipid metabolism. We validated five metabolites using authentic chemical reference standards, including aspartate and arginine, which are both significantly associated with PFOA, PFOS, and perfluorononanoic acid (PFNA). Conclusions. Using untargeted MWAS, we identified and verified several pathways and metabolites associated with PFAS exposures among AA pregnant women, which offer promising initial evidence to examine the underlying molecular mechanisms and provide opportunities for interventions to improve outcomes in exposed mothers and children.