Dysregulated Lipid and Fatty Acid Metabolism link Perfluoroalkyl Substances Exposure and Impaired Glucose Metabolism in Young Adults

Abstract

The aim of this project is to investigate the association between perfluoroalkyl substances (PFAS) exposure and altered metabolic pathways linked to increased cardiometabolic risk in young adults. The study population comprised 102 young adults (17-22 years, 60% Hispanic) enrolled in Southern California during 2014-2017. A spectrum of cardiometabolic outcomes were measured including oral glucose tolerance test (OGTT) measures, body fat percent, ectopic fat, and lipid profiles. High-resolution metabolomics was used to quantify plasma exposure levels of three PFAS congeners and intensity profiles of the untargeted metabolome. Fasting concentrations of 45 targeted metabolites involved in key metabolic pathways including fatty acid and lipid were used to replicate untargeted metabolomics findings. Bayesian Kernel Machine Regression (BKMR) was used to examine the associations between PFAS exposure mixture and cardiometabolic outcomes adjusting for covariates. Metabolome-wide association analysis followed by Mummichog pathway analysis were used to explore PFAS-associated metabolic pathways. Furthermore, the effect of PFAS exposure on the entire metabolic network including metabolomic profiles and multiple cardiometabolic traits were investigated by integrated network analysis. Higher exposure to perfluorooctanoic acid (PFOA) was associated with higher 30-minute glucose levels and glucose AUC during OGTTs (p<0.001). These associations were stronger among Hispanic participants. PFAS exposure was also associated with altered lipid pathways, including glycerophospholipid, glycosphingolipid and unsaturated fatty acids, which could contribute to the link between PFOA and higher glucose levels after OGTTs. Targeted metabolomics analysis further supported the findings that higher PFOA exposure was associated with higher levels of glycerol and short-chain acylcarnitines (p=0.004 and 0.046, respectively), which themselves were also associated with higher 30-min glucose (p<0.01). In conclusion, increased lipolysis and fatty acid oxidation could contribute to the biological mechanism linking PFAS exposure and impaired glucose metabolism among youth. The Hispanic population may be more susceptible to the adverse effect of PFAS on glucose metabolism.