Metabolic Signatures of Youth Exposure to Per- and Polyfluoroalkyl Substances

BACKGROUND AND AIM: Human exposure to per- and polyfluoroalkyl substances (PFAS), including perfluorooctane sulfonate (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA) is ubiquitous and has been associated with increased risk of metabolic disorders. Exposure during periods of development, including childhood, may exacerbate these effects. The purpose of this study was to identify metabolic pathways associated with youth exposure to PFAS and to test the generalizability of these associations in an independent cohort of young adults. METHODS: 310 overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR) and 135 young adults from the Southern California Children's Health Study (CHS) were included in analysis. Fasting blood plasma samples were used to determine concentrations of PFAS and to measure the plasma metabolome using liquid-chromatography/high resolution mass spectrometry (LC-HRMS). Individual and joint effects of PFAS were analyzed using a metabolome wide association study (MWAS) coupled with functional pathway analysis using Mummichog. Analyses were performed for each PFAS individually and for all PFAS in a single model using multivariate linear regression, and models were adjusted for important covariates. RESULTS:In both cohorts, PFAS concentrations were comparable to NHANES. In SOLAR and CHS, respectively, 13,706 and 19,110 features met quality control standards and were included in the analysis. For SOLAR participants, exposure to PFAS was associated with altered amino acid and lipid metabolism, and similar effects were observed in young adults from the CHS. For example, exposure to PFAS was associated with altered tryptophan metabolism (SOLAR: p=0.008; CHS: p=0.009), arginine and proline metabolism (SOLAR: p=0.02; CHS: p=0.09), and the carnitine shuttle (SOLAR: p=0.007; CHS: p=0.006). CONCLUSIONS:Exposure to PFAS in youth is associated with alterations in important amino acid and lipid metabolism pathways in two independent cohorts. These associations may help explain the adverse metabolic effects of PFAS exposure. KEYWORDS: Perfluoroalkyl substances, Metabolomics, Metabolism Disrupting Chemicals, Metabolic disorders, children