PFAS Exposures and the Human Metabolome: a Systematic Review of Epidemiological Studies

Background/Aim There is growing interest in understanding the health effects of exposure to per-/polyfluoroalkyl substances (PFAS) through the study of the human metabolome. We conducted a systematic review of epidemiologic studies evaluating the association between PFAS and metabolomics. Methods Following PRISMA guidelines, we searched two databases (EMBASE/PubMed) through February 28, 2022 and identified 27 eligible observational studies. We summarized the evidence for PFAS associations reported with individual metabolites or metabolic pathways to identify consistent findings and research gaps. Results Effects of twenty-six PFAS exposures have been evaluated using human metabolomic studies, with the most common exposure being legacy long-chain PFAS. Most studies measured exposures during adulthood (n=15), followed by prenatally/perinatally (n=9) and/or in childhood (n=6). Sample sizes ranged from 40 to 1,105 participants. A total of 18 studies used a non-targeted metabolomics approach, 7 studies used targeted approaches, and 2 studies included both. Metabolomics were measured in serum (n=16), plasma (n=9), urine (n=2), or semen samples (n=1). Only two studies integrated repeated metabolomics measures in plasma or urine. The majority of studies were cross-sectional (n=24), including four with prospective analyses of PFAS measured prior to metabolomics. Consistent associations (either up- or down-regulated) were reported between PFAS and amino acids, fatty acids, glycerophosphocholines, glycerolipids, sphingomyelins, bile acids, ceramides, and carnitines. Common enriched metabolic pathways included lipid metabolism, amino acid metabolism, carbohydrate metabolism, purine and urea cycle metabolism. Results for other pathways were less consistent across studies. Conclusion A growing body of literature has identified alterations in several metabolites and metabolic pathways that could underlie PFAS-associated metabolic disease in humans. Future studies should consider prospective designs optimizing methods for exposure-metabolomics analyses with longitudinal measures, tissue-specific effects, additional confounder adjustment, or assessment of emerging PFAS and mixture effects to address existing limitations in this field. Keywords PFAS, metabolomics, endocrine disrupting chemicals, systematic review.