Association between PFAS exposure and bilirubin metabolism: A metabolome-wide analysis in children

Legacy per- and polyfluoroalkyl substances (PFAS) are restricted, but the associations between emerging alternatives and bilirubin metabolism remain understudied in children. We conducted a cross-sectional study using data from Zhejiang ELEVEN cohort during 2021–2024. We analyzed the associations between 37 serum PFAS and bilirubin markers in 1303 children who aged 6–18 years, with metabolomics profiling conducted in 312 children using stratified random sampling approach. Multivariate linear and weighted quantile sum (WQS) regression models presented that higher levels of most PFAS were associated with elevated indirect bilirubin (IBIL), with the emerging substitute perfluoro-3,5,7,9–11-pentaoxadodecanoic acid (PFO5DoDA) showing the strongest weights. Metabolome-wide association and high-dimensional mediation analyses revealed that long chain unsaturated fatty acids, phosphatidylcholine (PC), and phosphatidylethanolamine (PE) significantly mediated the associations between PFAS and IBIL. Key mediating metabolites included oleate/vaccenate/elaidate/petroselinate (18:1), docosahexaenoate (DHA; 22:6n3), 1-myristoyl-2-palmitoyl-GPC (14:0/16:0), 1-oleoyl-2-linoleoyl-GPE (18:1/18:2), 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (P-18:0/20:4), 1-palmitoyl-2-docosahexaenoyl-GPC (16:0/22:6), 1-palmitoyl-2-docosahexaenoyl-GPC (16:0/22:6). These metabolites were significantly enriched in three core metabolic pathways including biosynthesis of unsaturated fatty acids, glycerophospholipid metabolism, and linoleic acid metabolism. Our findings indicate potential associations between emerging PFAS exposure and bilirubin metabolism in children, with specific lipid pathways possibly involved. Further experimental and prospective studies are warranted to verify these findings and elucidate the underlying mechanisms.