Cord serum metabolomic profiling associated with in utero exposure to per- and polyfluoroalkyl substances and birthweight discordance in twins: Findings from Wuhan Twin Birth Cohort

Emerging evidence links per- and polyfluoroalkyl substances (PFAS) exposure and metabolic disruptions to fetal growth retardation. However, earlier studies on singletons couldn't fully account for genetic factors. Therefore, we used a co-twin control study design to identify cord metabolomic signatures of PFAS exposure and assess its mediating role in twin birthweight discordance. We analyzed 204 twin neonates born from the Wuhan Twin Birth Cohort (August 2016-January 2018). Cord serum PFAS concentrations and untargeted metabolomic profiles were determined using liquid chromatography-tandem mass spectrometry. Within-twin metabolome-wide association analyses identified 69 metabolites (effect coefficients: 0.09-0.35) positively associated with log2-transformed perfluorooctanoic acid (PFOA) difference and 51 metabolites (effect coefficients: 0.08-0.38) positively associated with log2-transformed perfluoroheptane sulfonate (PFHpS) difference after false discovery rate (FDR) correction. PFAS-associated metabolites were primarily enriched in steroid hormone biosynthesis, arginine and proline metabolism, glycerophospholipid metabolism, and unsaturated fatty acid biosynthesis pathways. Five amino acids, one carbohydrate, one cofactor and vitamin, and five lipids mediated the relationship between PFHpS exposure difference and intra-twin birthweight difference, with mediation proportions ranging from 32.0% to 72.7%. This study is the first to use a within-twin comparison, providing new insights into the underlying mechanisms linking PFAS exposure with twin birthweight discordance.