Prenatal PFAS and longitudinal neurodevelopmental trajectories in preschoolers aged 3-7: effect modification by bile acid metabolism

Abstract

Bile acids (BAs) are crucial signaling molecules in neurodevelopment, and per- and polyfluoroalkyl substances (PFAS) exposure has been linked to adverse neurodevelopmental outcomes. However, the role of specific BAs in modifying the association between PFAS and longitudinal neurodevelopmental trajectories remains unknown. We quantified 32 PFAS in maternal serum and 17 BAs in serum from 3-year-old children in the Maoming Birth Cohort. Neurodevelopment was repeatedly evaluated using age-standardized instruments. PFAS effects were evaluated by logistic regression and grouped weighted quantile sum (GWQS). Random forest analysis identified six primary conjugated BAs associated with low neurodevelopmental trajectories, and their interactions with PFAS were assessed. Group-based trajectory modeling identified two neurodevelopmental trajectories: persistently high (n = 242) and low (n = 36). Higher prenatal levels of legacy PFAS were associated with low neurodevelopmental trajectories. GWQS regression revealed mixture effects for legacy PFAS [odds ratio (OR) = 2.18, 95% confidence interval (CI): 1.01-4.73]. Primary conjugated BAs [e.g., taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA)] modified the observed associations. The odds of perfluorooctane sulfonate-associated low neurodevelopmental trajectories were greater for children with lower TCDCA levels (OR = 2.70; 95%CI: 1.02-7.17; Pfor interaction = 0.0063) than for those with higher levels. Children with higher TCA levels exhibited lower odds of low neurodevelopmental trajectories than those with lower levels (Pfor interaction = 0.0088). Our findings provide longitudinal evidence on PFAS-related lower neurodevelopment and identify primary conjugated BAs as significant effect modifiers. The mechanisms underlying this effect modification require further investigation.