Role of one-carbon metabolism variants in the associations between perfluoroalkyl substances exposure and birth size in the Taiwan Birth Panel Study

Background: One-carbon metabolism (OCM) is crucial for fetal development, while perfluoroalkyl substances (PFAS) are associated with adverse birth outcomes and lower folate levels. PFAS may compete with folate for receptors, and OCM genes regulate folate metabolism; however, no study examined if OCM variants modified PFAS-birth outcome associations. The study investigated the relationship between OCM variants, prenatal PFAS exposure, and birth outcomes. Methods: We analyzed birth weight and head circumference data from 338 mother-infant pairs in the Taiwan Birth Panel Study. Cord blood concentrations of four PFAS were measured using ultra-performance liquid chromatography-tandem mass spectrometry. Infant genotypes were assessed with the Taiwan Biobank Array, and we focused on five single-nucleotide polymorphisms related to OCM reported in previous literature. Gene-environment interactions were assessed using generalized linear regression and two mixture modeling approaches: quantile g-computation and Bayesian Kernel Machine Regression. Results: Prenatal perfluorooctane sulfonate and perfluoroundecanoic acid exposure were associated with lower birth weight, and PFAS mixture exposure was associated with lower birth weight. PFAS exposure-birth weight associations were more obvious among those with reference genotypes. Different PFAS mixture-birth weight associations were observed across MTHFR rs1801133 and genotypes, and there were stronger inverse associations among individuals with MTHFD1 rs2236225 GG genotype. Associations between prenatal PFAS exposure and birth outcomes also differed by MTR rs1805087, MTRR rs1801394, and CBS rs234714 genotypes. In addition, we observed a stronger perfluorooctane sulfonate-head circumference association among participants with MTHFR rs1801133 GG genotype. Conclusion: Genetic variants in OCM pathways modified the associations between prenatal individual PFAS, mixture PFAS exposure, and reduced birth weight and head circumference.