Metabolomics insights into the prenatal exposure effects of polybrominated diphenyl ethers on neonatal birth outcomes

Effects of polybrominated diphenyl ethers (PBDEs) on neonatal birth outcomes vary across previous studies, and the related mechanism investigation remains poorly understood, especially at the metabolic level.To evaluate the associations between prenatal PBDEs exposure and neonatal birth outcomes including gestational age, neonatal weight, birth length, head circumference (HC), Apgar score at 1 min (Apgar1) and 5 min, and further reveal the underlying metabolic disorders in a population-based birth cohort study.Gas chromatography-triple quadrupole tandem mass spectrometry (GC-MS/MS) based targeted method and GC-MS based untargeted method were respectively conducted to obtain PBDE levels and metabolic profiles of 200 placental tissue samples from a typical e-waste recycling area (Guiyu) and reference area (Haojiang) in China. Spearman correlation and regression analyses were applied to assess the associations between the placental PBDE levels and birth outcomes. Metabolome-wide association studies and the meet-in-the-middle approach were employed to explore disruptions linking PBDE exposures and the corresponding adverse birth outcomes.Eight out of 27 PBDE congeners were detected in placenta with more than 50% frequency in at least one district and significantly higher in Guiyu than those in Haojiang. The lower HC and Apgar1 had significant associations with PBDE exposures after adjustment for potential confounders. A total of 66, 16 and 14 metabolites were significantly correlated with PBDE exposures, HC and Apgar1, respectively. 4 and 12 PBDE-related metabolites were significantly associated with the risks of decreasing neonatal HC and Apgar1. The disrupted metabolites were mainly involved in the pentose phosphate pathway, ascorbate metabolism, threonine metabolism, butanoate metabolism, lipid metabolism, and arginine biosynthesis.In this birth cohort, higher placental PBDE levels were significantly associated with the lower HC and Apgar1. The associations might be modified by multiple metabolic disturbances through increasing oxidative stress, mediating neurotoxicity, maternal gut microbiota dysbiosis and vasodilatation regulation.