Prenatal per- and polyfluoroalkyl substance (PFAS) exposure, metabolomic perturbation, and lower birth weight in African American women: a meet-in-the-middle approach

Abstract

BACKGROUND AND AIM: Prenatal exposures to per- and polyfluoroalkyl substances (PFAS) have been linked to restricted fetal growth. Pregnant African American (AA) women are disproportionately exposed to higher levels of select PFAS and experience higher rates of low birth weight than other races/ethnicities. However, the detailed molecular mechanisms underlying these disparities remain largely unknown. The purpose of this study is to investigate biological pathways and intermediate biomarkers underlying association between prenatal PFAS exposure and lower birth weight using high resolution plasma metabolomics among pregnant AA cohort. METHODS: Serum perfluorohexane sulfonic acid, perfluorooctane sulfonic acid, perfluorooctanoic acid, and perfluorononanoic acid meaurements, and untargeted plasma metabolomics profiling were conducted in 312 pregnant AA women in Atlanta, Georgia at 8-14 weeks of gestation using fasting blood samples. We utilized a high-resolution metabolomics workflow, including Metabolome-Wide Association Studies (MWAS), enriched pathway analyses, and chemical annotations, with the ‘meet-in-the-middle’ approach to identify the potential biological pathways and intermediate biomarkers of the PFAS-birth weight relationship. RESULTS:Among 25,516 metabolomic features extracted from the polar and nonpolar analytical columns, 320 features were significantly associated with serum PFAS and birth weight in the MWAS. After further validation using online databases or authentic chemical standards in the laboratory, we found 8 confirmed biomarkers including glycine, α-ketoisovalerate, uric acid, monoradylglycerol, and some polyunsaturated fatty acids and steroid hormones. In addition, 17 biological pathways associated with serum PFAS and birth weight were identified, including linoleate, vitamin D3, branched-chain amino acid, and fatty acid metabolism. The significant biomarkers and biological pathways identified were mostly involved in amino acid, lipid, and fatty acid metabolism or inflammation and oxidative stress. CONCLUSIONS:This study among pregnant AA found several maternal metabolic perturbations associated with serum PFAS concentrations and birth weight. Future studies are warranted to validate these findings and completely apprehend the underlying biological mechanisms. KEYWORDS: PFAS, metabolomics, birth weight