Environment international ·2 Nov 2026 ·Added 13 Nov 2026

Metabolomic signatures and pathways linking maternal PFAS concentrations to gestational age at birth: a meet-in-the-middle and high dimensional mediation analysis.

Susan S Hoffman, Anne Lang Dunlop, Dana Boyd Barr, Blake Rushing, Audrey J Gaskins, Todd Everson, Ashley Naimi, Stephanie M Eick, Shudi Pan, Youran Tan, Paula-Dene C Nesbeth, Kaitlin Rene Taibl, Susan L McRitchie, Susan Sumner, Kurunthachalam Kannan, Michele Marcus, Dean P Jones, Donghai Liang

DOI ↗

Abstract

BACKGROUND: Preterm birth disproportionately affects Black and African American populations. Greater exposure to environmental toxicants driven by environmental racism may contribute to these disparities. We aimed to identify metabolic intermediates linking maternal per- and polyfluoroalkyl substances (PFAS) exposure to gestational age at birth (GA). METHODS: We analyzed participants from the Atlanta African American Maternal Child Cohort (2014-2018) with maternal serum collected during early pregnancy (8-14 weeks; n = 307) and late pregnancy (24-30 weeks; n = 238). PFAS concentrations were measured using targeted exposure assessment, and untargeted metabolomics was conducted on maternal serum. GA was abstracted from medical records. We applied two complementary mediation frameworks, Meet-in-the-Middle (MITM) and High-dimensional Mediation Analysis (HIMA), to identify metabolites and pathways linking PFAS exposure with GA outcomes. RESULTS: Higher maternal concentrations of perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) were associated with increased risk of earlier GA. MITM identified 47 candidate metabolites in early pregnancy and 25 in late pregnancy. HIMA identified palmitoleic acid in early pregnancy and cortisol and N-acetyl-D-galactosamine in late pregnancy. Findings across the two approaches highlighted candidate metabolic signals and pathways, including the tricarboxylic acid cycle, bile acid biosynthesis, steroid hormone biosynthesis, and purine metabolism. CONCLUSIONS: Maternal PFAS exposure was associated with metabolic perturbations that may represent putative biological pathways related to gestational age at birth. This study offers new insights into the potential pathways by which maternal PFAS levels shape the maternal metabolome and influence GA using cutting-edge, targeted exposure assessment, untargeted metabolomics technologies, and high-dimensional mediation techniques.