The Mediation Role of the Placental IGF1 Signaling Pathway on Associations between Prenatal PFAS Exposure and Adverse Birth Outcomes: Evidence from Serial Mediation Models

Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) is associated with adverse birth outcomes, yet mechanistic pathways remain unclear. We measured 32 maternal serum PFAS (including their alternatives and isomers) and quantified placental mRNA levels of insulin-like growth factor 1 (<i>IGF1</i>), the IGF1 receptor (<i>IGF1R</i>), and the insulin receptor (<i>INSR</i>), alongside serum IGF1 and insulin levels, in 285 mother-infant pairs from the Maoming birth cohort. We applied simple, serial, and moderated mediation models to investigate placental IGF1 signaling as a mediator of PFAS-related preterm birth (PTB), low birth weight (LBW), and small-for-gestational-age (SGA). Simple mediation showed placental <i>IGF1R</i> mediated 15.08%-41.18% of associations between perfluorooctanesulfonate (PFOS) isomers and PTB (odds ratios [ORs-_{total effect}]: 1.06-1.10), LBW (ORs: 1.05-1.10), or SGA (ORs: 1.05-1.10). Serial mediation identified a sequential pathway: PFOS exposure correlated with altered <i>IGF1</i> expression, followed by <i>IGF1R</i> changes, and subsequent associations with PTB (ORs: 1.01-1.02), LBW (ORs: 1.01-1.02), and SGA (ORs: 1.01-1.02). Moderated mediation highlighted serum IGF1 and insulin as modifiers of these relationships. Molecular docking demonstrated preferential binding of branched PFOS to IGF1R's ligand-binding domains. This study integrates advanced mediation frameworks and molecular evidence to demonstrate that placental IGF1 signaling mediates PFAS-related adverse birth outcomes, elucidating mechanisms of developmental toxicity.