Placental PI3K-Akt signaling alterations are associated with maternal PFBS exposure and offspring anxiety-like behavior: Implications for the placenta–brain axis

Perfluorobutane sulfonate (PFBS) is a widely used short-chain per- and polyfluoroalkyl substance (PFAS) associated with neurodevelopmental disturbances, yet the underlying maternal–fetal mechanisms remain poorly understood. Herein, a gestational PFBS exposure rat model (0, 5, or 50 mg/kg) was established to assess placental alterations, offspring behavioral outcomes, and the molecular pathways linking placental dysfunction to neurodevelopmental effects. Prenatal PFBS exposure induced anxiety-like behaviors in offspring, as evidenced by reduced central area exploration (50 mg/kg) in the open field test and decreased open-arm time (5 and 50 mg/kg) in the elevated plus maze, without affecting general locomotion. At 50 mg/kg, PFBS caused histological damage on the maternal side of the placenta, characterized by cellular necrosis and intranuclear vacuolization, along with downregulation of monocarboxylate transporter 1 (MCT1) in the labyrinth zone, indicating impaired placental nutrient transport. Multi-omics analyses revealed disrupted placental transcriptomic and metabolomic profiles, particularly involving downregulation of PI3K-Akt signaling pathway genes and enrichment of neurodevelopment-related pathways. Integrative analysis revealed that decreased placental levels of acetylcholine chloride and N-carbamoylputrescine were positively correlated with anxiety-like behavior in offspring. Protein validation confirmed reduced PI3K and p-AKT expression in offspring brains, supporting involvement of PI3K-Akt signaling in placenta–brain crosstalk. Collectively, these findings suggest that prenatal PFBS exposure is associated with placental PI3K-Akt signaling disruption, altered placental metabolic profiles, and anxiety-like behavior in offspring. These results identify placental molecular and metabolic alterations as potential pathways linking prenatal PFBS exposure to neurodevelopmental outcomes and highlight the importance of incorporating placental assessments into developmental toxicity evaluations of PFAS compounds.