Computational Toxicology to Elucidate PFASs Causing Fetal Growth Restriction via Binding to and Degrading IGF1 Protein

Per- and polyfluoroalkyl substances (PFASs) have been associated with fetal growth restriction (FGR), although the underlying mechanisms remain elusive. Using computational toxicology, we identified 17 commercially prevalent PFASs that exhibit high absorption potential but are poorly metabolized and excreted. These compounds destabilize insulin-like growth factor 1 (IGF1) protein and disrupt the PI3K-AKT signaling pathway, thereby contributing to FGR. Specifically, molecular docking analysis revealed that PFASs can bind to the interaction region of IGF1 and IGF-binding proteins (IGFBPs) with perfluorodecanoic acid (PFDA), perfluorooctanesulfonate (PFOS), and perfluorononanoic acid (PFNS) showing the strongest binding affinities. Molecular dynamics simulations further revealed that PFDA, PFOS, and PFNS maintain stable conformational dynamics upon binding to IGF1, characterized by strong binding free energies and intermolecular forces similar to those of the original ligand. <i>In vitro</i> experiments confirmed that PFDA and PFOS form highly stable complexes with IGF1 protein at nanomolar affinities, reduce extracellular IGF1 protein levels, and inhibit trophoblast cell proliferation. Notably, supplementation with the recombinant IGF1 protein significantly ameliorated these adverse effects. Collectively, the present study has elucidated IGF1 as a direct target mediating PFAS-induced FGR with PFDA, PFOS, and PFNS playing significant roles, which provides novel insights for the development of preventive and therapeutic strategies targeting PFAS-related developmental disorders.