Early F-53B Exposure Induces Autism Spectrum Disorder-like Hypomyelination and Oligodendrocytes-Derived Exosomal Protein-Dependent Axonal Energy Imbalance

Recent epidemiological evidence links prenatal exposure to chlorinated polyfluorinated ether sulfonate (F-53B) to autism spectrum disorder (ASD)-associated neurodevelopmental deficits. However, mechanisms underlying F-53B-induced ASD-like pathology and oligodendrocyte dysfunction remain unclear. In this study, we exposed Sprague–Dawley rats to F-53B (0, 8, 80, 800 μg/kg/d from preconception through postweaning) and compared adverse outcomes to a valproic acid-induced ASD model. We found that F-53B crossed the blood-brain barrier, deposited in offspring brain, and induced ASD-like neurobehaviors, including social deficits, stereotypic behaviors, memory impairments, and reduced novelty preference. Neuropathologically, F-53B triggered hippocampal and callosal hypomyelination, delayed oligodendrocyte maturation, and disrupted neuronal mitochondrial cristae. Interestingly, plasma oligodendrocytes-derived exosomes (ODEXs) from F-53B-exposed offspring failed to restore neuronal adenosine triphosphate (ATP) levels and mitochondrial membrane potential in vitro. Proteomic profiling of ODEXs identified suppression of ATP synthesis-related proteins, notably chromodomain helicase DNA binding protein 8 (an ASD-characterized biomarker) and ATP citrate lyase. Molecular docking suggested F-53B could bind to their amino acid residues. Downregulation of these proteins in the hippocampus and corpus callosum aligned with behavioral and myelination abnormalities in rat offsprings. Our study establishes ODEX-mediated ATP synthesis disruption as central to F-53B-induced ASD-like pathology, urging reevaluation of perfluorooctanesulfonate alternatives for neurotoxicity.