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.