GenX exposure induces neurodevelopmental impairment and synaptic toxicity in hESC-derived cerebral organoids.

GenX, also known as hexafluoropropylene oxide dimer acid (HFPO-DA), was introduced in 2009 as a purportedly safer alternative to perfluorooctanoic acid (PFOA). However, nearly two decades of use have raised increasing safety concerns owing to its reported association with multiple forms of organ damage. However, only a few studies have systematically evaluated the molecular mechanisms underlying the neurotoxicity of GenX exposure. In this study, we aimed to investigate the neurodevelopmental impairments and synaptic toxicity induced by GenX during cortical development using human embryonic stem cell-derived cerebral organoids. We found that early exposure to GenX resulted in reduced organoid size and concentration-dependent deficits in basal neural progenitor cell proliferation. Moreover, GenX exposure prior to differentiation impaired synapse formation and decreased the number of excitatory synapses. We also found that early GenX exposure disrupted neural activity and altered neural network organization. RNA sequencing and Gene Ontology analyses revealed that these effects were associated with dysregulation of neuropeptide signaling pathways, synapse assembly, and postsynaptic organization. Collectively, these impairments in neurogenesis and neural activity indicate that GenX exerts neurotoxic effects and may pose a potential risk factor for neurodevelopmental disorders.