Comparative neurotoxic effects of PFOA and GenX in hiPSC-derived cortical neurons.

Per- and polyfluoroalkyl substances (PFAS) are widely used in daily consumer and industrial products, and human exposure to PFAS has been associated with various neuronal disorders, including Alzheimer's disease (AD), although the underlying mechanisms remain poorly understood. In this study, we investigated the neurotoxic effects of PFOA, a legacy PFAS, and GenX, its proposed "safer" alternative, using human induced pluripotent stem cell (hiPSC)-derived cortical neurons. To assess persistent neurotoxicity, neurons were assessed immediately after exposure and after a 7-day recovery. Neuronal resilience was evaluated using a secondary challenge assay targeting organelle-specific stressors. We identified distinct neurotoxic effects of PFOA and GenX, leading to increased risk of developing AD. PFOA exposure induced transient alteration in neuronal activity, neuron network morphology and synaptic density, but with persistent damage in mitochondria function, further corroborated with increased vulnerability towards mitochondria stress. GenX exposed neurons showed persistent alteration in neuronal network morphology and synaptic density, accompanied by persistent increase in vulnerability towards autolysosomal stress. Both PFOA and GenX triggered transient changes in AT8 and tau expression and conferred persistent vulnerability to tau-preformed fibrils (tau-PFF), implicating impaired proteostasis. Transcriptomic profiling further supported our findings. Collectively, our findings reveal divergent neurotoxic mechanisms of PFOA and GenX-mitochondrial damage versus autolysosomal stress-that converge on tau pathology, highlighting increased AD risk induced by PFAS exposure.