Human cerebral organoids reveal PFOA-induced axonal injury as a conserved mechanism of neurodevelopmental disruption

Perfluorooctanoic acid (PFOA), a persistent environmental contaminant of growing public health concern, has been epidemiologically linked to neurodevelopmental deficits, yet its direct pathogenic mechanisms remain poorly defined. Our study addresses this critical gap by employing a unique cross-species framework that integrates zebrafish behavior with human neural organoids—a innovative approach that bridges in vivo physiology with human-specific molecular insights. We demonstrate that embryonic PFOA exposure selectively impairs social behavior in zebrafish while sparing basic motor function, a deficit paralleled by disrupted network activity in human cortical organoids. Mechanistically, we identify a precise developmental disruption: PFOA blocks neuronal differentiation without altering progenitor proliferation, leading to transient growth impairment and lasting neuronal structural deficits. Cross-model transcriptomics revealed conserved axonal and synaptic pathway disruption, centered on downregulation of the structural gene NEFL, which we validated at the protein level. Our findings not only establish a new paradigm for PFOA neurotoxicity but also highlight the value of human neural organoids in environmental risk assessment. By directly linking molecular pathogenesis to functional impairment across species, this work provides crucial mechanistic evidence for regulatory decision-making and underscores the unique vulnerability of the developing human nervous system to environmental contaminants.