Copper and PFOS Co-Exposure Induces Synergistic Neurotoxicity via ROS-Mediated Mitophagy in C. elegans

Copper (Cu) and perfluorooctanesulfonic acid (PFOS) are ubiquitous environmental pollutants that frequently co-occur, each capable of inducing neurotoxicity individually. However, the combined toxicity and interactive mechanisms of their co-exposure remain unclear, hindering an accurate assessment of their combined environmental health risks. Using the Caenorhabditis elegans model, we investigated the effects of co-exposure to environmentally relevant concentrations. Compared to individual exposures, co-exposure triggered synergistic neurotoxicity, characterized by the loss of dopaminergic (DAergic) and glutamatergic (GLUergic) neurons, aggravated locomotor deficits, massive accumulation of reactive oxygen species (ROS), and a severe decline in mitochondrial membrane potential, accompanied by substantial mitochondrial ultrastructural damage and accumulation of autophagosomes. Mechanistically, the excessive oxidative stress induced by co-exposure aberrantly and persistently activated the ROS-mediated mitophagy pathway, thereby impairing mitochondrial quality control. Critically, intervention with N-acetylcysteine (NAC), an antioxidant, effectively mitigated the co-exposure-induced deficits, identifying oxidative stress as the central driver of the synergistic toxicity. Our findings reveal a novel mechanism by which Cu and PFOS exert synergistic neurotoxicity via the oxidative-stress–mitophagy axis, providing key scientific evidence for refining the assessment of their combined environmental pollution risks.