Co-exposure to PET and PFOA elicits time-dependent synergistic hepatotoxicity and a "two-hit" mechanism in the freshwater snail Cipangopaludina cathayensis.

Perfluorooctanoic acid (PFOA) and polyethylene terephthalate (PET) microplastics are prevalent co-contaminants in aquatic systems, yet their combined hepatotoxicity in benthic organisms remains poorly understood. In this 28-day study on the freshwater snail Cipangopaludina cathayensis, we report that co-exposure to PFOA (30 μg/L) and PET (1 mg/L) induces time-dependent synergistic hepatotoxicity. Comprehensive analyses revealed that combined exposure significantly exacerbated hepatopancreatic injury compared to individual treatments, accompanied by disturbances in oxidative stress, neurological function, and energy metabolism systems. Crucially, transcriptomic profiling of hepatopancreatic tissue uncovered a novel "two-hit" mechanism distinct from previous findings: simultaneous suppression of the mitochondrial apoptotic pathway (concurrent downregulation of bcl-2, bax, and Caspases) coupled with impaired function of the NRG-ErbB4-MAPK cytoprotective signaling axis. This unique molecular interplay impedes the clearance of damaged cells and disrupts endogenous repair programs, ultimately leading to irreversible hepatic damage. Our study provides groundbreaking multi-level evidence that microplastic-PFOA co-exposure can synergistically disrupt core cellular defense mechanisms in the hepatopancreas, establishing a crucial mechanistic foundation for ecological risk assessment of complex contaminant mixtures.