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Metalloplastic interaction triggers renal oxeiptosis: Novel insights into KEAP1/PGAM5/AIFM1 pathway in snakeheaded fish Channa punctatus
Summary
Researchers discovered that PVC microplastics combined with copper triggered a newly identified form of cell death called oxeiptosis in fish kidneys, marking the first time this pathway has been confirmed in an aquatic organism. The combined exposure was far more damaging than either pollutant alone, causing severe kidney tissue deterioration and oxidative damage. This finding is relevant because microplastics often carry heavy metals in the environment, and their combined effects on organs may be worse than expected.
Oxeiptosis, discovered in 2018, is a ROS-triggered, caspase-independent cell death pathway studied so far only in mammals. Our study provides the first validation of oxeiptosis in an aquatic organism, expanding the understanding of oxidative stress-mediated cell death pathways in fish. Channa punctatus were exposed to environmentally relevant concentrations of Polyvinyl chloride microplastics (PVC-MPs) (0.5 mg/L) and copper (0.85 mg/L), both individually and in combination, for 60 days. Renal responses were evaluated through reactive oxygen species (ROS) accumulation, oxidative damage to lipids, proteins, and nucleic acids, alterations in creatinine levels, nephro-architectural deterioration, and oxeiptotic cell death. Notably, the highest copper accumulation was detected in kidneys exposed to copper-loaded PVC-MPs. Elevated ROS levels were accompanied by a decline in reduced glutathione (GSH), alongside oxidative damage markers such as heightened lipid peroxidation (LPO), protein carbonylation (PC), and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Kidney dysfunction was evident from markedly increased creatinine levels, while pronounced renal architectural damage further reinforced the severity of toxicity. Molecular perturbations were more pronounced in kidneys exposed to the combined copper-PVC-MPs treatment. Transcriptional analyses indicated the upregulation of keap1, pgam5, and aifm1, with concurrent downregulation of nrf2, substantiating the occurrence of oxeiptosis. Additionally, Principal Component Analysis (PCA) and Pearson correlation analysis established strong associations between oxidative stress, molecular responses, and nephro-structural damage. These findings highlight that PVC-MPs act as carriers of heavy metals, amplifying oxidative stress and exacerbating renal dysfunction in aquatic organisms.