{"title":"Metalloplastic interaction triggers renal oxeiptosis: Novel insights into KEAP1/PGAM5/AIFM1 pathway in snakeheaded fish Channa punctatus","authors":"Jumman Bakhasha, Vaishnavi Saxena, Neeti Arya, Pradeep Kumar, Abha Trivedi","doi":"10.1016/j.etap.2025.104760","DOIUrl":null,"url":null,"abstract":"<div><div>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. <em>Channa punctatus</em> 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 <em>keap1, pgam5,</em> and <em>aifm1</em>, with concurrent downregulation of <em>nrf2</em>, 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.</div></div>","PeriodicalId":11775,"journal":{"name":"Environmental toxicology and pharmacology","volume":"118 ","pages":"Article 104760"},"PeriodicalIF":4.2000,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Environmental toxicology and pharmacology","FirstCategoryId":"93","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1382668925001358","RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENVIRONMENTAL SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍:
Environmental Toxicology and Pharmacology publishes the results of studies concerning toxic and pharmacological effects of (human and veterinary) drugs and of environmental contaminants in animals and man.
Areas of special interest are: molecular mechanisms of toxicity, biotransformation and toxicokinetics (including toxicokinetic modelling), molecular, biochemical and physiological mechanisms explaining differences in sensitivity between species and individuals, the characterisation of pathophysiological models and mechanisms involved in the development of effects and the identification of biological markers that can be used to study exposure and effects in man and animals.
In addition to full length papers, short communications, full-length reviews and mini-reviews, Environmental Toxicology and Pharmacology will publish in depth assessments of special problem areas. The latter publications may exceed the length of a full length paper three to fourfold. A basic requirement is that the assessments are made under the auspices of international groups of leading experts in the fields concerned. The information examined may either consist of data that were already published, or of new data that were obtained within the framework of collaborative research programmes. Provision is also made for the acceptance of minireviews on (classes of) compounds, toxicities or mechanisms, debating recent advances in rapidly developing fields that fall within the scope of the journal.