Reversal of neurodevelopmental toxicity induced by combined exposure to the neonicotinoid insecticides acetamiprid and imidacloprid in zebrafish through targeting DRP-1: insights into mitophagy and apoptosis mechanisms
{"title":"Reversal of neurodevelopmental toxicity induced by combined exposure to the neonicotinoid insecticides acetamiprid and imidacloprid in zebrafish through targeting DRP-1: insights into mitophagy and apoptosis mechanisms","authors":"Yuzhi Zhao, Shaozhuo Wang, Siyue Tan, Gaoyuan Wang, Haojie Zhou, Chengyu Geng, Chunjin Li, Yuewen He, Yifan Shi, Zhongxiu Deng, Siyu Chen, Qitong Yuan, Sirui Wang, Yuxi Yang, Xinyan Jiang, Wenqing He, Shou-Lin Wang, Huibin Dong, Chao Wang","doi":"10.1016/j.envpol.2025.126877","DOIUrl":null,"url":null,"abstract":"Neonicotinoid pesticides, including acetamiprid (ACE) and imidacloprid (IMI), are widely used due to their high efficacy and broad-spectrum activity. Despite IMI prohibition in certain countries by 2023, its residual effects, particularly in conjunction with ACE, which is frequently detected at elevated concentrations in rivers and surface waters, remain inadequately explored. In this study, the combined neurodevelopmental toxicity of ACE and IMI in zebrafish was investigated, with emphasis on mitochondrial dynamics and potential intervention strategies. We developed a 120-h acute exposure model using zebrafish embryos and a long-term chronic exposure model involving six months of environmentally relevant doses in adult zebrafish. Various parameters were systematically assessed using these models, including general toxicity, larval behavioral characteristics, outcomes of the novel tank diving test and light-dark test in adults, neurodevelopmental status, associated gene expression levels, and mitochondrial function. Furthermore, exposure experiments were conducted using transgenic zebrafish larvae <em>Tg</em> (<em>huc:eGFP</em>) and <em>Tg</em> (<em>hb9:eGFP</em>) to elucidate specific effects on the nervous system. Human neuroblastoma SK-N-SH cells were used to evaluate apoptosis, oxidative stress, ATP levels, mitochondrial membrane potential, and calcium ion concentrations. Protein markers associated with apoptosis (Bax, BCL-2, and Cleaved Caspase-3) and mitophagy (LC3A/B, P62, Parkin, and Pink-1) were analyzed. Additionally, DRP-1, Bax, and CytC levels were quantified in both mitochondrial and cytoplasmic fractions. The DRP-1 inhibitor Mdivi-1 was used to substantiate the role of mitochondrial dynamics. The results revealed a synergistic neurotoxic effect resulting from the combined exposure to ACE and IMI, which was characterized by impaired neural development, behavioral abnormalities, and mitochondrial dysfunction. Treatment with Mdivi-1 ameliorated these effects, reducing neurotoxicity in zebrafish. This study elucidates the synergistic neurodevelopmental toxicity of ACE and IMI, underscores the pivotal role of mitochondrial pathways, and provides insights into potential mitigation strategies for neonicotinoid-induced neurotoxicity.","PeriodicalId":311,"journal":{"name":"Environmental Pollution","volume":"16 1","pages":""},"PeriodicalIF":7.6000,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Environmental Pollution","FirstCategoryId":"93","ListUrlMain":"https://doi.org/10.1016/j.envpol.2025.126877","RegionNum":2,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENVIRONMENTAL SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Neonicotinoid pesticides, including acetamiprid (ACE) and imidacloprid (IMI), are widely used due to their high efficacy and broad-spectrum activity. Despite IMI prohibition in certain countries by 2023, its residual effects, particularly in conjunction with ACE, which is frequently detected at elevated concentrations in rivers and surface waters, remain inadequately explored. In this study, the combined neurodevelopmental toxicity of ACE and IMI in zebrafish was investigated, with emphasis on mitochondrial dynamics and potential intervention strategies. We developed a 120-h acute exposure model using zebrafish embryos and a long-term chronic exposure model involving six months of environmentally relevant doses in adult zebrafish. Various parameters were systematically assessed using these models, including general toxicity, larval behavioral characteristics, outcomes of the novel tank diving test and light-dark test in adults, neurodevelopmental status, associated gene expression levels, and mitochondrial function. Furthermore, exposure experiments were conducted using transgenic zebrafish larvae Tg (huc:eGFP) and Tg (hb9:eGFP) to elucidate specific effects on the nervous system. Human neuroblastoma SK-N-SH cells were used to evaluate apoptosis, oxidative stress, ATP levels, mitochondrial membrane potential, and calcium ion concentrations. Protein markers associated with apoptosis (Bax, BCL-2, and Cleaved Caspase-3) and mitophagy (LC3A/B, P62, Parkin, and Pink-1) were analyzed. Additionally, DRP-1, Bax, and CytC levels were quantified in both mitochondrial and cytoplasmic fractions. The DRP-1 inhibitor Mdivi-1 was used to substantiate the role of mitochondrial dynamics. The results revealed a synergistic neurotoxic effect resulting from the combined exposure to ACE and IMI, which was characterized by impaired neural development, behavioral abnormalities, and mitochondrial dysfunction. Treatment with Mdivi-1 ameliorated these effects, reducing neurotoxicity in zebrafish. This study elucidates the synergistic neurodevelopmental toxicity of ACE and IMI, underscores the pivotal role of mitochondrial pathways, and provides insights into potential mitigation strategies for neonicotinoid-induced neurotoxicity.
期刊介绍:
Environmental Pollution is an international peer-reviewed journal that publishes high-quality research papers and review articles covering all aspects of environmental pollution and its impacts on ecosystems and human health.
Subject areas include, but are not limited to:
• Sources and occurrences of pollutants that are clearly defined and measured in environmental compartments, food and food-related items, and human bodies;
• Interlinks between contaminant exposure and biological, ecological, and human health effects, including those of climate change;
• Contaminants of emerging concerns (including but not limited to antibiotic resistant microorganisms or genes, microplastics/nanoplastics, electronic wastes, light, and noise) and/or their biological, ecological, or human health effects;
• Laboratory and field studies on the remediation/mitigation of environmental pollution via new techniques and with clear links to biological, ecological, or human health effects;
• Modeling of pollution processes, patterns, or trends that is of clear environmental and/or human health interest;
• New techniques that measure and examine environmental occurrences, transport, behavior, and effects of pollutants within the environment or the laboratory, provided that they can be clearly used to address problems within regional or global environmental compartments.