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

IF 7.6 2区 环境科学与生态学 Q1 ENVIRONMENTAL SCIENCES
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
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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.

Abstract Image

通过靶向DRP-1逆转新烟碱类杀虫剂醋氨脒和吡虫啉联合暴露对斑马鱼神经发育毒性的影响:线粒体自噬和凋亡机制的见解
新烟碱类农药,包括醋氨脒(ACE)和吡虫啉(IMI),因其高效、广谱活性而被广泛应用。尽管到2023年,某些国家将禁止IMI,但其残留影响,特别是与ACE一起,在河流和地表水中经常检测到高浓度的ACE,仍未得到充分探索。在这项研究中,研究了ACE和IMI对斑马鱼神经发育的联合毒性,重点研究了线粒体动力学和潜在的干预策略。我们利用斑马鱼胚胎建立了一个120小时的急性暴露模型,并在成年斑马鱼中建立了一个涉及6个月环境相关剂量的长期慢性暴露模型。使用这些模型系统地评估了各种参数,包括一般毒性、幼虫行为特征、新型水箱潜水试验和成人光暗试验的结果、神经发育状态、相关基因表达水平和线粒体功能。此外,我们还利用转基因斑马鱼幼鱼Tg (huc:eGFP)和Tg (hb9:eGFP)进行了暴露实验,以阐明其对神经系统的特异性影响。我们使用人神经母细胞瘤SK-N-SH细胞来评估细胞凋亡、氧化应激、ATP水平、线粒体膜电位和钙离子浓度。分析与凋亡相关的蛋白标志物(Bax、BCL-2和Cleaved Caspase-3)和线粒体自噬(LC3A/B、P62、Parkin和Pink-1)。此外,测定线粒体和细胞质中DRP-1、Bax和CytC的水平。DRP-1抑制剂Mdivi-1被用来证实线粒体动力学的作用。结果显示,ACE和IMI联合暴露导致协同神经毒性作用,其特征是神经发育受损、行为异常和线粒体功能障碍。Mdivi-1治疗改善了这些效果,降低了斑马鱼的神经毒性。本研究阐明了ACE和IMI的协同神经发育毒性,强调了线粒体途径的关键作用,并为新烟碱诱导的神经毒性的潜在缓解策略提供了见解。
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来源期刊
Environmental Pollution
Environmental Pollution 环境科学-环境科学
CiteScore
16.00
自引率
6.70%
发文量
2082
审稿时长
2.9 months
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.
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