Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Lanzhou 730000, Gansu Province, China.
Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, Shaanxi Province, China.
Sci Total Environ. 2024 Dec 10;955:177077. doi: 10.1016/j.scitotenv.2024.177077. Epub 2024 Oct 31.
Antiviral drugs are widely used, yet their potential risks during early development, particularly within the central nervous system, remain contentious. Oseltamivir phosphate (OSE), a commonly prescribed antiviral, is increasingly detected in various environments. However, its toxicity to organisms and the underlying mechanisms are not well understood. In this study, we employed the zebrafish model to evaluate the developmental neurotoxic effects of OSE at environmentally and therapeutically relevant doses, through high-throughput behavioral analysis, in vivo two-photon imaging, transcriptomic sequencing, pharmacological intervention, and biochemical and molecular assays. Our results indicated that OSE exposure increased heart rate and induced pericardial edema in zebrafish larvae. Additionally, OSE-exposed larvae exhibited hyperactive behavior, impaired social interactions, and reduced habitual learning capacity. Although OSE at our selected levels did not significantly affect neuron count in the brain, it activated neuroinflammatory responses, altered blood vessel morphology, modulated neurotransmitter levels and the expression of neurodevelopment-related genes. Transcriptomic analysis revealed upregulation of mitochondria-related genes associated with oxidative phosphorylation. Further assessments of mitochondrial function demonstrated altered activities of respiratory chain complexes, reduced mitochondrial membrane potential (MMP), and decreased ATP content. Notably, co-treatment with mitochondrial protectants acetyl-l-carnitine-hydrochloride (ALC) or nicotinamide riboside (NR) effectively mitigated OSE-induced neurobehavioral disorders. These findings suggest that overuse of OSE can pose neurodevelopmental risks for both humans and animals, potentially attributable to mitochondrial dysfunction.
抗病毒药物被广泛应用，但它们在早期发育阶段（尤其是中枢神经系统）的潜在风险仍然存在争议。磷酸奥司他韦（OSE）是一种常用的抗病毒药物，在各种环境中都有越来越多的检测到。然而，其对生物体的毒性及其潜在的作用机制尚未得到充分的了解。在这项研究中，我们使用斑马鱼模型，通过高通量行为分析、体内双光子成像、转录组测序、药理学干预以及生化和分子检测，评估了 OSE 在环境相关和治疗相关剂量下对发育中的神经系统的神经毒性作用。我们的研究结果表明，OSE 暴露会增加斑马鱼幼鱼的心率并诱导心包水肿。此外，OSE 暴露的幼鱼表现出过度活跃的行为、社交互动受损以及习惯性学习能力下降。尽管我们选择的 OSE 水平没有显著影响大脑中的神经元数量，但它会激活神经炎症反应，改变血管形态，调节神经递质水平和神经发育相关基因的表达。转录组分析显示，与氧化磷酸化相关的线粒体相关基因上调。进一步评估线粒体功能表明，呼吸链复合物的活性降低，线粒体膜电位（MMP）降低，ATP 含量减少。值得注意的是，线粒体保护剂乙酰左旋肉碱盐酸盐（ALC）或烟酰胺核糖苷（NR）的联合治疗可以有效缓解 OSE 引起的神经行为障碍。这些发现表明，OSE 的过度使用可能会对人类和动物的神经发育造成风险，其潜在机制可能与线粒体功能障碍有关。
