Oseltamivir phosphate (Tamiflu) alters neurobehavior of zebrafish larvae by inducing mitochondrial dysfunction

被引：1

作者：

Wang, Shuang ^{[1
]}

Zou, Minjian ^{[1
]}

Zhu, Zhirui ^{[1
]}

Wang, Zuo ^{[1
]}

Li, Kemin ^{[1
]}

Ruan, Jiayi ^{[1
]}

Zhao, Bixi ^{[1
]}

Pan, Chuanyin ^{[2
]}

Lan, Xianyong ^{[2
]}

Zhang, Shengxiang ^{[1
]}

Foulkes, Nicholas S. ^{[3
]}

Zhao, Haiyu ^{[1
]}

机构：

[1] Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, No. 222 South Tianshui Road, Gansu Province, Lanzhou

[2] 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, Shaanxi Province, Yangling

[3] Institute of Biological and Chemical Systems, Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz Platz 1, Eggenstein-Leopoldshafen

来源：

Science of the Total Environment | 2024年 / 955卷

基金：

中国国家自然科学基金;

关键词：

In vivo two-photon imaging; Microglia; Neurodevelopmental toxicity; Oxidative phosphorylation; RNA-sequencing; Vascular development;

D O I：

10.1016/j.scitotenv.2024.177077

中图分类号：

学科分类号：

摘要：

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. © 2024 Elsevier B.V.

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