Ototoxin-induced cellular damage in neuromasts disrupts lateral line function in larval zebrafish
Ototoxin-induced cellular damage in neuromasts disrupts lateral line function in larval zebrafish
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DOI：
10.1016/j.heares.2011.12.001
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发表时间：
2012-02-01
期刊：
影响因子：
2.8
通讯作者：
Whitfield, Tanya T.
中科院分区：
文献类型：
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作者：
Buck, Lauren M. J.;Winter, Matthew J.;Whitfield, Tanya T.
许多上市药物的耳毒性是有据可查的，而且在临床前阶段缺乏方便的技术来识别和消除这种不良影响。我们已经评估了斑马鱼幼体，或者更具体地说，它的侧线神经肥大毛细胞，作为哺乳动物内耳毛细胞对耳毒素暴露反应的微板级体内替代模型的有效性。在这里，我们描述了斑马鱼幼虫暴露于一系列众所周知的人类和非人类哺乳动物耳毒素后，侧线神经鞘毛细胞损失的病理和功能后果的调查。使用先前描述的组织学分析，我们表明，暴露于一系列药物类别的代表后，毛细胞损伤以浓度依赖性的方式发生，包括氨基糖苷类抗生素，水杨酸盐和铂基化疗药物，以及重金属。此外，我们详细优化了一种半自动方法来分析斑马鱼幼虫的刻板惊吓反应，并利用这种方法来评估毛细胞损伤对这些动物听力功能的影响。功能评估显示，5日龄斑马鱼幼体在接受了一些先前被证明会导致毛细胞损伤和丢失的化合物治疗后，先天惊吓、流变和回避反应明显减弱。有趣的是，即使在侧线毛细胞荧光明显完全消失后，惊吓反射（尽管减弱）仍然存在，这表明内耳和侧线神经肥大毛细胞在这种反射反应中受到一定的影响。总的来说，这些数据为支持使用斑马鱼作为药物诱导的组织学和功能性耳毒性的临床前指标提供了证据。(C) 2011 Elsevier B.V.版权所有
The ototoxicity of a number of marketed drugs is well documented, and there is an absence of convenient techniques to identify and eliminate this unwanted effect at a pre-clinical stage. We have assessed the validity of the larval zebrafish, or more specifically its lateral line neuromast hair cells, as a microplatescale in vivo surrogate model of mammalian inner ear hair cell responses to ototoxin exposure. Here we describe an investigation of the pathological and functional consequences of hair cell loss in lateral line neuromasts of larval zebrafish after exposure to a range of well known human and non-human mammalian ototoxins. Using a previously described histological assay, we show that hair cell damage occurs in a concentration-dependent fashion following exposure to representatives from a range of drug classes, including the aminoglycoside antibiotics, salicylates and platinum-based chemotherapeutics, as well as a heavy metal. Furthermore, we detail the optimisation of a semi-automated method to analyse the stereotypical startle response in larval zebrafish, and use this to assess the impact of hair cell damage on hearing function in these animals. Functional assessment revealed robust and significant attenuation of the innate startle, rheotactic and avoidance responses of 5 day old zebrafish larvae after treatment with a number of compounds previously shown to induce hair cell damage and loss. Interestingly, a startle reflex (albeit reduced) was still present even after the apparent complete loss of lateral line hair cell fluorescence, suggesting some involvement of the inner ear as well as the lateral line neuromast hair cells in this reflex response. Collectively, these data provide evidence to support the use of the zebrafish as a pre-clinical indicator of drug-induced histological and functional ototoxicity. (C) 2011 Elsevier B.V. All rights reserved.