GABAA receptor and cell membrane potential as functional endpoints in cultured neurons to evaluate chemicals for human acute toxicity
GABAA receptor and cell membrane potential as functional endpoints in cultured neurons to evaluate chemicals for human acute toxicity
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DOI：
10.1016/j.ntt.2009.01.010
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发表时间：
2010-01-01
影响因子：
2.9
通讯作者：
Sunol, Cristina
中科院分区：
文献类型：
--
作者：
Galofre, Mireia;Babot, Zoila;Sunol, Cristina
对化学物质引起的人类健康危害的毒性风险评估主要依赖于从动物实验、人体研究和流行病学获得的数据。基于细胞毒性分析的体外急性毒性测试预测了70%-80%的啮齿动物和人类的毒性。神经系统特别容易受到化学物质的影响，这可能会导致不同的毒性特征。与神经功能不良有关的急性人类毒性通常是神经系统过度兴奋或抑制的结果。参与这些反应的主要分子和细胞机制包括GABA能、谷氨酸和胆碱能神经传递，细胞和线粒体膜电位的调节，以及对维持中枢神经系统功能至关重要的机制，如控制细胞能量。在这项工作中，测试了一系列用于制药、工业、杀生剂治疗或经常被吸毒者滥用的化学品对原代神经元培养的GABA(A)受体活性、GABA和谷氨酸转运、细胞膜电位和细胞活力的影响。GABA(A)受体功能被严重的人类中毒后观察到的癫痫发作的化合物所抑制。通常滥用的药物会抑制GABA的摄取，但不会抑制谷氨酸的摄取。大多数神经毒素改变了膜电位。GABA(A)受体、GABA摄取和细胞膜电位分析是那些在低浓度下确定有毒化学物质数量最多的方法。这些结果表明，如果使用表达与急性神经功能障碍相关的神经元靶点的体外模型，体外细胞分析可能会识别出对人类产生急性神经毒性的化合物。(C)2009 Elsevier Inc.保留所有权利。
Toxicity risk assessment for chemical-induced human health hazards relies mainly on data obtained from animal experimentation, human studies and epidemiology. In vitro testing for acute toxicity based on cytotoxicity assays predicts 70-80% of rodent and human toxicity. The nervous system is particularly vulnerable to chemical exposure which may result in different toxicity features. Acute human toxicity related to adverse neuronal function is usually a result of over-excitation or depression of the nervous system. The major molecular and cellular mechanisms involved in such reactions include GABAergic, glutamatergic and cholinergic neurotransmission, regulation of cell and mitochondrial membrane potential, and those critical for maintaining central nervous system functionality, such as controlling cell energy. In this work, a set of chemicals that are used in pharmacy, industry, biocide treatments or are often abused by drug users are tested for their effects on GABA(A) receptor activity, GABA and glutamate transport, cell membrane potential and cell viability in primary neuronal cultures. GABA(A) receptor function was inhibited by compounds for which seizures have been observed after severe human poisoning. Commonly abused drugs inhibit GABA uptake but not glutamate uptake. Most neurotoxins altered membrane potential. The GABA(A) receptor, GABA uptake and cell membrane potential assays were those that identified the highest number of chemicals as toxic at low concentrations. These results show that in vitro cell assays may identify compounds that produce acute neurotoxicity in humans, provided that in vitro models expressing neuronal targets relevant for acute neural dysfunctions are used. (C) 2009 Elsevier Inc. All rights reserved.