Teratological and Behavioral Screening of the National Toxicology Program 91-Compound Library in Zebrafish (Danio rerio)
Teratological and Behavioral Screening of the National Toxicology Program 91-Compound Library in Zebrafish (Danio rerio)
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DOI：
10.1093/toxsci/kfy266
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发表时间：
2019-01-01
影响因子：
3.8
通讯作者：
Lein, Pamela J.
中科院分区：
文献类型：
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作者：
Dach, Katharina;Yaghoobi, Bianca;Lein, Pamela J.
为了筛选目前没有毒性数据的成千上万种化学物质，有必要从活体啮齿动物模型转向替代模型，例如斑马鱼。在这里，我们使用去角质的热带5D野生型斑马鱼胚胎对国家毒理学计划（NTP）提供的91个化合物文库进行发育毒性筛选。该文库包含86种独特的化学物质，包括阴性对照、阻燃剂、多环芳烃（PAHs）、药物、工业化学品和杀虫剂。从受精后6小时（hpf）到受精后5天（dpf），鱼在胚胎培养基中暴露于5种浓度的每种化学物质或等量的媒介物（0.5% DMSO）。每天检查鱼的死亡率和致畸效应，并在4和5 dpf时评估光驱行为。文库中5个阴性对照化合物均未引起死亡/致畸，但有2个改变了行为。重复提供的化学品产生了类似的结果。总体而言，13种化合物导致死亡/致畸，但不会导致行为异常，24种仅影响行为，18种同时改变两个终点，其中行为在不导致死亡/致畸的浓度下受到影响（55/86命中）。在影响行为的化合物中，52%的化合物在4或5 dpf时导致行为异常。同一官能团内的化合物引起的行为异常不同，而不同官能团的化合物引起的行为模式相似。我们的数据表明，行为是发育毒性筛选的一个敏感终点，它整合了多种毒性作用模式，并受到测试时仔鱼年龄的影响。
To screen the tens of thousands of chemicals for which no toxicity data currently exists, it is necessary to move from in vivo rodent models to alternative models, such as zebrafish. Here, we used dechorionated Tropical 5D wild-type zebrafish embryos to screen a 91-compound library provided by the National Toxicology Program (NTP) for developmental toxicity. This library contained 86 unique chemicals that included negative controls, flame retardants, polycyclic aromatic hydrocarbons (PAHs), drugs, industrial chemicals, and pesticides. Fish were exposed to 5 concentrations of each chemical or an equal amount of vehicle (0.5% DMSO) in embryo medium from 6h post-fertilization (hpf) to 5 days post-fertilization (dpf). Fish were examined daily for mortality and teratogenic effects and photomotor behavior was assessed at 4 and 5 dpf. Of the 5 negative control compounds in the library, none caused mortality/teratogenesis, but two altered behavior. Chemicals provided in duplicate produced similar outcomes. Overall, 13 compounds caused mortality/teratology but not behavioral abnormalities, 24 only affected behavior, and 18 altered both endpoints, with behavior affected at concentrations that did not cause mortality/teratology (55/86 hits). Of the compounds that affected behavior, 52% caused behavioral abnormalities at either 4 or 5 dpf. Compounds within the same functional group caused different behavioral abnormalities, while similar behavioral patterns were caused by compounds from different groups. Our data suggest that behavior is a sensitive endpoint for developmental toxicity screening that integrates multiple modes of toxic action and is influenced by the age of the larval fish at the time of testing.