Advanced Morphological - Behavioral Test Platform Reveals Neurodevelopmental Defects in Embryonic Zebrafish Exposed to Comprehensive Suite of Halogenated and Organophosphate Flame Retardants
Advanced Morphological - Behavioral Test Platform Reveals Neurodevelopmental Defects in Embryonic Zebrafish Exposed to Comprehensive Suite of Halogenated and Organophosphate Flame Retardants
复制标题
DOI：
10.1093/toxsci/kfv044
复制
发表时间：
2015-05-01
影响因子：
3.8
通讯作者：
Tanguay, Robert L.
中科院分区：
文献类型：
--
作者：
Noyes, Pamela D.;Haggard, Derik E.;Tanguay, Robert L.
随着易燃塑料和电子设备的使用越来越多，以及更严格的消防安全标准，导致许多消费、商业和工业产品大量使用阻燃化学品。虽然阻燃剂的使用有所增加，但其安全性仍存在很大的不确定性，一些证据表明，阻燃剂对人类和环境健康具有毒性和风险。最近的努力集中在用非哺乳动物模型设计高通量生物平台，以评估和优先考虑危险信息有限的化学品。为了补充这些努力，本研究使用了一个新的胚胎斑马鱼形态和行为测试平台来表征44种卤化和有机磷阻燃剂的发育毒性，包括它们的几种已知代谢物。斑马鱼在受精后6至120h内暴露于阻燃剂中，浓度跨度为4个数量级(如从6.4 nM到A亩M)。在24和120HPF条件下评价阻燃对动物存活和发育的影响，并用两种光运动反应(PMR)检测神经行为的改变。与对照组相比，93%(41/44)的受试阻燃剂在一种或多种生物测试和浓度测试中产生了不良影响，其中以芳基磷酸酯(APE)为基础的单异丙基三芳基磷酸酯和溴化双酚-A类似物四溴双酚-A产生的畸形最多。系统聚类法表明，苯环上具有异丙基、丁基和甲苯取代基的APE阻燃剂聚集紧密，尤其有效。这两种PMR分析都高度预测了形态缺陷，支持将其用作评估致畸性的非致命性手段，这可能允许对老年动物的长期或延迟影响进行额外评估。综上所述，这里提出的证据表明，斑马鱼的神经发育对目前使用的许多阻燃剂高度敏感，可以用来了解对人类健康的潜在脆弱性。
The increased use of flammable plastics and electronic devices along with stricter fire safety standards has led to the heavy use of flame retardant chemicals in many consumer, commercial, and industrial products. Although flame retardant use has increased, a great deal of uncertainty surrounds their safety with some evidence showing toxicity and risk to human and environmental health. Recent efforts have focused on designing high-throughput biological platforms with nonmammalian models to evaluate and prioritize chemicals with limited hazard information. To complement these efforts, this study used a new morphological and behavioral testing platform with embryonic zebrafish to characterize the developmental toxicity of 44 halogenated and organophosphate flame retardants, including several of their known metabolites. Zebrafish were exposed to flame retardants from 6 to 120 h post fertilization (hpf) across concentrations spanning 4 orders of magnitude (eg, 6.4 nM to 64 A mu M). Flame retardant effects on survival and development were evaluated at 24 and 120 hpf, and neurobehavioral changes were measured using 2 photomotor response (PMR) assays. Compared to controls, 93% (41/44) of flame retardants studied elicited adverse effects among one or more of the bioassays and concentrations tested with the aryl phosphate ester (APE)-based mono-isopropylated triaryl phosphate and the brominated-bisphenol-A analog tetrabromobisphenol-A producing the greatest array of malformations. Hierarchical clustering showed that APE flame retardants with isopropyl, butyl, and cresyl substituents on phenyl rings clustered tightly and were particularly potent. Both PMR assays were highly predictive of morphological defects supporting their use as nonlethal means of evaluating teratogenicity that could allow for additional evaluations of long-term or delayed effects in older animals. Taken together, evidence presented here indicates that zebrafish neurodevelopment is highly sensitive to many flame retardants currently in use and can be used to understand potential vulnerabilities to human health.