INSERM UMR-S 973, 75013 Paris, France; University of Paris Diderot, 75013 Paris, France.
Harvard T.H. Chan School of Public Health, Boston, MA, USA; University of Southern Denmark, Odense, Denmark.
Toxicol Appl Pharmacol. 2018 Sep 1;354:56-63. doi: 10.1016/j.taap.2018.02.014. Epub 2018 Feb 21.
The need to prevent developmental brain disorders has led to an increased interest in efficient neurotoxicity testing. When an epidemic of microcephaly occurred in Brazil, Zika virus infection was soon identified as the likely culprit. However, the pathogenesis appeared to be complex, and a larvicide used to control mosquitoes responsible for transmission of the virus was soon suggested as an important causative factor. Yet, it is challenging to identify relevant and efficient tests that are also in line with ethical research defined by the 3Rs rule (Replacement, Reduction and Refinement). Especially in an acute situation like the microcephaly epidemic, where little toxicity documentation is available, new and innovative alternative methods, whether in vitro or in silico, must be considered. We have developed a network-based model using an integrative systems biology approach to explore the potential developmental neurotoxicity, and we applied this method to examine the larvicide pyriproxyfen widely used in the prevention of Zika virus transmission. Our computational model covered a wide range of possible pathways providing mechanistic hypotheses between pyriproxyfen and neurological disorders via protein complexes, thus adding to the plausibility of pyriproxyfen neurotoxicity. Although providing only tentative evidence and comparisons with retinoic acid, our computational systems biology approach is rapid and inexpensive. The case study of pyriproxyfen illustrates its usefulness as an initial or screening step in the assessment of toxicity potentials of chemicals with incompletely known toxic properties.
为了预防发育性脑紊乱，人们对高效神经毒性测试的兴趣日益浓厚。当巴西出现小头症疫情时，寨卡病毒感染很快被确定为可能的罪魁祸首。然而，其发病机制似乎很复杂，一种用于控制传播病毒的蚊子的杀虫剂很快被认为是一个重要的致病因素。然而，要确定相关且高效的测试，同时符合 3R 规则（替代、减少和优化）定义的伦理研究，这具有挑战性。特别是在像小头症疫情这样的急性情况下，几乎没有毒性文献可用，必须考虑新的和创新的替代方法，无论是体外还是基于计算机的方法。我们使用整合系统生物学方法开发了一个基于网络的模型，以探索潜在的发育性神经毒性，并应用该方法来检测广泛用于预防寨卡病毒传播的杀虫剂吡丙醚。我们的计算模型涵盖了广泛的可能途径，通过蛋白质复合物提供了吡丙醚与神经紊乱之间的机制假设，从而增加了吡丙醚神经毒性的可能性。虽然仅提供了初步证据，并与视黄酸进行了比较，但我们的计算系统生物学方法快速且廉价。吡丙醚的案例研究说明了它在评估具有不完全已知毒性特性的化学物质的毒性潜力方面作为初始或筛选步骤的有用性。
