Retinoids and developmental neurotoxicity: Utilizing toxicogenomics to enhance adverse outcome pathways and testing strategies.
Retinoids and developmental neurotoxicity: Utilizing toxicogenomics to enhance adverse outcome pathways and testing strategies.
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DOI：
10.1016/j.reprotox.2020.06.007
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Robinson JF
中科院分区：
文献类型：
--
作者：
Chen H;Chidboy MA;Robinson JF
在毒理学研究中使用基因组方法大大提高了我们确定与发育神经毒性（DNT）相关的环境化学品分子特征的能力。将这些方法与不良结果途径（AOP）整合，这是一个将环境暴露转化为不良发育表型的框架，可以潜在地为DNT测试策略提供信息。在这里，使用视黄酸（RA）作为一个案例的例子，我们表明，整合毒理基因组学档案的AOP框架，可以用来建立一个化学测试的范例。RA是哺乳动物中枢神经系统（CNS）发育的多个方面的关键调节信号分子，包括后脑形成/图案化和神经元分化，并且RA信号通路的失衡与DNT相关。虽然机制尚未解决，但环境化学物质可以通过破坏RA信号通路引起DNT。首先，我们回顾了RA和其他维甲酸暴露和DNT的文献证据，以定义与RA胚胎生物利用度和后脑发育不平衡相关的临时AOP。接下来，通过整合毒理基因组学数据集，我们定义了一个与人类和啮齿动物模型中RA诱导的发育神经毒性（RA-DNT）相关的转录组学特征，并对斑马鱼模型数据进行了测试，证明了整合到AOP框架中的潜力。最后，我们展示了如何系统地利用这些方法来识别化学危害，通过测试RA-DNT签名对唑类，一个拟议的一类化合物，改变RA信号。这项研究的暂定AOP可以在未来扩展，以更好地定义与RA信号传导和毒性相关的DNT生物标志物。
The use of genomic approaches in toxicological studies has greatly increased our ability to define the molecular profiles of environmental chemicals associated with developmental neurotoxicity (DNT). Integration of these approaches with adverse outcome pathways (AOPs), a framework that translates environmental exposures to adverse developmental phenotypes, can potentially inform DNT testing strategies. Here, using retinoic acid (RA) as a case example, we demonstrate that the integration of toxicogenomic profiles into the AOP framework can be used to establish a paradigm for chemical testing. RA is a critical regulatory signaling molecule involved in multiple aspects of mammalian central nervous system (CNS) development, including hindbrain formation/patterning and neuronal differentiation, and imbalances in RA signaling pathways are linked with DNT. While the mechanisms remain unresolved, environmental chemicals can cause DNT by disrupting the RA signaling pathway. First, we reviewed literature evidence of RA and other retinoid exposures and DNT to define a provisional AOP related to imbalances in RA embryonic bioavailability and hindbrain development. Next, by integrating toxicogenomic datasets, we defined a relevant transcriptomic signature associated with RA-induced developmental neurotoxicity (RA-DNT) in human and rodent models that was tested against zebrafish model data, demonstrating potential for integration into an AOP framework. Finally, we demonstrated how these approaches may be systematically utilized to identify chemical hazards by testing the RA-DNT signature against azoles, a proposed class of compounds that alters RA-signaling. The provisional AOP from this study can be expanded in the future to better define DNT biomarkers relevant to RA signaling and toxicity.
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