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.

在毒理学研究中使用基因组方法大大提高了我们定义与发育神经毒性 (DNT) 相关的环境化学物质分子谱的能力。将这些方法与不良结果途径 (AOP) 相结合，这是一种将环境暴露转化为不良发育表型的框架，可能会为 DNT 测试策略提供信息。在这里，我们以视黄酸 (RA) 为例，证明将毒物基因组学特征整合到 AOP 框架中可用于建立化学测试范式。RA 是一种关键的调节信号分子，参与哺乳动物中枢神经系统 (CNS) 发育的多个方面，包括后脑形成/模式化和神经元分化，RA 信号通路的失衡与 DNT 相关。虽然机制仍未解决，但环境化学物质可通过破坏 RA 信号通路导致 DNT。首先，我们回顾了 RA 和其他类维生素 A 暴露和 DNT 的文献证据，以确定与 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，通过整合毒物基因组数据集，我们在人类和啮齿动物模型中定义了与 RA 诱导的发育神经毒性 (RA-DNT) 相关的转录组特征，并针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，我们展示了如何通过测试针对唑类的 RA-DNT 特征来系统地利用这些方法来识别化学危害，一类提议的改变 RA 信号的化合物。本研究的临时 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。