Table1_An integrative systems biology strategy to support the development of adverse outcome pathways (AOPs): a case study on radiation-induced microcephaly.DOCX

Adverse Outcome Pathways (AOPs) are useful tools for assessing the potential risks associated with exposure to various stressors, including chemicals and environmental contaminants. They provide a framework for understanding the causal relationships between different biological events that can lead to adverse outcomes (AO). However, developing an AOP is a challenging task, particularly in identifying the molecular initiating events (MIEs) and key events (KEs) that constitute it. Here, we propose a systems biology strategy that can assist in the development of AOPs by screening publicly available databases, literature with the text mining tool AOP-helpFinder, and pathway/network analyses. This approach is straightforward to use, requiring only the name of the stressor and adverse outcome to be studied. From this, it quickly identifies potential KEs and literature providing mechanistic information on the links between the KEs. The proposed approach was applied to the recently developed AOP 441 on radiation-induced microcephaly, resulting in the confirmation of the KEs that were already present and identification of new relevant KEs, thereby validating the strategy. In conclusion, our systems biology approach represents a valuable tool to simplify the development and enrichment of Adverse Outcome Pathways (AOPs), thus supporting alternative methods in toxicology.

不良结局途径（Adverse Outcome Pathways, AOPs）是评估各类应激源（包括化学物质与环境污染物）暴露相关潜在风险的实用工具。该途径可为理解可引发不良结局（Adverse Outcome, AO）的不同生物学事件间的因果关系提供框架。然而，构建AOP是一项极具挑战性的工作，尤其在识别构成该途径的分子起始事件（molecular initiating events, MIEs）与关键事件（key events, KEs）方面。本研究提出一种系统生物学策略，可通过检索公开数据库、借助文本挖掘工具AOP-helpFinder分析文献，并开展通路与网络分析，辅助AOP的构建。该方法操作简便，仅需输入待研究的应激源与不良结局名称即可。通过该策略，可快速识别潜在的KEs，以及提供KEs间机制关联信息的相关文献。我们将所提出的策略应用于新近构建的辐射诱导小头畸形相关AOP 441，验证了已有的KEs，并发现了新的相关KEs，从而证实了该策略的有效性。综上，本研究提出的系统生物学方法是简化AOP构建与富集的宝贵工具，可为毒理学领域的替代方法提供支撑。