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一种数据驱动的不良后果途径网络生成方法的开发:以EATS模式为例的案例研究。

Development of a data-driven approach to Adverse Outcome Pathway network generation: a case study on the EATS-modalities.

作者信息

Wiklund Linus, Caccia Sara, Pípal Marek, Nymark Penny, Beronius Anna

机构信息

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Università degli Studi di Milano, Milano, Italy.

出版信息

Front Toxicol. 2023 May 9;5:1183824. doi: 10.3389/ftox.2023.1183824. eCollection 2023.

Abstract

Adverse Outcome Pathways (AOPs) summarize mechanistic understanding of toxicological effects and have, for example, been highlighted as a promising tool to integrate data from novel and methods into chemical risk assessments. Networks based on AOPs are considered the functional implementation of AOPs, as they are more representative of complex biology. At the same time, there are currently no harmonized approaches to generate AOP networks (AOPNs). Systematic strategies to identify relevant AOPs, and methods to extract and visualize data from the AOP-Wiki, are needed. The aim of this work was to develop a structured search strategy to identify relevant AOPs in the AOP-Wiki, and an automated data-driven workflow to generate AOPNs. The approach was applied on a case study to generate an AOPN focused on the Estrogen, Androgen, Thyroid, and Steroidogenesis (EATS) modalities. A search strategy was developed with search terms based on effect parameters in the ECHA/EFSA Guidance Document on Identification of Endocrine Disruptors. Furthermore, manual curation of the data was performed by screening the contents of each pathway in the AOP-Wiki, excluding irrelevant AOPs. Data were downloaded from the Wiki, and a computational workflow was utilized to automatically process, filter, and format the data for visualization. This study presents an approach to structured searches of AOPs in the AOP-Wiki coupled to an automated data-driven workflow for generating AOPNs. In addition, the case study presented here provides a map of the contents of the AOP-Wiki related to the EATS-modalities, and a basis for further research, for example, on integrating mechanistic data from novel methods and exploring mechanism-based approaches to identify endocrine disruptors (EDs). The computational approach is freely available as an R-script, and currently allows for the (re)-generation and filtering of new AOP networks based on data from the AOP-Wiki and a list of relevant AOPs used for filtering.

摘要

不良结局途径(AOPs)总结了对毒理学效应的机制理解,例如,已被视为将来自新数据和方法的数据整合到化学风险评估中的一种有前景的工具。基于AOPs的网络被认为是AOPs的功能实现,因为它们更能代表复杂的生物学过程。与此同时,目前尚无统一的方法来生成AOP网络(AOPNs)。需要用于识别相关AOPs的系统策略,以及从AOP-Wiki中提取和可视化数据的方法。这项工作的目的是开发一种结构化搜索策略,以识别AOP-Wiki中的相关AOPs,以及一种自动化的数据驱动工作流程来生成AOPNs。该方法应用于一个案例研究,以生成一个专注于雌激素、雄激素、甲状腺和类固醇生成(EATS)模式的AOPN。基于欧洲化学品管理局/欧洲食品安全局关于内分泌干扰物识别的指导文件中的效应参数,制定了带有搜索词的搜索策略。此外,通过筛选AOP-Wiki中每条途径的内容,排除不相关的AOPs,对数据进行人工整理。从Wiki下载数据,并利用计算工作流程自动处理、过滤和格式化数据以进行可视化。本研究提出了一种在AOP-Wiki中对AOPs进行结构化搜索的方法,并结合了用于生成AOPNs的自动化数据驱动工作流程。此外,这里展示的案例研究提供了与EATS模式相关的AOP-Wiki内容图谱,以及进一步研究的基础,例如,整合来自新方法的机制数据和探索基于机制的方法来识别内分泌干扰物(EDs)。该计算方法可作为R脚本免费获取,目前允许根据AOP-Wiki的数据和用于过滤的相关AOPs列表(重新)生成和过滤新的AOP网络。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cec8/10203404/2c3ca7ee9fd6/ftox-05-1183824-g001.jpg

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Appl In Vitro Toxicol. 2022 Mar 1;8(1):2-13. doi: 10.1089/aivt.2021.0010. Epub 2022 Mar 17.
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