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Adverse outcome pathways: Application to enhance mechanistic understanding of neurotoxicity
Pharmacology & Therapeutics ( IF 13.5 ) Pub Date : 2017-05-18 , DOI: 10.1016/j.pharmthera.2017.05.006
Anna Bal-Price , M.E. (Bette) Meek

Recent developments have prompted the transition of empirically based testing of late stage toxicity in animals for a range of different endpoints including neurotoxicity to more efficient and predictive mechanistically based approaches with greater emphasis on measurable key events early in the progression of disease. The adverse outcome pathway (AOP) has been proposed as a simplified organizational construct to contribute to this transition by linking molecular initiating events and earlier (more predictive) key events at lower levels of biological organization to disease outcomes. As such, AOPs are anticipated to facilitate the compilation of information to increase mechanistic understanding of pathophysiological pathways that are responsible for human disease.

In this review, the sequence of key events resulting in adverse outcome (AO) defined as parkinsonian motor impairment and learning and memory deficit in children, triggered by exposure to environmental chemicals has been briefly described using the AOP framework. These AOPs follow convention adopted in an Organization for Economic Cooperation and Development (OECD) AOP development program, publically available, to permit tailored application of AOPs for a range of different purposes.

Due to the complexity of disease pathways, including neurodegenerative disorders, a specific symptom of the disease (e.g. parkinsonian motor deficit) is considered as the AO in a developed AOP. Though the description is necessarily limited by the extent of current knowledge, additional characterization of involved pathways through description of related AOPs interlinked into networks for the same disease has potential to contribute to more holistic and mechanistic understanding of the pathophysiological pathways involved, possibly leading to the mechanism-based reclassification of diseases, thus facilitating more personalized treatment.



中文翻译:

不良结果途径:用于增强对神经毒性的机械理解的应用

最近的发展促使基于经验的动物后期毒性试验在一系列不同的终点(包括神经毒性)向更有效和可预测的基于机械的方法过渡,并更加强调疾病进展早期的可测量关键事件。不良结局途径(AOP)已被提议作为简化的组织结构,通过将较低分子生物学组织水平上的分子起始事件和早期(更具预测性的)关键事件与疾病结局联系起来,为这一转变做出贡献。因此,AOP有望促进信息的汇编,以增强对造成人类疾病的病理生理途径的机械理解。

在这篇综述中,使用AOP框架简要描述了导致不良结局(AO)的关键事件的顺序,这些不良事件被定义为儿童因暴露于环境化学物质而导致的帕金森氏运动障碍和学习与记忆不足。这些AOP遵循经济合作与发展组织(OECD)AOP开发计划中通过的公约,该计划可公开获得,以允许为各种不同目的量身定制AOP的应用。

由于疾病途径(包括神经退行性疾病)的复杂性,在发达的AOP中,该疾病的一种特定症状(例如帕金森氏运动障碍)被认为是AO。尽管描述必然受到当前知识范围的限制,但是通过描述与同一疾病相关的网络互连的相关AOP的描述,可以进一步对所涉及的途径进行表征,从而有可能有助于对所涉及的病理生理学途径进行更全面和更全面的了解,从而可能导致基于机制的疾病重分类,从而有助于更个性化的治疗。

更新日期:2017-05-18
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