Adverse outcome pathways: Application to enhance mechanistic understanding of neurotoxicity

作者：Anna Bal‐Price, Mary E. Meek · 发表于：Pharmacology & Therapeutics · 年份：2017 · DOI：10.1016/j.pharmthera.2017.05.006 · 被引用次数：115 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Pesticide Exposure and Toxicity、Neuroscience and Neuropharmacology Research

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 limi...