Institut de Radioprotection et de Sûreté Nucléaire, St. Paul Lez Durance, Provence, France.
Department of Health and Exercise Science, Morrison College Family of Health, University of St. Thomas, Saint Paul, Minnesota, USA.
Environ Mol Mutagen. 2024 Oct;65 Suppl 3:57-84. doi: 10.1002/em.22622. Epub 2024 Sep 4.
Understanding radiation-induced non-cancer effects on the central nervous system (CNS) is essential for the risk assessment of medical (e.g., radiotherapy) and occupational (e.g., nuclear workers and astronauts) exposures. Herein, the adverse outcome pathway (AOP) approach was used to consolidate relevant studies in the area of cognitive decline for identification of research gaps, countermeasure development, and for eventual use in risk assessments. AOPs are an analytical construct describing critical events to an adverse outcome (AO) in a simplified form beginning with a molecular initiating event (MIE). An AOP was constructed utilizing mechanistic information to build empirical support for the key event relationships (KERs) between the MIE of deposition of energy to the AO of learning and memory impairment through multiple key events (KEs). The evidence for the AOP was acquired through a documented scoping review of the literature. In this AOP, the MIE is connected to the AO via six KEs: increased oxidative stress, increased deoxyribonucleic acid (DNA) strand breaks, altered stress response signaling, tissue resident cell activation, increased pro-inflammatory mediators, and abnormal neural remodeling that encompasses atypical structural and functional alterations of neural cells and surrounding environment. Deposition of energy directly leads to oxidative stress, increased DNA strand breaks, an increase of pro-inflammatory mediators and tissue resident cell activation. These KEs, which are themselves interconnected, can lead to abnormal neural remodeling impacting learning and memory processes. Identified knowledge gaps include improving quantitative understanding of the AOP across several KERs and additional testing of proposed modulating factors through experimental work. Broadly, it is envisioned that the outcome of these efforts could be extended to other cognitive disorders and complement ongoing work by international radiation governing bodies in their review of the system of radiological protection.
了解放射性对中枢神经系统（CNS）的非致癌影响对于医疗（如放射治疗）和职业（如核工作者和宇航员）暴露风险评估至关重要。在此，采用不良结局途径（AOP）方法，综合认知能力下降领域的相关研究，以确定研究空白、制定对策，并最终用于风险评估。AOP 是一种分析构建，用于以简化形式描述从分子起始事件（MIE）到不良结局（AO）的关键事件。本研究利用机制信息构建了一个 AOP，为能量沉积到学习和记忆障碍这一 AO 的关键事件关系（KER）提供了经验支持，涉及多个关键事件（KE）。该 AOP 的证据是通过对文献进行有文件记录的范围审查获得的。在该 AOP 中，MIE 通过六个 KEs 与 AO 相关联：氧化应激增加、脱氧核糖核酸（DNA）链断裂增加、应激反应信号改变、组织驻留细胞激活、促炎介质增加和异常神经重塑，包括神经细胞及其周围环境的非典型结构和功能改变。能量沉积直接导致氧化应激、DNA 链断裂增加、促炎介质增加和组织驻留细胞激活。这些相互关联的 KEs 可导致异常的神经重塑，从而影响学习和记忆过程。已确定的知识空白包括在多个 KER 中提高对 AOP 的定量理解，并通过实验工作进一步测试拟议的调节因子。总的来说，预计这些努力的结果可以扩展到其他认知障碍，并补充国际辐射监管机构在审查放射保护系统方面的工作。
