Adverse Outcome Pathway on Deposition of Energy Leading to Learning and Memory Impairment

The present Adverse Outcome Pathway (AOP) describes the linkage between cognitive decline, including learning and memory impairment, initiated by the Deposition of Energy (DoE) from ionizing radiation in the central nervous system. Ionizing radiation causes an excess of reactive oxygen species (ROS), leading to oxidative stress and increased DNA strand breaks. This damage activates tissue-resident microglia and astrocytes, which release proinflammatory mediators and alter stress response signaling. Chronic neuroinflammation impairs normal synaptic function and leads to abnormal neural remodeling. These events disrupt communication between neurons, ultimately resulting in measurable deficits in cognitive function. While the biological plausibility of this AOP is strong, particularly due to its relevance to space travel and radiotherapy, the overall weight of evidence remains moderate. Quantitative understanding of dose-response relationships between key events is limited, especially in low-dose exposure scenarios, introducing uncertainty in predictions. Nevertheless, this AOP is broadly applicable to both environmental and clinical radiation exposures.