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Relationship: 2841


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increase, DNA strand breaks leads to Increase, Neural Remodeling

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Deposition of Energy Leading to Learning and Memory Impairment adjacent Moderate Low Vinita Chauhan (send email) Open for citation & comment

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens Low NCBI
mouse Mus musculus Moderate NCBI
rat Rattus norvegicus Low NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male Moderate
Female Low

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Juvenile Low
Adult Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

DNA single strand breaks (SSBs) and double strand breaks (DSBs) can lead to cell cycle arrest and apoptosis (Madabhushi, Pan and Tsai, 2014; Michaelidesova et al., 2019). In proliferative cells like neural stem/progenitor cells this will reduce neurogenesis within the brain (Alt and Schwer, 2018; Lee and McKinnon, 2007; Michaelidesova et al., 2019). Although the role of DSBs is less well-characterized in mature neurons (Lee and McKinnon, 2007; Thadathil fsylet al., 2019), some evidence suggests that unrepaired DNA strand breaks could also have deleterious effects in these neurons (Wang et al., 2017). Furthermore, there is evidence that DNA strand breaks can induce changes to neural plasticity and synaptic activity through changes in gene expression (Konopka and Atkin, 2022; Thadathil et al., 2019). This can occur via changes in N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptor activity or changes in the expression of early response genes (ERGs) that encode transcription factors controlling processes like neurite outgrowth, synapse development and maturation and the balance between excitatory and inhibitory synapses (Konopka and Atkin, 2022). 

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

The strategy for collating the evidence to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Overall Weight of Evidence: Moderate

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The biological plausibility between DNA strand breaks leading to neural remodeling is supported by literature.  

Neural remodeling due to DNA strand breaks can occur through apoptosis (Abner and McKinnon, 2004; Desai et al., 2022; Madabhushi, Pan and Tsai, 2014; Michaelidesova et al., 2019; Wang et al., 2017; Zhu et al., 2019). Newly post-mitotic neurons with DSBs may undergo checkpoint mediated apoptosis as a mechanism to prevent their incorporation into the nervous system as mature neurons (Alt and Schwer, 2018; Lee and McKinnon, 2007). In response to DSBs, developing neural progenitor cells and a trace number of neural stem cells will undergo cell cycle arrest at critical stages. In the mammalian genome, DNA strand breaks can regulate checkpoint activation through the activation of phosphoinositide 3-kinase (PI3K)-related family of serine/threonine kinases (PIKK), ataxia telangiectasia mutated (ATM) and ATM/RAD3-related (ATR), that can phosphorylate many downstream proteins (Wang et al., 2017). Specifically, DSBs can activate ATM which phosphorylates p53, which can then act on apoptosis factors, p53-upregulated modulator of apoptosis (PUMA), CD95 (Fas/APO1) and apoptotic peptidase activating factor 1 (Apaf1) (Zhu et al., 2019). Activation of this pathway in proliferating cells like neuronal precursors can reduce neurogenesis (Wang et al., 2017; Michaelidesova et al., 2019). 

DNA strand breaks can also lead to changes in synaptic activity, neural plasticity, proliferation, and differentiation. Neurons communicate electrically and chemically through synaptic contacts. Neural plasticity refers to the ability of the nervous system to modify its structure, function or connections in response to stimuli. DNA damage can modulate the activity and expression of glutamate receptors, including NMDA/AMPA, which are involved in synaptic activity, plasticity and neuronal activation in the central nervous system. The changes in receptor activity and expression modulate neuronal gene expression and lead to changes in plasticity (Konopka and Atkin, 2022). Additionally, changes in ERG expression following DNA damage can lead to certain neural remodeling changes, such as neurite outgrowth, synapse development and maturation (Konopka and Atkin, 2022). As well, inhibition of the cell cycle by DNA strand breaks can impair neurogenesis through decreased differentiation and proliferation of neural stem cells (NSCs) (Michaelidesova et al., 2019). 

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

None identified. 

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Modulating factor  


Effects on the KER  




Treatment reduced the expression of γ-H2AX and reduced apoptosis 

Huang et al., 2021 

Lithium chloride 

Reduced the level of γ-H2AX and increased proliferation of neural stem cells. 

Zanni et al., 2015 

Minocycline (an antibiotic shown to reduce radiation-induced memory loss) 

Treatment inhibited the increase in γ-H2AX and p-ATM and reduced apoptosis. 

Zhang et al., 2017 


DNA ligase IV-null mutation 

Mice with this mutation show greatly increased levels of apoptosis compared to wild-type mice due to reduced DNA repair following irradiation. 

Barazzuol et al., 2015 


Hippocampal neurogenesis is more pronounced in younger mice. 

Proliferative potential of neuronal precursors in the hippocampus, determined by Ki-67 immunostaining, was significantly reduced in juvenile mice but not significantly affected in adult mice after irradiation. 

Schmal et al., 2019 

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Some studies suggest that neuron activity can generate DNA DSBs. Specifically, it has been shown that γ-H2AX foci can be formed by the activation of NMDA a nd AMPA glutamate receptors (reviewed by Konopka and Atkin, 2022). Activity induced DSBs in mature neurons subsequently influence gene expression and neuronal activity (Alt and Schwer, 2018). 

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Evidence for this relationship is derived from studies that use human-derived cells and mouse models, with most of the evidence in mice. There is in vivo evidence in male animals. Most evidence is from adult models. 


List of the literature that was cited for this KER description. More help

Abner, C. W. and P. J. McKinnon. (2004), "The DNA double-strand break response in the nervous system", DNA Repair, Vol. 3/8–9, Elsevier, Amsterdam,

Acharya, M. M. et al. (2010), "Consequences of ionizing radiation-induced damage in human neural stem cells", Free Radical Biology and Medicine, Vol. 49/12, Elsevier, Amsterdam,

Alt, F. W. and B. Schwer. (2018), "DNA double-strand breaks as drivers of neural genomic change, function, and disease", DNA Repair, Vol. 71, Elsevier, Amsterdam,

Barazzuol, L., L. Ju, and P. A. Jeggo. (2017), “A coordinated DNA damage response promotes adult quiescent neural stem cell activation”, PLoS biology, 15(5), PLOS, San Francisco, 

Barazzuol, L. et al. (2015), "Endogenous and X-ray-induced DNA double strand breaks sensitively activate apoptosis in adult neural stem cells", Journal of Cell Science, Vol. 128/19, The Company of Biologists, Cambridge,

Desai, R. I. et al. (2022), "Impact of spaceflight stressors on behavior and cognition: A molecular, neurochemical, and neurobiological perspective", Neuroscience & Biobehavioral Reviews, Vol. 138, Elsevier, Amsterdam,

Huang, Y. et al. (2021), "Mesenchymal Stem Cell-Conditioned Medium Protects Hippocampal Neurons From Radiation Damage by Suppressing Oxidative Stress and Apoptosis", Dose-Response, Vol. 19/1, SAGE Publications

Konopka, A. and J. D. Atkin. (2022), "The Role of DNA Damage in Neural Plasticity in Physiology and Neurodegeneration", Frontiers in Cellular Neuroscience, Vol. 16, Frontiers,

Lee, Y. and P. J. McKinnon. (2007), "Responding to DNA double strand breaks in the nervous system", Neuroscience, Vol. 145/4, Elsevier, Amsterdam,

Madabhushi, R., L. Pan and L.-H. Tsai. (2014), "DNA Damage and Its Links to Neurodegeneration", Neuron, Vol. 83/2, Elsevier, Amsterdam,

Michaelidesova, A. et al. (2019), "Effects of Radiation Therapy on Neural Stem Cells", Genes, Vol. 10/9, MDPI, Basel,

Schmal, Z. et al. (2019), "DNA damage accumulation during fractionated low-dose radiation compromises hippocampal neurogenesis", Radiotherapy and Oncology, Vol. 137, Elsevier, Amsterdam,

Thadathil, N. et al. (2019), "DNA double-strand breaks: a potential therapeutic target for neurodegenerative diseases", Chromosome Research, Vol. 27/4, Springer Nature,

Wang, H. et al. (2017), "Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?", Mechanisms of Ageing and Development, Vol. 161, Elsevier, Amsterdam,

Zanni, G. et al. (2015), "Lithium increases proliferation of hippocampal neural stem/progenitor cells and rescues irradiation-induced cell cycle arrest in vitro", Oncotarget, Vol. 6/35,

Zhang, L. et al. (2017), "The inhibitory effect of minocycline on radiation-induced neuronal apoptosis via AMPKα1 signaling-mediated autophagy", Scientific Reports, Vol. 7/1, Springer Nature,

Zhu, L.-S. et al. (2019), "Emerging Perspectives on DNA Double-strand Breaks in Neurodegenerative Diseases", Current Neuropharmacology, Vol. 17/12, Bentham Science Publishers,