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AOP: 483

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

Deposition of Energy Leading to Learning and Memory Impairment

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Deposition of Energy Leading to Learning and Memory Impairment
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.5

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Ahmad Sleiman1, Kathleen Miller2, Danicia Flores3, Jaqueline Kuan3, Kaitlyn Altwasser3, Benjamin Smith3, Hailey Adams4 Tatiana Kozbenko3, Robyn Hocking3, Carole Yauk5, Ruth Wilkins3, Vinita Chauhan3  

(1) Institut de Radioprotection et de Sûreté Nucléaire, St. Paul Lez Durance, Provence, France 

(2) National Institute of Aerospace, Hampton, Virginia, USA 

(3) Consumer and Clinical Radiation Protection Bureau, Environmental and Radiation Health Sciences Directorate, Health Canada, Ottawa, Ontario, Canada 

(4) Radiation Protection Bureau, Environmental and Radiation Health Sciences Directorate, Health Canada, Ottawa, Ontario, Canada

(5) Department of Biology, University of Ottawa, Ottawa, Ontario, Canada

Consultants 

Scott Wood1, Janice Huff2, Christelle-Adam Guillermin3, Nobuyuki Hamada4

(1) NASA Johnson Space Center, Houston, Texas, USA 

(2) NASA Langley Research Center, Hampton, Virginia, USA 

(3) Institut de Radioprotection et de Sûreté Nucléaire, St. Paul Lez Durance, Provence, France 

(4) Biology and Environmental Chemistry Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry (CRIEPI), Tokyo, Japan

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Vinita Chauhan   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Vinita Chauhan

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on July 24, 2024 15:44

Revision dates for related pages

Page Revision Date/Time
Deposition of Energy March 08, 2024 11:49
Oxidative Stress March 08, 2024 12:28
Tissue resident cell activation March 22, 2023 16:03
Increase, Pro-Inflammatory Mediators March 22, 2023 10:19
Increase, Abnormal Neural Remodeling March 10, 2024 16:35
Increase, DNA strand breaks March 08, 2024 12:05
Impairment, Learning and memory June 26, 2023 12:44
Altered Stress Response Signaling July 24, 2024 15:28
Energy Deposition leads to Oxidative Stress March 08, 2024 13:28
Energy Deposition leads to Abnormal Neural Remodeling February 14, 2024 08:32
Energy Deposition leads to Tissue resident cell activation March 21, 2023 13:56
Energy Deposition leads to Impairment, Learning and memory March 21, 2023 15:58
Increase, Pro-Inflammatory Mediators leads to Impairment, Learning and memory March 21, 2023 16:06
Oxidative Stress leads to Altered Stress Response Signaling July 24, 2024 13:15
Oxidative Stress leads to Tissue resident cell activation February 13, 2024 17:01
Tissue resident cell activation leads to Increase, Pro-Inflammatory Mediators February 16, 2024 11:20
Increase, Pro-Inflammatory Mediators leads to Abnormal Neural Remodeling February 16, 2024 11:33
Abnormal Neural Remodeling leads to Impairment, Learning and memory March 21, 2023 15:38
Altered Stress Response Signaling leads to Abnormal Neural Remodeling July 24, 2024 13:44
Increase, DNA strand breaks leads to Abnormal Neural Remodeling March 21, 2023 16:22
Oxidative Stress leads to Increase, DNA strand breaks March 08, 2024 14:44
Energy Deposition leads to Increase, DNA strand breaks March 08, 2024 12:44
Increase, DNA strand breaks leads to Altered Stress Response Signaling July 24, 2024 13:15
Ionizing Radiation May 07, 2019 12:12

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

An adverse outcome pathway (AOP) is described from the molecular initiating event (MIE) of deposition of energy to the adverse outcome (AO) of learning and memory impairment. This AOP uses well-understood mechanistic events that encompass oxidative stress, DNA damage, tissue resident cell activation, altered signaling pathways, neuroinflammation, and their interactions, leading to eventual neural remodeling. The empirical evidence to support this AOP is primarily derived from studies that utilize ionizing radiation stressors relevant to space travel and radiotherapy treatments. Following deposition of energy (MIE, KE#1686), the adjacent key events are oxidative stress (KE#1392), tissue resident cell activation (KE#1492) and increased DNA strand breaks (KE#1635). Uncontrolled radical production within the cell has an adjacent connection with increased DNA strand breaks (KE#1635), altered signaling pathways (KE#2066) and tissue resident cell activation (KE#1492). Tissue resident cell activation has an adjacent connection to increased proinflammatory mediators (KE#1493). Prolonged neuroinflammation and altered signaling pathways have adjacent connections with neural remodeling (KE#2098) and subsequently learning and memory impairment (AO, KE#341). The AOP also includes multiple non-adjacent connections between key events. The overall evidence for this AOP is moderate. Despite multiple knowledge gaps that are present, the evidence demonstrates a high-level of biological plausibility. The quantitative understanding is low as there is high uncertainty in the quantitative predictions between the KEs. This AOP has wide applicability and is particularly relevant to exposures from long-duration space flight and medical exposures using radiation therapy. 

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Understanding the impact of ionizing radiation on non cancer outcomes of the central nervous system (CNS) is essential as there are many possibilities for exposure including from medical procedures and occupational settings (e.g. astronuats). Various studies have reported cognitive deficits after high-doses of radiation from radiotherapy treatments, though there is a reported individual variability in human cohorts (Greene-Schloesser et al., 2012; Katsura et al., 2021; Turnquist et al., 2020). In preclinical animal models, studies suggest that even low-to-moderate doses of ionizing radiation from heavy ions can cause structural and functional impairments to the CNS including reductions in neurogenesis, changes in dendritic properties, activation of glial cells, and neuronal remodeling (Cekanaviciute et al., 2018; Kiffer et al., 2019b). However, how key changes in structural and functional properties of the CNS from ionizing radiation exposure are related to changes in cognitive function have yet to be delineated. Furthermore, preclinical studies also suggest that ionizing radiation may impact two major cognitive processes: learning and memory. Learning is the ability to create new associative or non-associative relationships and memory is the ability to recall sensory, short-term or long-term information (Desai et al., 2022, Kiffer et al., 2019b). Both learning and memory involve multiple brain areas including the hippocampal region, as well as the amygdala, the prefrontal cortex and the basal ganglia (Cucinotta et al., 2014; Desai et al., 2022; NCRP Commentary, 2016). Thus far, direct pathways linking  radiation to key cellular and molecular events leading to an AO of impaired learning and memory have not been established.   This AOP can serve as a starting pathway for expansion to other cognitive disorders and CNS diseases from an MIE of deposition of energy. 

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

The development strategy for this AOP has been described by Kozbenko et al., 2022. In brief, a structured literature search was conducted that included screening and prioritization of the references. Initial searches involved study inclusion through key words relevant to the MIE and AO, followed by focused searches for each of the KEs and KERs. Studies at all levels of biological organization, regardless of the species, life stage, or sex, were considered. References were excluded using a Population, Exposure, Outcome, Endpont (PEOE) statement. Studies were included if they met definitions of a population (human, mouse, rat, etc.), exposure (i.e., radiation), and/or mention of one of the key events (KEs) or outcome (AO) of interest. Studies were excluded if they lacked full text, and/or were not a peer-reviewed manuscript (i.e., thesis/dissertations, presentations, posters or conference abstracts). Non-English studies were included provided the data could be identified within the abstract. Relevant studies were identified in the context of the modified Bradford Hill criteria, which contain biological plausibility, temporal-, dose-, incidence-concordance, and essentiality. 

Pre-screening was completed using SWIFT Review (http://www.sciome.com/swift-review/version 1.43). In SWIFT, software generated tags were created based on study abstracts that helped group references and create lists to aid in prioritizing relevant studies. Reviewers could include or exclude references based on the tags and abstracts.  DistillerSR (Evidence Partners. www.evidencepartners.com/products/distillersr-systematic-reviewsoftware released 12.06.2020 version 2.34.0R) was then used in a three-level screening exercise: Title and Abstract (Level 1), Full-Text (Level 2), and Data Extraction (Level 3). Human screeners used the PEOE statement to assess relevance for inclusion or exclusion. At the data extraction level, studies needed to support elements of  the Bradford Hill criteria, including taxonomic (human, animal) and life-stage (adult, children) applicability. A final screening of all studies was conducted manually to ensure data was relevant to the KERs in the pathway in the context of the Bradford Hill criteria. No risk-of-bias evaluation was undertaken.  

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1686 Deposition of Energy Energy Deposition
KE 1392 Oxidative Stress Oxidative Stress
KE 2244 Altered Stress Response Signaling Altered Stress Response Signaling
KE 1492 Tissue resident cell activation Tissue resident cell activation
KE 2097 Increase, Pro-Inflammatory Mediators Increase, Pro-Inflammatory Mediators
KE 2098 Increase, Abnormal Neural Remodeling Abnormal Neural Remodeling
KE 1635 Increase, DNA strand breaks Increase, DNA strand breaks
AO 341 Impairment, Learning and memory Impairment, Learning and memory

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
All life stages High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI
rabbit Oryctolagus cuniculus Low NCBI
dog Canis lupus familiaris Low NCBI
pigs Sus scrofa Low NCBI
cow Bos taurus Low NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Unspecific High
Male Moderate
Female Low

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Summary of evidence (KE & KER relationships and evidence) 

This AOP was derived from data that investigates the CNS of humans, animals and cellular models following exposure to ionizing radiation. Stressors in the present pathway include a range of doses (low (<0.1 Gy) to high (>1 Gy) doses), dose rates and radiation qualities (low-LET and high-LET) with an emphasis on low-to-moderate (0.1-1 Gy) dose heavy-ion studies relevant to space travel. The goal of this AOP is to model the connectivity of the MIE of deposition of energy through the cellular and biological KEs that lead to the AO of impaired learning and memory. The KEs chosen for this AOP had strong biological plaucibility with available empirical evidence, however, other KEs may be added later to incorporate new mechanisms and AOs into its broader network. The pathway is applicable to  multiple stressors of deposition of energy including radiation exposure from space travel and radiotherapy.  

Biological Plausibility 

The overall biological plausibility in this AOP is high. The KERs in the AOP have either moderate or high evidence for mechanistic relationships between the upstream and downstream KEs. The KEs are well-studied, and an understanding of the structural and functional linkages are well-established.  

This AOP is initiated with deposition of energy. Deposition of energy can damage DNA via direct mechanisms, by which the electrons ionize DNA molecules themselves, or via indirect mechanisms, by which the ionization of water produces hydroxyl radicals that can damage DNA bases causing DNA strand breaks (Nikjoo et al., 2016; Wilkinson et al., 2023) or directly upregulating enzymes involved in reactive oxygen and nitrogen species (RONS) production (i.e., catalase)  (de Jager, Cockrell and Du Plessis, 2017). Both reactive oxygen species (ROS) as well as reactive nitrogen species (RNS) (Ahmadi et al., 2022; Karimi et al., 2017; Slezak et al., 2015; Tahimic & Globus, 2017; Wang et al., 2019a) may be produced after deposition of energy. If RONS cannot be eliminated quickly and efficiently by the cell’s defense system, oxidative stress ensues (Balasubramanian, 2000; Ganea & Harding, 2006; Karimi et al., 2017). Within the brain, oxidative stress can lead to the activation of microglial cells (Fishman et al., 2009; Schnegg et al., 2012; Zhang et al., 2017) and astrocytes (Daverey & Agrawal, 2016; Wang et al., 2017). These cells then release pro-inflammatory mediators and initiate antioxidant defenses (Lee, Cha & Lee, 2021; Simpson & Oliver, 2020). However, if the antioxidant capacity is overwhelmed, chronic inflammation may result. 

Oxidative stress can also lead to altered signaling pathways. Directly, ROS causes oxidation of amino acid residues resulting in conformational changes, protein expansion, and protein degradation. This can cause changes in the activity and level of signaling proteins (Ping et al., 2020; Li et al., 2013). Oxidation of key functional amino acids can also alter the activity of signaling proteins, resulting in downstream alterations in signaling pathways (Ping et al., 2020; Schmidt-Ullrich et al., 2000; Valerie et al., 2007; Lehtinen & Bonni, 2006; Ramalingam & Kim, 2012). DNA strand breaks from oxidative damage can activate DNA damage response signaling and modify the expression of other signaling proteins (Ping et al., 2020; Nagane et al., 2021; Schmidt-Ullrich et al., 2000; Valerie et al., 2007). 

Both increased pro-inflammatory mediators and altered signaling pathways can lead to neural remodeling. Various pro-inflammatory cytokines can affect neural remodeling, the most common being IL-1β, TNF-α, IL-6 and IFN-γ. During an inflammatory response, these cytokines act on different receptors to initiate several signaling pathways to induce neuronal degeneration, apoptosis or to propagate further pro-inflammatory responses (Mousa & Bakhiet, 2013; Prieto & Cotman, 2018). These signaling pathways include, but are not limited to PI3K/Akt pathways, MAPK pathways, senescence signaling, and apoptosis pathways. The PI3K/Akt and MAPK pathways are involved in many processes in neurons, including cell survival, morphology, proliferation, differentiation, and synaptic activity (Davis and Laroche, 2006; Falcicchia et al., 2020; Long et al., 2021; Mazzucchelli and Brambilla, 2000; Mielke and Herdegen, 2000; Nebreda and Porras, 2000; Rai et al., 2019; Rodgers and Theibert, 2002; Sherrin, Blank, and Todorovic, 2011). The apoptosis pathway influences cell number, while senescence signaling can influence the regenerative potential of the cell and therefore, neurogenesis (Betlazar et al., 2016; McHugh and Gil, 2018; Mielke and Herdegen, 2000). Disruptions to components of these pathways will lead to neuronal remodeling, which includes alterations in both morphological properties and functional properties of the neurons (Betlazar et al., 2016; Davis and Laroche, 2006; Mazzucchelli and Brambilla, 2000; Nebreda and Porras, 2000). However, the biological changes that follow perturbation of these pathways is not understood in every context and cell type, making the biological plausibility for this relationship moderate (Nebreda and Porras, 2000). Decreased morphological properties of neurons, including reductions in dendritic complexities and spine densities, as well as altered functional properties of neurons including altered synaptic signaling and neurogenesis, has been associated with learning and memory impairment (Bálentová & Adamkov, 2020; Hladik & Tapio, 2016; Monje & Palmer, 2003; Romanella et al., 2020; Tomé et al., 2015). 

Empirical Support (Temporal, Dose, and Incidence Concordance) 

This AOP demonstrates moderate empirical evidence to support the modified Bradford Hill criteria. Overall, many studies demonstrated that upstream KEs occurred at lower or the same doses and at earlier or the same times as downstream KEs. There were some inconsistencies where the KEs were only measured at one dose or time. The evidence collected was gathered from various studies using in vitro and in vivo rat, mice, rabbit, squirrel, bovine and human models. Various stressors were applied, including UV, UVB, UVA, gamma ray, X-ray, protons, alpha particle, neutron, and heavy ion irradiation. 

Regarding time concordance, deposition of energy occurs immediately following irradiation, and downstream events will always occur at a later time-point. DNA damage occurs within nanoseconds of deposition of energy with DNA strand breaks measured from seconds to minutes later and altered signaling measured minutes to days later (Acharya et al., 2010; Antonelli et al., 2015; Mosconi et al., 2011; Rogakou et al., 1999; Rothkamm and Lo, 2003; Sabirzhanov et al., 2020; Zhang et al., 2017). Rapid increases in ROS (Limoli et al., 2004; Giedzinski et al., 2005; Suman et al., 2013) and activation of microglia and astrocytes have been observed within hours of irradiation and can persist for 12 months (Kyrkanides et al., 1999; Hwang et al., 2006; Suman et al., 2013). For tissue resident cell activation and increase in pro-inflammatory mediators, studies generally show that these events occur at a similar time frame (Parihar et al., 2018; Liu et al., 2010; Dong et al., 2015; Lee et al., 2010; Zhou et al., 2017). The alteration of signaling pathways is a molecular-level KE like oxidative stress, and both can occur concurrently (Xu et al., 2019), although increased ROS levels can be initiated significantly before altered signaling pathways (Suman et al., 2013). Neural remodeling has been observed at various time points from hours to months after exposure to a stressor, and its upstream KEs (altered signaling and increased pro-inflammatory mediators) generally appear earlier (Kanzawa et al., 2006; Limoli et al., 2004; Pius-Sadowska et al., 2016) or at similar times, respectively (Zonis et al., 2015; Wong et al., 2004, Green et al., 2012; Ryan et al., 2013; Vallieres et al., 2002). In response to irradiation, impaired learning and memory is typically observed at similar time-points of neural remodeling due to the timing of measurements (Raber et al., 2004; Parihar et al., 2016; Madsen et al., 2003; Winocur et al., 2006; Rola et al., 2004).  

Regarding dose concordance, multiple studies also demonstrate that the upstream KEs occur at lower or the same doses as downstream KEs as energy is deposited immediately at any dose of radiation. Some studies report a linear-dose-dependent increases in DNA strand breaks for a large range of doses (Antonelli et al., 2015; Hamada et al, 2006; Rübe et al., 2008). In addition, neural precursor cells irradiated with protons at 1, 2, 5 and 10 Gy showed a dose-dependent increase in ROS levels (Giedzinski et al., 2005). In another study, activation of microglia and astrocytes were seen at doses as low as 5 cGy that persisted to 30 cGy (Parihar et al., 2018). However, dose concordance is not consistently observed across studies, which can be attributed to differences in experimental design. Some studies also only measured the key events at one dose, which presented further inconsistencies.  

Few studies showed incidence concordance where the upstream KE demonstrated a greater change than the downstream KE following a stressor. Not all KERs displayed an incident-concordant relationship, but for those that did, only a small proportion of the empirical evidence supported this relationship. For example, mice exposed to 2 Gy of gamma irradiation showed increases of pro-apoptotic markers p53 and BAX by 8.4- and 2.3-fold, respectively. A 0.6-fold decrease in Bcl-2 (anti-apoptotic marker) was also observed, and gamma rays cause a decrease in cortical thickness by 0.9-fold (Suman et al., 2013).

Uncertainties, Inconsistencies, and Data Gaps 

There are a few inconsistencies in this AOP. Some studies show sex-specific changes in the KEs. For example, two studies reported that tissue resident cell activation was not affected in female mice after 0.3 and 0.5 Gy of radiation (Krukowski et al., 2018a; Parihar et al., 2020) while a separate study showed that only female mice had activated cells after 2 Gy (Raber et al., 2019). Another study reported a greater radiation-induced reduction in neurogenesis in male mice compared with female mice (Kalm et al., 2013). More research is necessary to identify if these results are sex-specific or due to other modulating factors.  

There have been some inconsistencies reported in the KER Deposition of Energy (KE#1686) to Increase DNA Strand Breaks (KE#1635). For example, dose-rates and radiation quality may influence dose-response relationships (Brooks et al., 2016, Sutherland et al., 2000; Nikjoo et al., 2001; Jorge et al., 2012). More research is necessary to understand the impact low-doses of ionizing radiation exposure on DNA damage as some studies report low-dose exposures may invoke protection against spontaneous genomic damage (as reviewed by ICRP (2007) and UNSCEAR (2008)).  

Anatomical location of change in the KEs may impact its response. For example, in response to ionizing radiation, changes occurred in hippocampal dendritic spines CA1 subregion of hippocampus but not in the dorsal dentate gyrus (Kiffer et al., 2019a).  

Changes in KEs and the AO may be dose and stressor specific when assessed using animal models. For example, cue feared conditioning, a measure of learning and memory had different responses in mice at 0.2 Gy vs. 1 Gy of 28Si exposure (Whoolery et al., 2017). Also in mice, object memory was impaired after 0.1 or 0.25 Gy 16O exposure and social novelty learning was impaired after 0.25 Gy 16O exposure, but neither dose impaired short-term spatial memory (Kiffer et al., 2019a). 

Changes in signaling pathways may provide inconsistent outcomes in neural remodeling.  For example, the p38 pathway is involved in many, often opposing, biological processes (Nebreda and Porras, 2000). Furthermore, the MAPK pathways can exhibit varied responses after exposure to oxidative stress (Azimzadeh et al., 2015).  

Many studies do not report direct measures of oxidative stress. As free radicals are quickly scavenged, the quantitative understanding of this relationship can be inconsistent, due to varied response of antioxidant enzymes across experimental conditions and time measurements. This has led to some inconsistencies within the KERs. For example, in contrast to other studies demonstrating an increase in oxidative stress following deposition of energy, neutron radiation decreased malondialdehyde, a product of oxidative stress (Chen et al., 2021).  

Finally, many of the KERs do not include studies in humans. More research could be done to observe these relationships in human models. 

There were multiple challenges present in the development of this AOP which identified gaps in the data. The majority of the evidence for this AOP is extracted from preclinical animal and cellular models. Therefore, the low availability of human studies presents a challenge as translation of the animal and cellular models to humans is difficult due to differences in physiology, methods and measurements. In addition, although both age and sex are listed as modulating factors, there is more research necessary to elucidate the interaction between age and sex on the KEs, particularly how these factors may modulate the causal connectivity of the relationships and the AO. Direct comparisons between studies were also difficult due to differences in model, radiation quality, dose, dose rate and endpoint which led to some inconsistencies. Many studies reported limited dose ranges or time-points and often measured a single KE, limiting evidence for direct KERs.  The current AOP has low quantitative evidence supporting the KERs, however, this AOP can be expanded with experiments that further exemplify the level of dose- and time- concordance across multiple endpoints.  This will improve the quantitative understanding of the relationships which can then support the development of risk models and tools for mitigating risk. 

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

 This AOP is relevant to vertebrates, such as humans, mice, rats. The taxonomic evidence supporting the AOP comes from the use of human (Homo sapiens), human-derived cell line, beagle dog (Canis lupus familiaris), rat (Rattus orvegicus), and mouse (Mus musculus) studies. Across all species, most available data was derived from adult and adolescent models with a moderate to high level of evidence compared to less available data from preadolescent models. Many of the KEs demonstrated moderate to high evidence for males and low evidence for females. In multiple KEs, sex was unspecified. 

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Overall, the KEs in this AOP demonstrate moderate essentiality. Essentiality is demonstrated when upstream KEs are blocked or inhibited eliciting a change in the downstream KE.  

Essentiality of the Deposition of Energy (MIE, KE#1686) 

  • Deposition of energy is difficult to test for essentiality as deposition of energy is a physical stressor and cannot be blocked/decreased using chemicals. Since deposited energy initiates events immediately, the removal of deposited energy, a physical stressor, also supports the  essentiality of the key event. Studies that do not deposit energy are observed to have no downstream effects.   

Essentiality of Oxidative Stress (KE#1392) 

  • The effect of antioxidants on altered signaling pathways (KE#2066) 

  • Antioxidants including Melandrii Herba extract, N-acetyl-L-cysteine (NAC), gallocatechin gallate/epigallocatechin-3-gallate, Cornus officinalis (CC) and fermented CC (FCC), L-165041, fucoxanthin, and edaravone were shown to decrease phosphorylation of MAPKs such as ERK1/2, JNK1/2 and p38 after exposure to radiation, H2O2 or lipopolysaccharide (LPS) (Lee et al., 2017; Deng et al., 2012; Park et al., 2021; Tian et al., 2020; Schnegg et al., 2012; Zhao et al., 2017; Zhao et al., 2013; El-Missiry et al., 2018).  

  • The effects of antioxidants on tissue resident cell activation (KE#1492) 

  • Antioxidants including Kukoamine A (KuA) and curcumin were found to reduce levels of microglia and astrocyte activation (Zhang et al. 2017; Daverey & Agrawal, 2016; Wang et al., 2017). 

  • The effect of knocking out a ROS-producing enzyme 

  • A knockout model of mitochondrial superoxide dismutase 2 (SOD2) resulted in an increase in reactivity of microglial cells (Fishman et. al 2009). 

Essentiality of Increase, DNA Strand Breaks (KE#1635)  

  • The effects of blocking DNA strand breaks on altered signaling (KE#2066) 

  • Treatment with mesenchymal stem cell-conditioned medium (MSC-CM) reduced γ-H2AX, decreased the levels of p53, Bax, cleaved caspase 3 and increased the levels of Bcl-2 in HT22 cells irradiated with 10 Gy of X-rays (Huang et al., 2021). 

  • The inhibition of microRNA (miR)-711 decreased levels of DNA damage markers, p-ATM, p-ATR and γ-H2AX, and decreased signaling molecules including p-p53, p21 and cleaved caspase 3 (Sabirzhanov et al., 2020). 

  • The effects of blocking DNA strand breaks on neural remodeling (KE#2098) 

  • Treatment of HT22 hippocampal neuronal cells with minocycline inhibited the expression of γ-H2AX and the p-ATM/ATM ratio as well as reduced apoptosis following X-ray exposure (Zhang et al., 2017). Similarly, MSC-CM reduced the expression of γ-H2AX and reduced apoptosis, reversing the changes induced by X-ray radiation (Huang et al., 2021). 

  • Lithium chloride was also shown to reduce γ-H2AX levels and increase proliferation in neural stem cells irradiated with 60Co gamma rays (Zanni et al., 2015).  

Essentiality of Altered Signaling Pathways (KE#2066)  

  • The effects of modulating cell signaling on neural remodeling (KE#2098) 

  • Knockout models of key molecules in the MAPK pathways and apoptotic pathway reduced apoptotic activity and restored neuron numbers induced by simulated ischemic stroke or radiation (Tian et al., 2020; Chow, Li and Wong, 2000; Limoli et al., 2004). 

  • Inhibition of key signaling molecules involved in the MAPK pathways and the PI3K/Akt pathway restored neural stem cell numbers, neuronal differentiation, and neuronal structure induced by radiation (Eom et al., 2016; Kanzawa et al., 2006; Zhang et al. 2018) 

Essentiality of Tissue Resident Cell Activation (KE#1492)  

  • The effects of modulating cell activation on pro-inflammatory mediators (KE#1493) 

  • Drugs including tamoxifen, retinoic acid, N-acetyl-L-cysteine (NAC), SP 600125 (SP), a specific c-jun kinase inhibitor, and NS-398, a microglial activator attenuated the activation of tissue-resident cells and consequently reduced the levels of pro-inflammatory mediators (Liu et al., 2010; van Neerven et al., 2010; Komatsu et al., 2017; Ramanan, 2008; Kyrkanides et al., 2002). 

Essentiality of Pro-Inflammatory Mediators (KE#1493)  

  • The effects of modulating pro-inflammatory mediators on neural remodeling (KE#2098) 

  • Treatments including MW-151, a selective inhibitor of pro-inflammatory cytokine production, KuA, and histamine restored neurogenic signaling, hippocampal apoptosis, and neuronal complexity (Jenrow et al., 2013; Zhang et al., 2017; Saraiva et al., 2019). 

  • Multiple studies use cytokine receptor antagonists or knock-out key receptors to block the effects of IL-1β, TNF-α, and CCL2, which preserves neuron survival (Green et al., 2012; Ryan et al., 2013; Wu et al., 2012; Chen and Palmer, 2013). Complement component 3 (C3) knockout models also caused increased synaptic number, reduced neuron loss and ameliorated synaptic morphology impairment (Shi et al., 2017). 

  • The effects of modulating pro-inflammatory mediators on learning and memory impairment (AO, KE#341) 

  • Anti-inflammatory drugs or hormones including MW-151, a selective inhibitor of pro-inflammatory cytokine production, lidocaine, an anesthetic with anti-inflammatory properties, ethyl-eicosapentaenoate (E-EPA) and 1-[(4-nitrophenyl)sulfonyl]-4-phenylpiperazine (NSPP), both of which are anti-inflammatory drugs and α-Melanocyte stimulating hormone (α-MSH), which antagonizes the effects of pro-inflammatory cytokines, have rescued the impairments seen in learning and memory (Bhat et al., 2020; Gonzalez et al., 2009; Jenrow et al., 2013; Taepavarapruk & Song, 2010; Tan et al., 2014). 

Essentiality of Neural Remodeling (KE#2098) 

No identified studies describe essentiality of neural remodeling as it cannot be blocked / decreased using chemicals.  

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

1. Support for Biological Plausibility of KERs 

Defining Question 

High (Strong) 

Moderate 

Low (Weak) 

Is there a mechanistic relationship between KEup and KEdown consistent with established biological knowledge? 

Extensive understanding of the KER based on extensive previous documentation and broad acceptance; Established mechanistic basis 

KER is plausible based on analogy to accepted biological relationships, but scientific understanding is not completely established 

There is empirical support for statistical association between KEs, but the structural or functional relationship between them is not understood 

Deposition of Energy (MIE, KE#1686) → Oxidative Stress (KE#1392) 

High 

There is high evidence surrounding the biological plausibility of deposition of energy leading to increased oxidative stress. When energy reaches a cell, it reacts with water and organic materials to produce ROS. Oxidative stress occurs when antioxidant systems cannot eliminate ROS.  

Deposition of Energy (MIE, KE#1686) → Tissue Resident Cell Activation (KE#1492) 

High 

There is high evidence surrounding biological plausibility of deposition of energy leading to tissue resident cell activation. It is well understood that deposition of radiation energy leads to a recruitment of immune cells within the local tissue which can induce an immune and inflammatory response, characterized by the recruitment and activation of local macrophages in the brain. 

Oxidative Stress (KE#1392) → Increase, DNA Strand Breaks (KE#1635) 

High 

There is high evidence surrounding biological plausibility of oxidative stress leading to DNA strand breaks. Oxidative stress can induce DNA damage by oxidizing or deleting DNA bases leading to strand breaks.  

Increase, DNA Strand Breaks (KE#1635) → Altered Signaling Pathways (KE#2066) 

High 

There is high evidence surrounding biological plausibility of increased DNA strand breaks to altered signaling pathways.  DNA strand breaks induce DNA damage responses which result in the induction of various signaling pathways.  

Oxidative Stress (KE#1392) → Tissue Resident Cell Activation (KE#1492) 

Moderate 

There is moderate evidence surrounding biological plausibility of increased oxidative stress leading to tissue resident cell activation. Increases in oxidative stress elicits activation of microglial cells and astrocytes in the brain. Activated microglia and astrocytes release pro-inflammatory mediators and promote antioxidant defenses. Feedforward and feedback loops of RONS and inflammatory pathways make the direct link between oxidative stress and microglial cell or astrocyte activation difficult to discern. 

Oxidative Stress (KE#1392) → Altered Signaling Pathways (KE#2066) 

High 

There is high evidence surrounding the biological plausibility of increased oxidative stress to altered signaling pathways. Oxidative stress can lead to altered signaling pathways both directly and indirectly. Directly, oxidative stress conditions can lead to oxidation of amino acid residues. This causes conformational changes, protein expansion, and protein degradation, leading to changes in the activity and level of signaling proteins that result in downstream alterations in signaling pathways. Indirectly, oxidative stress can damage DNA causing changes in the expression of signaling proteins as well as the activation of DNA damage response signaling.  

Altered Signaling Pathways  (KE#2066) → Increase, Neural Remodeling (KE#2098) 

Moderate 

There is moderate evidence surrounding biological plausibility of altered signaling pathways to neural remodeling. Neural remodeling is controlled by signaling pathways in the brain, including PI3K/Akt pathway, MAPK pathways, senescence pathways, and apoptosis pathways. The PI3K/Akt and MAPK pathways are involved in many processes in neurons, including cell survival, morphology, proliferation, differentiation, and synaptic activity.  The apoptosis pathway influences cell numbers, while the senescence pathway can influence neurogenesis. Disruptions to components of these pathways will lead to neural remodeling in a relationship that is structurally well-understood.  However, the biological changes that follow perturbation of these pathways is not understood in every context and cell type.  

Tissue Resident Cell Activation (KE#1492) → Increase, Pro-inflammatory Mediators (KE#2097)  

High 

There is high evidence surrounding biological plausibility of tissue resident activation to increase in pro-inflammatory mediators. In the brain, activated astrocytes and microglia undergo gliosis and proliferate, releasing pro-inflammatory mediators and production of cytokines. This response is normal after exposure to pathogens, but prolonged activation can prolong the inflammatory response. Cytokines and chemokines can also increase the permeability of the blood-brain barrier, further increasing pro-inflammatory mediator levels.   

Increase, Pro-inflammatory Mediators (KE#2097) → Increase, Neural Remodeling (KE#2098) 

Moderate 

There is moderate evidence surrounding the biological plausibility of increased pro-inflammatory mediators to neural remodeling. There are various pro-inflammatory cytokines that can affect neuronal integrity an inflammatory response and these cytokines act on different receptors to initiate several signaling pathways to induce neuronal degeneration, apoptosis or to propagate pro-inflammatory responses. However, the exact mechanistic relationship remains to be elucidated due to the complexity of cytokine cascading events. 

Increase, Neural Remodeling (KE#2098) → Impairment, Learning and Memory (AO, KE#341)   

Moderate 

There is moderate evidence surrounding biological plausibility of neural remodeling leading to impaired learning and memory. Evidence of neural remodeling, such as reductions in spine density, reduced adult neurogenesis and impaired neuronal networks are associated with cognitive impairments, as evident from studies in multiple different species.  

Deposition of Energy (MIE, KE# 1686) →  Increase, Neural Remodeling (KE#2098) 

Moderate 

There is moderate evidence surrounding biological plausibility of deposition of energy to neural remodeling. Irradiation induces oxidative stress and neuroinflammation, which alter neuronal integrity. Many reviews examine the radiation-induced neuronal damage and identify correlation with oxidative stress and neuroinflammatory mechanisms.  

Deposition of Energy (MIE, KE#1686) → Impairment, Learning and Memory (AO, KE#341)   

High 

There is high evidence surrounding biological plausibility of deposition of energy to impaired learning and memory. Energy deposition in the form of ionizing radiation can result in behavioural changes and impairments in learning and memory. Under normal conditions, diminished cognitive functions is influenced by aging or can occur if there is a predisposition to neurodegenerative diseases such as Alzheimer’s, however, exposure to ionizing radiation may accelerate risk for age-related cognitive decline. 

Deposition of Energy (MIE, KE#1686) → Increase, DNA Strand Breaks (KE#1635) 

High 

There is high evidence surrounding biological plausibility of deposition of energy to DNA strand breaks. Direct DNA damage can occur after deposition of energy by direct oxidation of the DNA. Indirect DNA damage from deposition of energy can also occur via generation of ROS that can subsequently oxidize and damage DNA.  

Increase, DNA Strand Breaks (KE#1635) → Increase, Neural Remodeling (KE#2098) 

Moderate 

There is moderate evidence surrounding biological plausibility of increased DNA strand breaks to increase, neural remodeling. DNA strand breaks may initiate apoptotic signaling and impact synaptic activity, neural plasticity, differentiation, and proliferation.   

Pro-inflammatory Mediators (KE#2097) → Impairment, Learning and Memory (AO, KE#341)   

Moderate 

There is moderate support for the biological plausibility of the key event relationship between pro-inflammatory mediators to impaired learning and memory. In a neuroinflammatory response, pro-inflammatory mediators including cytokines induce physiological and/or structural changes within the brain that can ultimately lead to impaired learning and memory. The exact mechanistic relationship is still unclear due to the complexity of cytokine cascading events. 

Review of the Empirical support for each KER 

Defining Question 

High (Strong) 

Moderate 

Low (Weak) 

Does KEupstream occur at lower doses and earlier time points than KEdownstream; is the incidence or frequency of KEupstream greater than that for KEdownstream for the same dose of tested stressor?    

There is a dependent change in both events following exposure to a wide range of specific stressors (extensive evidence for temporal, dose-response and incidence concordance) and no or few data gaps or conflicting data. 

There is demonstrated dependent change in both events following exposure to a small number of specific stressors and some evidence inconsistent with the expected pattern that can be explained by factors such as experimental design, technical considerations, differences among laboratories, etc 

There are limited or no studies reporting dependent change in both events following exposure to a specific stressor (i.e., endpoints never measured in the same study or not at all), and/or lacking evidence of temporal or dose-response concordance, or identification of significant inconsistencies in empirical support across taxa and species that don’t align with the expected pattern for the hypothesised AOP 

Deposition of Energy (MIE, KE#1686) → Oxidative Stress (KE#1392) 

High 

 Ample evidence from in vitro and in vivo rat, mice, rabbit, squirrel, bovine and human models support time and dose response effects related to deposition of energy from various ionizing radiation sources leading to an increase in oxidative stress. 

Deposition of Energy (MIE, KE#1686) → Tissue Resident Cell Activation (KE#1492) 

Moderate 

 With increasing dose of ionizing radiation, there are increasing amounts of resident tissue activation in both astrocytes and microglial cells. Multiple studies show dose-response and time-response effects with both high and low dose studies, as well as time ranges from hours to months, though additional studies at low-doses would improve empirical support.  

Oxidative Stress (KE#1392) → Increase, DNA Strand Breaks (KE#1635) 

Moderate 

Empirical evidence from in vivo and in vitro studies demonstrates increased DNA strand breaks from oxidative stress. Multiple studies show dose-response effects, though time response effects are difficult to monitor for both KEs.  

Increase, DNA Strand Breaks (KE#1635) → Altered Signaling Pathways (KE#2066) 

Moderate 

A few studies demonstrate dose-concordance, and multiple studies demonstrate time-concordance for this relationship. DNA strand breaks were observed prior to altered signaling pathways.  

Oxidative Stress (KE#1392) → Tissue Resident Cell Activation (KE#1492) 

 Moderate 

 The literature demonstrates that an increase in the level of stressor related to oxidative stress results in an increase in cellular activation of microglial cells or astrocytes and this relationship is consistent between studies. However, dose and time concordance are unclear as there is limited data that describes oxidative stress occurring at lower doses or before tissue resident cell activation.  

Oxidative Stress (KE#1392) → Altered Signaling Pathways (KE#2066) 

Moderate 

 Many studies demonstrate dose-concordance, and few demonstrate time-concordance for this relationship. Oxidative stress was often observed at lower, or the same doses as altered signaling and sometimes also at earlier times as altered signaling. However, only a few specific stressors are used in this KER and inconsistencies are present, likely due to different experimental designs.  

Altered Signaling Pathways (KE#2066)  Increase, Neural Remodeling (KE#2098) 

 Moderate 

 Many studies demonstrate dose-concordance in multiple signaling pathways. Studies have also shown that signaling pathways are altered before neural remodeling is observed. However, inconsistent changes in signaling pathways may be due to the context-dependence of signaling pathways as they can have different biological processes.  

Tissue Resident Cell Activation (KE#1492) → Increase, Pro-inflammatory Mediators (KE#2097)  

Moderate 

 Studies consistently observed changes in astrocyte and microglial activation at lower or the same dose as increased pro-inflammatory mediators and many studies also found changes in astrocyte and microglial activation earlier or at the same time as increased pro-inflammatory mediators. However, inconsistencies could be due to differences in experimental conditions.  

Increase, Pro-inflammatory Mediators (KE#2097) → Increase, Neural Remodeling (KE#2098) 

Moderate 

 There are multiple studies that show time-concordance, though studies on dose-concordance are lacking. Studies suggest that pro-inflammatory mediators are increased before neural remodeling occurs, reporting changes as early as 3 hours and persisting as long as 3 months. However, additional studies describing dose-concordance would improve empirical support.  

Increase, Neural Remodeling (KE#2098) → Impairment, Learning and Memory (AO, KE#341)   

Moderate 

 Multiple studies suggest dose- and time-response effects of deposited energy leading to neural remodeling and impaired learning and memory. However, additional studies at low doses would improve empirical support. Also, discrepancies in the data may be due to experimental set up and type of exposure from the stressor.  

Deposition of Energy (MIE, KE#1686) →  Increase, Neural Remodeling (KE#2098) 

Moderate 

 Multiple studies suggest dose- and time-response effects of deposition of energy to neuronal remodeling. Studies report changes at very low doses. However, responses may be dependent on exposure type. Also, additional studies describing time-concordance would improve empirical support.  

Deposition of Energy (MIE, KE#1686) → Impairment, Learning and Memory (AO, KE#341)   

Moderate 

 Various studies show that ionizing radiation can lead to impairments in learning and memory in a dose and time dependent manner. Although the impairment to learning and memory is well-studied across various doses and over multiple time points, studies often do not show impaired learning and memory with every cognitive test used, contributing to inconsistency in the relationship. 

Deposition of Energy (MIE, KE#1686) → Increase, DNA Strand Breaks (KE#1635) 

High 

There is ample empirical evidence demonstrating the relationship between deposition of energy and increase, DNA strand breaks.  Multiple studies in various models show both dose-concordance and time-concordance.  

Increase, DNA Strand Breaks (KE#1635) → Increase, Neural Remodeling (KE#2098) 

Moderate 

Multiple studies demonstrate that increased DNA strand breaks lead to increased neural remodeling. However, additional studies describing both dose-concordance and time-concordance would improve empirical support.  

Increase, Pro-inflammatory Mediators (KE#2097) → Impairment, Learning and Memory (AO, KE#341)   

Moderate 

 Evidence shows that pro-inflammatory mediators increase at lower or the same stressor doses than impaired learning. Also, pro-inflammatory mediators increase before impaired learning and memory is observed. Significant inconsistencies in empirical support across taxa and species that do not align with the expected pattern have not been identified. 

Support for Essentiality of KEs 

Defining Question 

High (Strong) 

Moderate 

Low (Weak) 

Are downstream KEs and/or the AO prevented if an upstream KE is blocked? 

Direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important KEs 

Indirect evidence that sufficient modification of an expected modulating factor attenuates or augments a KE 

No or contradictory experimental evidence of the essentiality of any of the KEs 

MIE, KE#1686: Deposition of energy 

Moderate 

Deposition of energy is difficult to test for essentiality as deposition of energy is a physical stressor and cannot be blocked/decreased using chemicals. In the absence of energy deposition or presence of shielding as demonstrated there should be no alterations to the relevant downstream KE.   

KE#1392: Oxidative stress 

Moderate 

Treatments with antioxidants, which reduce oxidative stress, attenuate downstream microglial activation and DNA strand breaks. 

KE#1635: Increase, DNA Strand Breaks 

Moderate 

Prevention of DNA strand breaks, for example treatment with mesenchymal stem cell-conditioned medium or minocycline, has restored altered signaling and neural remodeling.  

KE#2066: Altered Signaling Pathways 

Moderate 

Knockout models or inhibition of key signaling molecules, have all been shown to influence the effects of signaling pathways on neural remodeling through the attenuation of stressor-induced changes in neuronal morphology and growth. The KE has also been shown to be modulated by sex and exercise. 

KE#1492: Tissue Resident Cell Activation 

Moderate 

For example, the attenuation of the activation of tissue-resident cells and consequent reduction in pro-inflammatory mediators has been reported using multiple drugs.  

KE#2097: Increase, Pro-inflammatory Mediators 

Moderate 

Treatments with anti-inflammatory drugs, antioxidants or hormones have influenced the effects of pro-inflammatory mediators and improved neuronal structure and function. Anti-inflammatory drugs have also influenced the effects of pro-inflammatory mediators and rescued the impairments seen in learning and memory.  

KE#2098: Neural Remodeling 

Moderate 

No identified studies describe essentiality of neural remodeling as it cannot be blocked / decreased using chemicals.   

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Multiple factors can modulate this AOP, most of which are listed in the table below. Other modulating factors that influence the AOP are knockout models or receptor antagonists (Tian et al., 2020; Chow, Li and Wong, 2000; Limoli et al., 2004; Eom et al., 2016; Kanzawa et al., 2006; Zhang et al. 2018; Green et al., 2012; Ryan et al., 2013; Wu et al., 2012; Chen and Palmer, 2013; Shi et al., 2017). 

Modulating Factor 

MF details 

Effects on the KER 

References 

Antioxidants 

Catalase, glutathione peroxidase, superoxide dismutase, peroxiredoxins, vitamin E, C, carotene, lutein, zeaxanthin, selenium, zinc, alpha-lipoic acid, melatonin, gingko biloba leaf, fermented gingo biloba leaf, Nigella sativa oil, thymoquinone, ferulic acid, Kukoamine A, curcumin, high antioxidant diet, α-tocopherol, α-lipoic acid 

Adding or withholding antioxidants will decrease or increase the level of oxidative stress respectively 

Zigman et al., 1995; Belkacémi et al., 2001; Chitchumroonchokchai et al., 2004; Fatma et al., 2005; Jiang et al., 2006; Fletcher, 2010; Karimi et al., 2017; El-Mesallamy et al., 2018; Hua et al., 2019; Kang et al., 2020; Yang et al., 2020; Manda et al., 2008; Limoli et al., 2007; Manda et al., 2007a; Ismail et al., 2016; Demir et al., 2019; Chen et al., 2021, Zhang et al., 2017, Wang et al., 2017; Daverey & Agrawal, 2016, Ávila-Escalante et al., 2020, Hladik & Tapio, 2016,  Manda et al., 2007b 

Drugs 

Modulators of tissue resident cell activation (ex. tamoxifen, retinoic acid, NAC, SP 600125, NS-398), pro-inflammatory mediators (ex. MW-151, lidocaine, E-EPA, NSPP, α-MSH), and drugs that inhibit DNA damage (lithium chloride, minocycline).  

Several drugs have attenuated the activation of tissue-resident cells and reduced the levels of pro-inflammatory mediators to consequently ameliorate the downstream KE. Drugs that inhibit DNA damage reduced the expression of γ-H2AX and reduced cellular apoptosis. 

Liu et al., 2010; van Neerven et al., 2010; Komatsu et al., 2017; Ramanan, 2008; Kyrkanides et al., 2002; Bhat et al., 2020; Gonzalez et al., 2009; Jenrow et al., 2013; Taepavarapruk & Song, 2010; Tan et al., 2014; Zhang et al., 2017; Zanni et al., 2015 

Age 

Age of organism  

Aging can impact multiple KEs. For example, older organisms have lower levels of antioxidants and an increased likelihood of oxidative stress. Older age is also associated with greater tissue resident cell activation and aging tissue becomes more sensitive to immune signals and increases inflammation. Age is associated with reduced hippocampal neurogenesis and greater radiation-related decrements in learning and memory.  

Liguori et al., 2018; Hanslik, Marino & Ulland, 2021; Casciati et al., 2016; Patterson, 2015; Barrientos et al., 2009; Barrientos et al., 2012. 

Sex 

Sex of organism 

The sex of the organism studied can impact several KEs. For example, male mice typically showed an increase in microglia activation, while female mice showed no significant changes. Female mice were also protected from radiation-induced impairments in learning and memory. However, not all studies found this trend. 

Krukowski et al., 2018a; Parihar et al., 2020; Raber et al., 2019 

Prior Disease 

Neurodegenerative diseases like Alzheimer’s and Parkinson’s 

Generates an environment of increased oxidative stress and promotes the activation of glial cells. 

Hanslik, Marino & Ulland, 2021 

Genetics 

Polymorphism that increases the expression of the APOE4 gene increases the risk of developing Alzheimer’s diseases, which generally consists of a decline in memory, thinking and language. MicroRNA expression such as miR-711.  

In homozygous human APOE4 knock-in mice, a dramatic increase in pro-inflammatory cytokines TNF-a, IL-1β and IL-6 was seen after LPS injection compared to the APOE2 and APOE3 alleles, suggesting that APOE4 is implicated in a greater inflammatory response. Inhibition of miR-711 reduced DNA damage responses and signaling molecules.  

Hunsberger et al., 2019; Zhu et al., 2012; Sabirzhanov et al., 2020 

  

Exercise 

Forced running in 30-minute intervals twice per day, 5 times per week for 3 weeks. 

Forced running after irradiation completely restored the levels of the signaling molecules in the BDNF-pCREB pathway and slightly restored neurogenesis. 

Ji et al., 2014 

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Overall quantitative understanding for the KERs in the AOP is low. Despite evidence supporting the KERs, there is limited understanding of the trends of the relationships between KEs. In the KERs of this AOP, there are positive relationships between the KEs (i.e., an increase in the upstream KE elicits a change in the downstream KE); however, the trends and shapes of the relationships are not well established due to differences in experimental parameters, such as model, radiation type, doses, dose rate, and time of measurements. The measures of the KEs cannot be precisely predicted based on relevant measures of the other KEs in the KER and the quantitative descriptions does not account for all known modulating factors and feedback or feedforward mechanisms.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

This AOP was developed to bring together mechanistic knowledge in the area of impairments in learning and memory from exposure to  radiation. It includes studies from multiple species at multiple life stages and radiation exposures that contain different doses, dose-rates, and radiation qualities. Relevant studies have been  selected, consolidated, and reported using the framework.  

There are multiple considerations for potential applications of the AOP. Since exposure to radiation can occur in humans from multiple events, including occupational settings, accidental exposures, nuclear events, radiotherapy treatment and space travel, understanding its impact on CNS structure and function is essential. This AOP outlines a biological framework for the connection between the MIE and AO. It can be expanded to other pathophysiologies of the CNS. The qualitaive information presented within each KER can be used to inform on risk-model strategies,  countermeasure development, and identification of gaps in the evidence base where more research is necessary. Importantly, this AOP is a dynamic document so it can be modified as new evidence emerges.

References

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

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, Pergamon, https://doi.org/10.1016/j.freeradbiomed.2010.08.021. 

Ahmadi, M. et al. (2022), “Early responses to low-dose ionizing radiation in cellular lens epithelial models”, Radiation research, Vol. 197/1, Radiation Research Society, Bozeman, https://doi.org/10.1667/RADE-20-00284.1 

Antonelli, A.F. et al. (2015), "Induction and Repair of DNA DSB as Revealed by H2AX Phosphorylation Foci in Human Fibroblasts Exposed to Low- and High-LET Radiation: Relationship with Early and Delayed Reproductive Cell Death", Radiation Research, Vol 183/4, BioOne, Washington, httrps://doi.org/10.1667/RR13855.1. 

Azimzadeh, O. et al. (2015), "Integrative proteomics and targeted transcriptomics analyses in cardiac endothelial cells unravel mechanisms of long-term radiation-induced vascular dysfunction", Journal of Proteome Research, Vol. 14/2, American Chemical Society, Washington, https://doi.org/10.1021/pr501141b 

Balasubramanian, D (2000), “Ultraviolet radiation and cataract”, Journal of ocular pharmacology and therapeutics, Vol. 16/3, Mary Ann Liebert Inc., Larchmont, https://doi.org/10.1089/jop.2000.16.285.   

Bálentová, S. and M. Adamkov. (2020), "Pathological changes in the central nervous system following exposure to ionizing radiation", Physiological Research, Czech Academy of Sciences, https://doi.org/10.33549/PHYSIOLRES.934309. 

Barrientos, R. M. et al. (2009), "Time course of hippocampal IL-1 β and memory consolidation impairments in aging rats following peripheral infection", Brain, Behavior, and Immunity, Vol. 23/1, Elsevier, Amsterdam, https://doi.org/10.1016/j.bbi.2008.07.002

Barrientos, R. M. et al. (2012), "Aging-related changes in neuroimmune-endocrine function: Implications for hippocampal-dependent cognition", Hormones and Behavior, Vol. 62/3, Elsevier, Amsterdam, https://doi.org/10.1016/j.yhbeh.2012.02.010

Belkacémi, Y. et al. (2001), “Lens epithelial cell protection by aminothiol WR-1065 and anetholedithiolethione from ionizing radiation”, International journal of cancer, Vol. 96, John Wiley & Sons, Ltd., Hoboken, https://doi.org/10.1002/ijc.10346. 

Betlazar, C. et al. (2016), "The impact of high and low dose ionising radiation on the central nervous system", Redox Biology, Vol. 9, Elsevier, Amsterdam, https://doi.org/10.1016/j.redox.2016.08.002

Bhat, K. et al. (2020), "1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine treatment after brain irradiation preserves cognitive function in mice", Neuro-Oncology, Vol. 22/10, Oxford University Press, Oxford, https://doi.org/10.1093/neuonc/noaa095

Brooks, A.L., D.G. Hoel & R.J. Preston (2016), "The role of dose rate in radiation cancer risk: evaluating the effect of dose rate at the molecular, cellular and tissue levels using key events in critical pathways following exposure to low LET radiation.", International Journal of Radiation Biology, Vol. 92/8, Taylor & Francis, London,  doi:10.1080/09553002.2016.1186301. 

Casciati, A. et al. (2016), "Age-related effects of X-ray irradiation on mouse hippocampus", Oncotarget, Vol. 7/19, https://doi.org/10.18632/oncotarget.8575. 

Cekanaviciute, E., S. Rosi and S. V. Costes. (2018), "Central nervous system responses to simulated galactic cosmic rays", International Journal of Molecular Sciences, Multidisciplinary Digital Publishing Institute (MDPI) AG, Basel, https://doi.org/10.3390/ijms19113669

Chen, Z. and T. D. Palmer. (2013), "Differential roles of TNFR1 and TNFR2 signaling in adult hippocampal neurogenesis", Brain, Behavior, and Immunity, Vol. 30, Elsevier Inc., Amsterdam, https://doi.org/10.1016/j.bbi.2013.01.083. 

Chen, Y. et al. (2021), “Effects of neutron radiation on Nrf2-regulated antioxidant defense systems in rat lens”, Experimental and therapeutic medicine, Vol. 21/4, Spandidos Publishing Ltd, Athens, https://doi.org/10.3892/etm.2021.9765.   

Chitchumroonchokchai, C. et al. (2004), “Xanthophylls and α-tocopherol decrease UVB-induced lipid peroxidation and stress signaling in human lens epithelial cells”, The Journal of Nutrition, Vol. 134/12, American Society for Nutritional Sciences, Bethesda, https://doi.org/10.1093/jn/134.12.3225.   

Chow, B. M., Y.-Q. Li and C. S. Wong. (2000), "Radiation-induced apoptosis in the adult central nervous system is p53-dependent", Cell Death & Differentiation, Vol. 7/8, Springer Nature, https://doi.org/10.1038/sj.cdd.4400704

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