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Relationship: 2837

Title

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

Energy Deposition leads to Increase, Neural Remodeling

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Energy Deposition

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increase, Neural Remodeling

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	non-adjacent	Moderate	Low	Brendan Ferreri-Hanberry (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
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	Low	NCBI
dog	Canis lupus familiaris	Low	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	High
Female	Low
Unspecific	Low

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Adult	Moderate
Not Otherwise Specified	Low
Juvenile	Low

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

Energy deposition through ionizing radiation can lead to chemical changes including bond breakages and the generation of by-products, such as free radicals from water hydrolysis, which can change cellular homeostasis (Einor et al., 2016; Martinez-López & Hande, 2020; Reisz et al., 2014). This energy can come in many forms (i.e., gamma rays, X-rays, alpha particles, heavy ions, protons), to produce a range in complexity of damage (Drobny, 2013). When deposited onto neurons, oxidative stress can affect neuronal signaling through the induction of alterations to the neuronal architecture and synaptic activity. The energy can further cause necrosis and demyelination, and decrease neurogenesis and synaptic complexity; these together are important to maintain the integrity of the neurons (Cekanaviciute et al., 2018; J. R. Fike et al., 1984; Hladik & Tapio, 2016). Furthermore, there can also be disruptions in neuronal signaling, as well as changes to drebrin cluster and postsynaptic density proteins (PSD), which are known to regulate dendritic spine morphogenesis. Together these can lead to neural remodeling (Takahashi et al., 2003).

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 Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

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

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

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

One study shows that at a high dose of 90 Gy (X-rays), hippocampal dendritic spine length is increased compared to the control (Shirai et al., 2013). Kiffer et al. found a decrease in spine length in the CA1 subregion of the hippocampus; however, there was an increase in spine length and dendritic complexity in the dorsal dentate gyrus after exposure to 0.5 Gy 1H and 0.1 Gy 16O (Kiffer et al., 2020). Further research involving different regions of the brain is required to identify the effects of deposition of energy on the dentate gyrus.
The study by Krukowski et al. (2018a), as highlighted in a review by Cekanaviciute et al. (2018), found a lack of cellular changes in hippocampal synapse loss and microgliosis in females subjected to low dose ionizing radiation. Another study highlighted in this review showed greater reduction in new neuronal survival in male than female mice in response to 28Si irradiation (Whoolery et al., 2017). Additional data is required to determine if these differences are sex-related or due to other factors. There is a lack of studies performed on female subjects to identify specific sex-related effects of deposited energy on neuron integrity.
Previous studies have found transient changes in neurogenesis after exposure to 56Fe ions at varying doses ranging from 10 cGy to 1 Gy (DeCarolis et al., 2014; Miry et al., 2021https://pubmed.ncbi.nlm.nih.gov/25170435/https://pubmed.ncbi.nlm.nih.gov/33619310/). These studies found early decreases in neurogenesis, although DeCarolis et al. reported that this reduction returned to normal as early as 7 days post-irradiation. In a separate study, Miry et al. (2021) found that at 12 months post-exposure, neurogenesis levels significantly exceeded controls. Other inconsistent studies include Acharya et al. (2019) and Bellone et al. (2015); the former reported decreases in CA1 pyramidal neuron excitability after exposure to 18 cGy of neutron radiation, whereas the latter study reported increases in post-synaptic excitability within CA1 neurons after 0.5 Gy of proton irradiation.

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	Details	Effects on the KER	References
Drug	SB415286 – a potent and selective cell-permeable, ATP-competitive GSK-3β inhibitor, as GSK-3β induces apoptosis in response to various conditions	Treatment with SB415286 provided significant neuroprotection against radiation necrosis within the brain at 45 Gy.	Jiang et al., 2014
Diet	N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) – a melatonin metabolite which has antioxidant properties.	AMFK treatment ameliorated levels of reactive oxygen species, and increased number of immature neurons and proliferating cells post-irradiation in vivo. Without the treatment, exposure to radiation led to a significant decrease in DCX positive cells by 81% and Ki-67 positive cells by 86%. (AMFK) treatment provided protection to immature neurons by 45.38% and proliferating cells by 52.35%.	Manda et al., 2008b
Drug	PLX5622-1200 ppm (PLX) diet that contains CSF1-R (colony stimulating factor 1 receptor) inhibitor that induces depletion of microglia within 3 days.	The PLX diet was able to significantly increase the levels of the presynaptic protein, synapsin 1 after exposure to helium irradiation.	Krukowski et al., 2018b

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

The table below provides some representative examples of quantitative linkages between the two key events. It was difficult to identify a general trend across all the studies due to differences in experimental design and reporting of the data. All data is statistically significant unless otherwise stated.

Dose Concordance

Reference	Experimental Description	Results
Acharya et al., 2019	In vivo. Male mice were irradiated with 252Cf neutrons at a dose rate of 1 mGy per day for 180 days. The mice were then sacrificed, and brains were removed to conduct whole-cell electrophysiology on the pyramidal neurons in the dorsal hippocampus.	18 cGy of neutron radiation caused pyramidal neurons to be more hyperpolarized with a mean difference score (Mdiff) of -2.56 mV. CA1 pyramidal neurons exhibited a decrease in excitability (Mdiff = 30.8 pA) at 18 cGy.
Vipan Kumar Parihar & Limoli, 2013	In vivo. Male transgenic mice were exposed to cranial gamma irradiation at a dose of 1 or 10 Gy. This was done using a 137Cs irradiator at a dose rate of 2.07 Gy/min. After tissue harvesting, fluorescent imaging was performed on hippocampal neurons expressing the enhanced green fluorescent protein (EGFP) transgene to analyze changes in dendritic tree.	Dose-dependent reductions in the number of dendritic branch points, length, and area at both 10 and 30 days after gamma irradiation. Significant increase in PSD-95 (postsynaptic scaffolding protein) expression of 2.7-fold at 10 Gy at both time-points, and 1.7- and 2.2-fold increases for 1 Gy at 10 and 30 days, respectively. 1.8- and 3.7-fold decrease in filopodia at 1 and 10 Gy.
Vipan K. Parihar, Pasha et al., 2015	In vitro. Male transgenic mice were exposed to whole body proton irradiation at a dose of 0.1 or 1 Gy. This was done using 250 MeV plateau phase protons at a dose rate of 0.25 Gy/min. Mice were sacrificed 10 or 30 days post-irradiation, then fluorescent imaging was performed on hippocampal neurons expressing the EGFP transgene to analyze changes in dendritic tree. Immunohistochemistry was also performed to measure synaptic proteins.	Dose-dependent increases in postsynaptic density protein 95 (PSD-95) expression of 1.8- (0.1 Gy) and 2.1-fold (1 Gy) at 30 days in the dentate gyrus after proton irradiation. Dose-dependent reduction in synaptophysin expression of 1.3- (0.1 Gy) and 1.9-fold (1 Gy) in the dentate hilus. Dose-dependent and time-dependent decreases in number of filopodia spines (2.9- and 3.7-fold decreases at 10 and 30 days at 1 Gy).
Mizumatsu et al., 2003	In vivo. Male mice were exposed to cranial X-irradiation at 1, 2, 5 and 10 Gy (rate of 175 cGy/min). Confocal microscopy was then used to assess changes in neurogenesis and neuronal proliferation.	Numbers of immature neurons in the subgranular zone reduced by 36, 51, 56, and 67% at 1, 2, 5, and 10 Gy, respectively, indicative of decreased neurogenesis. Decrease in number of neural cells by 41, 53, and 61% at 2, 5, and 10 Gy, indicative of increased apoptosis.
Rola et al., 2005	In vivo. Male mice received whole-body irradiation with iron or carbon ions at doses of 1, 2 or 3 Gy. These were delivered at dose rates of 0.87 ± 0.16 Gy/min and 1.23 ± 0.07 Gy/min for iron and carbon ions, respectively. Confocal microscopy and immunohistochemistry were then performed to analyze proliferating neurons and neurogenesis.	56Fe irradiation led to 48% (1 Gy, 3 months old), 76% (3 Gy, 3 months), 81% (1 Gy, 9 months old), and 65% (3 Gy, 9 months) decreases in proliferating (Ki67-positive) cells in the dentate subgranular zone and 34% (1 Gy, 3 months), 71% (3 Gy, 3 months), 59% (1 Gy, 9 months), and 89% (3 Gy, 9 months) decreases in immature neurons (DCx-positive cells). 12C irradiation led to 25% (1 Gy, 9 months) and 72% (3 Gy, 9 months) decreases in Ki67-positive cells and 20% (1 Gy, 9 months) and 62% (3 Gy, 9 months) decreases in DCx-positive cells.
Chiang et al., 1993	In vivo. Male mice were exposed to 2, 8, 20, 30, 36 and 45 Gy of X-irradiation at a dose rate of 238 cGy/min. ELISA was performed to analyze CNPase levels.	CNPase (myelin-associated enzyme) levels were decreased to approximately 85% after 20, 30, and 45 Gy before increasing to normal values at 15 days. At 60 days, 20 Gy CNPase levels peaked with an approximate increase to 110% before decreasing to 84% at 180 days. At 30 Gy, CNPase levels peaked after 120 days at 86% before decreasing to 64% after 270 days. At 45 Gy, CNPase levels continued to decrease to 73% 180 days post-irradiation.
Allen et al., 2015	In vitro. Male mice received whole-body iron irradiation at 0.5 Gy (dose rate was not indicated). Golgi staining was performed for spine analysis and Sholl analysis for dendritic morphology quantification.	Dentate gyrus spine density 34% decreased after 0.5 Gy 56Fe irradiation. Dentate gyrus dendritic length decreased by 20% at 79.0 and 100.8 μm from soma and 27% at 120.9 and 130.2 μm from soma. CA1 basal spine density decreased by 32%. A peak decrease of 49% in CA1 dendritic length was observed at 77 μm from soma. CA3 apical spine density decreased by 20%.
Vipan K. Pariar et al., 2016	In vitro. Male transgenic mice and male rats were exposed to charged particles (16O and 48Ti at 600 MeV/n) at dose rates between 0.05 and 0.25 Gy/min. After tissue harvesting, confocal imaging was used for EGFP expressing neurons to assess neuronal morphometry 15 weeks post exposure.	Total dendritic length was decreased by 25%, 28%, 33%, and 34%; number of dendritic branch points decreased by 25%, 27%, 25%, and 27% respectively; and number of dendritic branches by 15%, 83%, 32%, and 28%, for 16O – 5 cGy, 16O – 30 cGy, 48Ti – 5 cGy, and 48Ti – 30 cGy, respectively.
Shirai et al., 2013	In vitro. Hippocampal cultures were exposed to 30, 60 and 90 Gy of X-irradiation at a rate of 86.7 cGy/min. Green fluorescent protein (GFP) transfection was used to analyze the effects of X-ray irradiation on dendritic spine morphology and density. Fluorescent immunohistochemistry was used to evaluate cytoskeletal proteins within dendritic spines.	Significant increase in dendritic spine length at 90 Gy by 1.2-fold. No change in width of dendritic spines. Number of F-actin clusters decreased by 1.4- (30 Gy), 1.57- (60 Gy), and 1.4-fold (90 Gy). Number of drebrin clusters decreased by 1.3- (30 and 60 Gy) and 1.4-fold (90 Gy).
Okamoto et al., 2009	In vitro. Primary neurons from the hippocampi of fetal rats were exposed to 0.5, 4 and 10 Gy of X-irradiation. Immunofluorescence was performed to analyze synaptic proteins and TUNEL staining was performed to identify neuronal apoptosis.	Significant increase in apoptosis of neurons of 1.3- (0.5 Gy), 1.9- (4 Gy), and 2.5-fold (10 Gy) at 7 days post-irradiation and 1.4- (0.5 Gy), 2.3- (4 Gy), and 2.6-fold (10 Gy) at 14 days post-irradiation. Significant decrease in F-actin clusters of 1.4-fold (10 Gy) at 7 days, and 1.4- (4 Gy) and 1.5-fold (10 Gy) at 14 days. Significant decrease in drebrin of 1.8-fold (10 Gy) at 7 days, and 1.7- (4 Gy) and 1.5-fold (10 Gy) at 14 days. Significant decrease in Synapsin-I of 1.1-fold (10 Gy) at 14 days.
Vipan K. Parihar, Allen, et al., 2015	In vivo. Male transgenic mice (with EGFP transgene) were exposed to 5-30 cGy of charged particles (16O and 48Ti) at dose rates between 0.5 and 1.0 Gy/min. After tissue harvesting, confocal microscopy, imaging and neuronal morphometry were performed to evaluate dendritic complexity and spine density 8 weeks post radiation exposure.	Significant reductions in number of dendritic branches by 1.5- (16O – 30 cGy), 1.8- (48Ti – 5 cGy), and 1.7-fold (48Ti – 30 cGy), number of branch points by 1.5- (16O – 30 cGy), 1.4- (48Ti – 5 cGy), and 1.8-fold (48Ti – 30 cGy), total dendritic length by 1.5- (16O – 5 cGy), 1.8- (16O – 30 cGy), 1.5- (48Ti – 5 cGy), and 1.7-fold (48Ti – 30 cGy), number of spines by 1.5- (16O – 5 cGy), 1.8- (16O – 30 cGy), 1.7- (48Ti – 5 cGy), 1.9-fold (48Ti – 30 cGy), and spine density by 1.7- (16O – 5 cGy), 1.6- (16O – 30 cGy), 1and 1.5-fold (48Ti – 5 and 30 cGy). Significant increase in PSD-95 puncta by 1.5-fold (all doses and radiation types) 8 weeks post-irradiation.
Kiffer et al., 2020	In vivo. Male mice received whole-body 1H and 16O irradiation at 0.5 and 0.1 Gy, respectively. The dose rates were 18-19 cGy/min (1H irradiation) and 18-33 cGy/min (16O irradiation). Golgi staining was performed for dendritic morphology quantification and spine analyses.	Dentate gyrus dendritic complexity increased by 1.4-fold after 0.5 Gy (1H) and 0.1 Gy (16O) combined irradiation.
Klein et al., 2021	In vivo. Male mice received whole-body simulated galactic cosmic irradiation (1H, 16O, 4He, 28Si, 56Fe) at 5 and 30 cGy. The dose rate was 5 cGy/min for the mixed-ion simulated galactic cosmic radiation (GCR). Electrophysiological measurements were then taken to assess changes in synaptic signaling within the CA1 region of the hippocampus.	30 cGy of mixed-ion GCR causes CA1 pyramidal neurons to have elevated amplitudes in the spontaneous inhibitory postsynaptic currents (sIPSC) with a mean difference score (Mdiff) of 5.54 pA. There was also a decrease in the sIPSC rise times (Mdiff = -0.45 ms). These results show that GCR leads to enhanced inhibitory synaptic signaling.

Time Concordance

References	Experimental Description	Results
Vipan K. Parihar, Pasha, et al., 2015	In vitro. Male transgenic mice were exposed to whole body proton irradiation at a dose of 0.1 or 1 Gy. This was done using 250 MeV plateau phase protons at a dose rate of 0.25 Gy/min. Mice were sacrificed at 10 or 30 days post-irradiation, then fluorescent imaging was performed on hippocampal neurons expressing the EGFP transgene to analyze changes in dendritic tree. Immunohistochemistry was also performed to measure synaptic proteins.	Time-dependent increase in PSD-95 of 1.6- (10 days) and 2.1-fold (30 days). Time-dependent decrease in synaptophysin of 1.4- (10 days) and 1.9-fold (30 days) in the dentate hilus.
Bellone et al., 2015	In vivo. Male mice received whole-body irradiation with 0.5 Gy of 150 MeV protons at a rate of 1.5-2.5 Gy/min. Electrophysiological experiments were conducted to measure synaptic response changes.	After 9 months, exposure to 0.5 Gy of proton irradiation resulted in an increase in postsynaptic excitability by 53% at 1.50 mA stimulation. Synaptic efficacy was increased by 118%. fEPSP (excitatory postsynaptic potential) slopes increased approximately 15 – 46% at least 60 minutes post-stimulation. There were no changes in presynaptic ability.
J. R. Fike et al., 1984	In vivo. Male beagle dogs were exposed to 10, 15, 30 Gy of X-irradiation at a rate of 3 Gy/min. Computed tomography (CT) scan and histological examination were performed to identify differences in tissue density within the cerebrum.	Animals receiving 10 Gy had no response up to 12 months. Time to maximum computed tomography (CT) response was 6.3 months for 15 Gy and 5.2 months for 30 Gy.
Chakraborti et al., 2012	In vitro. Male mice were irradiated with a single dose of 10 Gy from a 137Cs source at a rate of 1.67 Gy/min. After harvesting, neurons underwent Golgi staining to analyze changes in spine density and morphology.	10 Gy of gamma irradiation led to a time-dependent decrease in spine density in the dentate gyrus by 11.9% (1 week) and 26.9% (1 month), a significant reduction in proportion of mushroom spines by 24.3% (1 week) and 15.7% (1 month), a significant decrease in the number of thin spines by 11.49% (1 week) and 13.2% (1 month), and a significant increase in number of mushroom spines by 12.1% (1 week) and 25.3% (1 month).
Okamoto et al., 2009	In vitro. Primary neurons from the hippocampi of fetal rats were exposed to 0.5, 4 and 10 Gy of X-rays. Immunofluorescence was performed to analyze synaptic proteins and TUNEL staining was performed to identify neuronal apoptosis.	Significant increase in apoptosis of neurons of 1.3- (0.5 Gy), 1.9- (4 Gy), and 2.5-fold (10 Gy) at 7 days post-irradiation and 1.4- (0.5 Gy), 2.3- (4 Gy), and 2.6-fold (10 Gy) at 14 days post-irradiation. Significant decrease in F-actin clusters of 1.4-fold (10 Gy) at 7 days, and 1.4- (4 Gy) and 1.5-fold (10 Gy) at 14 days. Significant decrease in drebrin of 1.8-fold (10 Gy) at 7 days, and 1.7- (4 Gy) and 1.5-fold (10 Gy) at 14 days. Significant decrease in Synapsin-I of 1.1-fold (10 Gy) at 14 days.
Panagiotakos et al., 2007	In vitro. Female Sprague Dawley rat brains were irradiated with X-rays at 25 Gy (117.5 cGy/min) while shielding the olfactory bulb. Immunohistochemistry, stereological analysis, fluorescence intensity quantification, electron microscopy and magnetic resonance imaging were preformed to assess long term radiation damage 24 h to 15 months post irradiation.	The number of BrdU+ cells in the subventricular zone (SVZ) decreased significantly 15 months post irradiation (average number of BrdU+cells was 5,541+/−624 compared to the control group of 34,680+/−9,413). Doublecortin (DCX)-expressing neuroblasts were lost permanently immediately post irradiation.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

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

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 comes from dog, rat, and mouse models, with a lot of evidence in mice. There is in vivo evidence in both male and female animals, a large amount of evidence in males. Animal age is occasionally not indicated in studies, but most evidence is in adult rodent models.