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Relationship: 2832

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 Tissue resident cell activation

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

Tissue resident cell activation

Key Event Relationship Overview

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

AOPs Referencing Relationship

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

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	Low	NCBI
mouse	Mus musculus	Moderate	NCBI
rat	Rattus norvegicus	Moderate	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	Moderate

Life Stage Applicability

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

Term	Evidence
All life stages	Moderate

Key Event Relationship Description

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

Deposition of energy refers to particles that have sufficient energy to penetrate biological tissue leading to ionization events that can break water molecules and form free radicals. These can damage sensitive macromolecules such as DNA, protein and lipids (Chen, Oyarzabal & Hong, 2016; Mavragani et al., 2016). Ionization events occur from many types of radiation including, X-rays, gamma-rays, alpha particles, beta particles, heavy ions, and neutrons. X-rays and gamma rays induce sparse ionization events and energy is exponentially absorbed by tissues. Conversely, energetic charged particles can cause dense ionization events, leading to clustered damage and secondary ionization events (Niemantsverdriet et al., 2012).

When sufficient energy is deposited it can damage the cellular environment; this releases danger signals either passively when the ionization events induce cell death, or actively by cells undergoing life threatening stress (Denning et al., 2019; Vénéreau, Ceriotti & Bianchi, 2015). These signaling molecules, such as alarmins or damage-associated molecular pattern molecules (DAMPs), promote an inflammatory and regenerative environment by activating tissue resident cells (Chen, Oyarzabal & Hong, 2016; Vénéreau, Ceriotti & Bianchi, 2015). Resident immune cells, such as macrophages and dendritic cells, use pattern recognition receptors on their surfaces to detect alarmins and DAMPs which initiate their activation and proliferation (Chen, Oyarzabal & Hong, 2016; Mavragani et al., 2016). Activated cells can then regulate the recruitment of circulating immune cells and initiate inflammation to remove damaged cells, eliminate harmful stimuli, and promote tissue repair (Schaue et al., 2015; Roh & Sohn, 2018). However, uncontrolled inflammation can then lead to a state of disease progression.

Evidence Collection Strategy

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

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

Evidence Supporting this KER

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

Overall Weight of Evidence: Moderate

Biological Plausibility

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

There is strong biological evidence and mechanistic understanding linking deposition of energy to tissue resident activation. It is widely accepted that deposition of energy can cause the activation of resident tissue cells (Di Maggio et al., 2015; Frey et al., 2015; Mavragani et al., 2016; Multhoff & Radons, 2012; Pinto et al., 2016; Rodel et al., 2012; Schaue et al., 2015; Yahyapour et al., 2018; Zhao & Robbins, 2009; Rienecker et al., 2021). Ionization of local tissue leads to direct tissue damage, reduced cellular homeostasis, genotoxic stress, and oxidative stress (Mavragani et al., 2016; Yahyapour et al., 2018). This damage can initiate tissue resident cell activation (Davies et al., 2013; Langston, Shibata & Horng, 2017; Rienecker et al., 2021). Primary damage and follow-on free-radical events typically occur within microseconds, but the inflammatory response carries on the damage through waves of reactive oxygen species generation as well as cytokine and chemokine release (Schaue et al., 2015). The resultant loss of cellular homeostasis, as well as primary and secondary cellular damage leads to the release of DAMPs (Mavragani et al., 2016; Yahyapour et al., 2018). Resident cells then use pattern recognition receptors to detect DAMPs resulting in their activation through a series of intracellular signaling cascades (Mavragani et al., 2016; Yahyapour et al., 2018).

There are many resident cells that become activated in response to radiation damage including lymphocytes, neutrophils, endothelial cells, and dendritic cells. Among the resident cells, macrophages are present in virtually all tissues and are the first line of defense against foreign pathogens and stressors. Resident macrophages have a ramified morphology with long, dynamic processes and are constantly surveying for signals of injury or infection (Betlazar et al., 2016; Paladini et al., 2021). They are also scavenger cells which engulf metabolites and debris from surrounding apoptotic cells to maintain healthy organs and tissues. When damage is detected, local macrophages become activated and move to the site of injury, where they signal other immune cells and release cytokines, chemokines, and other soluble molecules to mediate wound healing and initiate an inflammatory response (Hladik & Tapio, 2016; Paladini et al., 2021; Yahyapour et al., 2016; Rienecker et al., 2021). Resident macrophages detect endogenous cellular components released from damaged, stressed, or dying cells through pattern recognition receptors such as toll-like receptors (TLRs) (Chen, Oyarzabal & Hong, 2016; Yahyapour et al., 2016). TLRs can detect a wide variety of DAMPs including those potentially formed by deposition of energy ( i.e., oxidized DNA, uric acid, ATP and high-mobility group box 1 protein) (Yahyapour et al., 2016). When TLRs detect DAMPs in the extracellular environment, they initiate intracellular signaling cascades that lead to the nuclear translocation of transcription factors, such as nuclear factor-κB (NF-κB), to induce the production of proinflammatory cytokines and chemokines (Chen, Oyarzabal & Hong, 2016; Yahyapour et al., 2018). The resident macrophages also initiate granulocyte-macrophage colony formation and recruitment of early myeloid progenitors to the site of injury (Schaue et al., 2015).

This response has been shown to occur across organs and tissue types using the same underlying mechanisms (Chen, Oyarzabal & Hong, 2016, Mavragani et al., 2016, Schaue et al., 2015). However, tissues are distinct in the types of activated cells and the resulting inflammatory responses. For example, the liver hosts the largest population of macrophages (Kupper cells) and is enriched with T lymphocytes or natural killer cells (Szabo, Mandrekar & Dolganiuc, 2007). Local Kupper cells use pattern recognition receptors to detect local radiation damage which leads to their activation (Szabo, Mandrekar & Dolganiuc, 2007). Activated cells secrete proinflammatory mediators, recruit macrophages and regulate the response of local T lymphocytes (Szabo, Mandrekar & Dolganiuc, 2007). In the lungs, radiation damage is first detected by local epithelial cells that produce pro-inflammatory mediators including cytokines and reactive oxygen species (Chen et al., 2018). These mediators stimulate mucus secretion by goblet cells and recruit macrophages and dendritic cells to initiate inflammation (Moldoveanu et al., 2009). In some organs, such as the brain, resident immune cells are abundant because the organ is separated from the immune system by the blood brain barrier to protect it from infection by foreign cells (Banks & Erickson, 2010). It has been shown that brain exposure to ionizing radiation can initiate activation of other types of resident immune cells, such as microglia and astrocytes (Betlazar et al., 2016). Microglial cells are the first line of defense in response to radiation damage and become activated in response to DAMPs released from local damaged cells (Betlazar et al., 2016). Microglia cells release pro-inflammatory mediators to regulate an inflammatory response and recruit additional immune cells to the site of injury (Betlazar et al., 2016). Microglia can subsequently induce astrocyte activation via the COX-2 pathway in the presence of a stressor (Betlazar et al., 2016; Cucinotta et al., 2014; Paladini et al., 2021). When damage is detected, astrocytes proliferate and form scar tissue via reactive gliosis (Makale et al., 2017).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

The empirical evidence surrounding this KER comes from research using in vitro and in vivo models. All organ systems are vulnerable to tissue resident activation from deposition of energy, however, provided below are consistent example of evidence from brain studies. Tissue resident cell activation is typically determined in the brain through the observation of the activation or proliferation of brain-resident immune cells, microglia and astrocytes.

The data consistently shows that direct deposition of energy can elicit damage to tissues and induce resident immune cell activation. The literature space is populated with studies examining effects of high doses (>2 Gy) of radiation with sparse studies examining effects for lower dose exposures (<1 Gy). Much of the high dose evidence is from work exposing rodent models to doses between 0 and 200 cGy of heavy ions and/or protons via whole body irradiation (Allen et al., 2020; Krukowski et al., 2018a; Parihar et al., 2020; Parihar et al., 2018; Parihar et al., 2016; Poulose et al., 2011; Raber et al., 2019; Sumam et al., 2013). Some studies exposing rodents to high energy particles use high dose ranges (up to 4 Gy) (Cummings et al., 2007; Rola et al., 2008). Also included are studies using high doses (1-10 Gy) of X-rays or gamma rays used in a clinical setting (Acharya et al., 2016; Casciati et al., 2016; Chen et al., 2016; Hua et al., 2012; Hwang et al., 2006; Mizumatsu et al., 2003; Monje et al., 2002; Rola et al., 2007; Rola et al., 2004). In addition, very high-dose studies, using doses up to 25-45 Gy were included which showed consistent tissue resident activation following deposition of energy (Chiang, McBride & Withers, 1993; Dey et al., 2020; Kyrkanides et al., 1999; Moravan et al., 2011).

Dose Concordance

The literature supports the dose-concordance of the relationship between energy deposition and tissue resident cell activation, specifically glial cells, following exposure to ionizing radiation. Some studies, using exposures involving 16O, 48Ti, 4He and protons, observed significant increases in activation at doses of 5, 15, 30 or 50 cGy (Allen et al., 2020; Krukowski et al., 2018a; Parihar et al., 2016; Parihar et al., 2018; Parihar et al., 2020). These studies report an approximate 1.25- to 5-fold increase in microglia markers post-irradiation. Astrocyte activation was not reported in these studies. Other lower dose studies observed a radiation dose-dependent 1.3- to 14-fold increase in markers indicating activation of astrocytes and/or microglia (Casiati et al., 2016; Cummings et al., 2007; Poulose et al., 2011; Raber et al., 2019; Rola et al., 2008; Suman et al., 2013). These studies used 56Fe, protons, 16O or 28 Si, gamma rays and X-rays at doses ranging from 1-4 Gy. Various stressors at moderate doses further support the dose concordance of energy deposition and activation of tissue resident cells (Acharya et al., 2016; Dey et al., 2020; Hua et al., 2012; Monje et al., 2002; Rola et al., 2007; Rola et al., 2004). Consistency in the dose-response relationship was mostly exhibited at the higher doses (2-10 Gy), with reports showing a steady dose-dependent increase in resident tissue activation (Chen et al., 2016; Casciati et al., 2016; Hwang et al., 2006; Rola et al., 2008). With very high doses of radiation (up to 45 Gy), significant increases of GFAP and Mac-I levels in glia are observed (Chiang, McBride & Withers, 1993; Kyrkanides et al., 1999; Mizumatsu et al., 2003; Moravan et al., 2011). Additionally, increase in CD68+ cells have been shown following a total dose of 26 Gy (Dey et al., 2020). Further studies using mouse primary microglial cultures irradiated with X-rays at 10 Gy have shown a 2.5-fold increase in tissue resident cell activation. In vivo mice irradiated with 30 Gy also show a 9-fold increase in microglial activation (Xu et al., 2015). In general, these studies highlight that with an increase in deposited energy larger amounts of primary and secondary tissue damage occurs, which leads to increased proliferation and activation of resident immune cells.

Time Concordance

Many long-term and a few short-term studies find tissue-resident cell activation after deposition of energy. Mice irradiated with 35 Gy of gamma rays show activated astrocytes and microglia 4 h after irradiation (Kyrkanides et al., 1999). Rats irradiated with X-rays at 15 Gy show activation of astrocytes at 6 h (Hwang et al., 2006). Many studies show 1.2- to 3-fold increased activation one or a few days after irradiation in rats and mice (Casciati et al., 2016; Hwang et al., 2006; Kyrkanides et al., 1999; Moravan et al., 2011; Poulose et al., 2011). Furthermore, it has also been shown that activation continues until 1 year, measured after weeks and months, with a maximum 14-fold increase in marker levels shown after 2 months post-irradiation (Acharya et al., 2016; Allen et al., 2020; Casciati et al., 2016; Chiang, McBride & Withers, 1993; Chen et al., 2016; Cummings et al., 2007; Dey et al., 2020; Hua et al., 2012; Kyrkanides et al., 1999; Mizumatsu et al., 2003; Monje et al., 2002; Moravan et al., 2011; Parihar et al., 2020; Parihar et al., 2018; Parihar et al., 2016; Poulose et al., 2011; Raber et al., 2019; Rola et al., 2008; Rola et al., 2004; Suman et al., 2013).

Incidence Concordance

No available data.

Essentiality

Since deposition of energy is a physical stressor, it can be shielded, but chemicals cannot effectively block or decrease it. Thus further research is required to determine the effect of shielding radiation on the activation of tissue resident cells. 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.

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

There is no consensus about sex-related responses to radiation exposure and the resulting activation of tissue resident cells. Krukowski et al. (2018a) and Parihar et al. (2020) found that female mice were immune to the effects of 0.3 and 0.5 Gy radiation on cell activation, while Raber et al. (2019) found that only female mice showed increased activated cells after 2 Gy.
A large amount of uncertainty surrounds the impact of low-dose ionizing radiation on tissue resident cell activation. More evidence is required to determine the relationship between ionizing radiation at doses < 1 Gy and tissue-resident cell activation.

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
Sex	Male and female mice had different responses in tissue resident cell activation following irradiation.	Male mice typically showed an increase in microglia activation, while female mice showed no significant changes. However, not all studies found this trend.	Krukowski et al., 2018a; Parihar et al., 2020; Raber et al., 2019
Drug	Colony stimulating factor 1 receptor inhibitor PLX5622 (eliminates microglia).	PLX5622 reduced the number of activated microglia.	Acharya et al., 2016; Allen et al., 2020; Krukowski et al., 2018b
Drug	P2X7 receptor (associated with microglial activation) inhibitor Brilliant Blue G.	Treatment attenuated the increase in microglial activation both in vivo and in vitro after irradiation.	Xu et al., 2015
Age	10-day-old and 10-week-old mice.	At 10 days old, irradiated mice showed increased glial activation, while at 10 weeks old they did not show significant changes in activation.	Casciati et al., 2016
Age	7-, 17- and 27-month-old mice.	Activation of microglia after irradiation decreased as age was increased.	Hua et al., 2012
Genetics	Extracellular SOD knockout mice.	Microglial activation was increased more in SOD knockout mice than wild-type mice after 5 Gy gamma rays.	Rola et al., 2007

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

Dose Concordance

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.

Reference	Experiment description	Result
Suman et al., 2013	In vivo. 6- to 8-week-old female C57BL/6J mice were irradiated with either 1.6 Gy 56Fe ions or 2 Gy gamma rays (137Cs source) both at 1 Gy/min. GFAP levels in the cerebral cortex measured by immunoblotting were used to indicate astrocyte activation.	GFAP levels increased 2.2-fold in the gamma ray irradiated group and 4.3-fold in the 56Fe ion irradiated group.
Poulose et al., 2011	In vivo. 2-month-old male Sprague-Dawley rats were irradiated with 5, 50 and 100 cGy 16O particles. GFAP was measured by western blot in the hippocampus.	At maximum, GFAP increased 1.2-fold after 5 and 50 cGy and 1.3-fold after 100 cGy.
Parihar et al., 2016	In vivo. Male Thy1-EGFP transgenic mice were irradiated with 600 MeV/amu charged particles (16O and 48Ti) (0.05 to 0.25 Gy/min) at 0.05 and 0.3 Gy. Activated glial cells were indicated by ED1 markers through immunostaining.	Number of activated microglia increased with dose, with a greater fold difference following 48Ti radiation than 16O. A maximum 1.9-fold change was observed at 30 cGy 48Ti at 27 weeks.
Parihar et al., 2018	In vivo. Male C57BL/6J mice were irradiated with He ions at 5 and 30 cGy (5 cGy/min). ED1 cells were used as markers for activated microglia by immunostaining and DAPI counterstaining.	ED1+ cells increased 3.5-fold after 5 cGy and 3.8-fold after 30 cGy, indicating microglial activation.
Parihar et al., 2020	In vivo. Mice were irradiated with low doses ( ≤≤ 30 cGy) of helium ions. Brain tissue sections were stained to identify microglia activation by CD68+ cells.	A 2.5-fold increase in CD68+ cells was observed in the male irradiated group following 30 cGy irradiation, indicating microglia activation. No increase in CD68+ was seen in the female mice.
Krukowski et al., 2018a	In vivo. C57B16/J mice were exposed to GCR at 0, 15, 50 cGy (252 MeV/amu protons, 249.3 MeV/amu helium ions, and 594.4 MeV/amu oxygen ions). Microglia were stained and levels were measured by Iba-1.	50 cGy male cohorts showed a significant 3- to 5-fold increase in Iba-1 + cells compared to the controls, indicating activated microglia in the dorsal hippocampus. No change was observed in the females.
Allen et al., 2020	In vivo. Mice were exposed to 4He irradiation (400 MeV/amu) at 30 cGy. CD68+ cells and Iba-1 immunochemistry were used to measure activated microglia. GFAP was measured to determine astrogliosis.	1.25-fold change in CD68+ cells was observed in the 30 cGy group compared to the controls. Iba-1+ microglia cells did not change significantly. No change in GFAP expression, a marker indicative of astrogliosis.
Cummings et al., 2007	In vivo. Sprague-Dawley rats were irradiated with 56Fe ions (600 MeV/amu) with 4 Gy dose. GFAP immunochemistry was used to identify astrogliosis.	There was a significant increase in GFAP+ cells 6 and 12 months post irradiation with 4 Gy.
Rola et al., 2008	In vivo. Male mice were irradiated with 0.5-4 Gy 56Fe ions. CD68+ cells determined microglia activation and BrdU identified neurogenesis.	Dose dependent increase was observed in BrudU+/CD68+ cells indicating newly born activated microglia. Significant increases of 3.4, 4.4 and 14-fold were observed at 1 Gy, 2 Gy and 4 Gy, respectively.
Raber et al., 2019	In vivo. Mice were irradiated with 1 GeV protons, 16O or 28Si (0, 25, 50, or 200 cGy). ELISA was used to detect levels of CD68 for activated microglia.	Cortical CD68 levels were increased by 1.7-fold in females irradiated with 200 cGy. This effect was not seen in males.
Hwang et al., 2006	In vivo and in vitro. Sprague-Dawley rats were irradiated with X-rays at 2-10 Gy and 15 Gy. Immunostaining, RT-PCR and western blot were used to analyze GFAP protein levels.	A dose dependent fold increase of cells with processed morphology was found. A 12- to 29.5-fold increase in activated morphology was observed in an astrocyte mixed-culture irradiated with 0-10 Gy.
Mizumatsu et al., 2003	In vivo. 2-month-old male C57BL/J6 mice were irradiated with X-rays at 175 cGy/min. New activated microglia in the hippocampus were determined with BrdU and CD68 staining.	A dose-dependent increase in BrdU/CD68+ cells was observed. No cells were activated without irradiation, 14% were after 2 Gy, 38% were after 5 Gy and 54% were after 10 Gy.
Hua et al., 2012	In vivo. Male FxBN rats were irradiated with 10 Gy of 137Cs gamma rays. CD68 was labelled with ED-1 in the hippocampus to show activated microglia.	The density of ED-1+ microglia increased 2- to 3-fold after 10 Gy.
Rola et al., 2007	In vivo. 8-week-old C57BL/6J mice were irradiated with 5 Gy X-rays. Microglial generation and activation in the hippocampus was determined by BrdU and CD68 staining.	The number of BrdU/CD68+ cells increased 1.3-fold.
Chen et al., 2016	In vitro. Human CHME5 microglia were irradiated with 137Cs gamma rays (LET 0.9 keV/µm) delivered over 1-3 min. Activated cells were determined by morphology as well as western blot for CR3/43 and Glut-5 activation markers.	CR3/43 and Glut-5 were both observed after 8 Gy, but just slightly or not at all after 0.5 Gy. At 8 Gy, microglia demonstrated an activated morphology.
Monje et al., 2002	In vivo. Adult female Fischer 344 rats were irradiated with X-rays at 175 cGy/min with two fractions of 5 Gy. Activated astrocytes and microglia were determined in the hippocampus through GFAP and ED-1 staining, respectively.	The percent of GFAP+ cells increased from 5.4% to 7.4% after 10 Gy. The percent of ED-1+ cells increased from 0% to 22% after 10 Gy.
Casciati et al., 2016	In vivo. Female and male C57BL/6 mice were irradiated with X-rays. Activated astrocytes and microglia were determined in the hippocampus through GFAP and Iba-1 staining, respectively.	Iba-1+ cells increased 1.5-fold after 2 Gy, while GFAP+ cells increased 1.3-fold after 2 Gy. No changes in GFAP were seen after 0.1 Gy.
Acharya et al., 2016	In vivo. 6-month-old male C57Bl/6J mice were irradiated with 9 Gy X-rays. Microglia activation was determined by CD68 staining.	In the hippocampus, CD68+ cells increased 1.75-fold, while in the medial prefrontal cortex, they increased 1.25-fold.
Rola et al., 2004	In vivo. 21-day-old male C57BL/J6 mice were irradiated with 5 Gy X-rays at 1.75 Gy/min. Microglial and astrocyte activation was determined by CD68 and GFAP staining, respectively, double-stained with BrdU for gliogenesis in the subgranular zone.	CD68+ cells increased 2.5-fold, while GFAP+ cells increased 2-fold.
Dey et al., 2020	In vivo. 6-month-old male C57BL/6J mice received X-ray irradiation in fractions of 8.67 Gy/day (1.10 Gy/min) on alternating days for a total dose of 26 Gy. Activated microglia were determined through CD68 staining in the hippocampus.	In the CA1 region, CD68+ cells increased 3-fold, while in the CA3 region they increased 5-fold.
Chiang, McBride & Withers, 1993	In vivo. 12-week-old male C3Hf/Sed/Kam mice were irradiated with X-rays (238 cGy/min). Activated astrocytes and microglia were determined through GFAP and Mac-1 immunohistochemistry, respectively.	GFAP+ cells in the hippocampus and corpus callosum increased 1.5-fold after 30 and 36 Gy, and 2-fold after 45 Gy. Mac-1+ cells in the corpus callosum increased after 2 (1.2-fold), 20 (1.9-fold), 30 (2-fold), 36 (1.8-fold) and 45 Gy (2.8-fold).
Kyrkanides et al., 1999	In vivo. Male C3H/HeN mice were irradiated with 60Co gamma rays (35 Gy, 0.9 Gy/min). Activated astrocytes and microglia were determined through GFAP and Mac-1 immunohistochemistry, respectively.	Mac-1 and GFAP levels both showed greatly increased expression after 35 Gy.
Moravan et al., 2011	In vivo. 8- to 10-week-old male C57BL/6J mice were irradiated with 137Cs gamma rays at 1.25 Gy/min. GFAP expression was measured by RT-qPCR.	GFAP increased 2- to 3-fold after 25 and 35 Gy, but not significantly after 5 and 15 Gy.
Xu et al., 2015	In vivo and in vitro. Primary microglia from male BALB/c mice were irradiated with 30 Gy using a 6 MV β-ionizing-ray linear accelerator. Male BALB/c mice were irradiated with 10 Gy X-rays. Microglial cell activation was determined through morphology and Iba-1 immunohistochemistry.	In vitro, 10 Gy resulted in a 2.5-fold increase in activated microglia. In vivo, 30 Gy resulted in a 9-fold increase in activated microglia.

Time Concordance

Reference	Experiment description	Result
Suman et al., 2013	In vivo. 6- to 8-week-old female C57BL/6J mice were irradiated with either 1.6 Gy 56Fe or 2 Gy 137Cs gamma rays both at 1 Gy/min. GFAP levels in the cerebral cortex measured by immunoblotting were used to indicate astrocyte activation.	GFAP levels were increased 2.2-fold in the gamma irradiated group and 4.3-fold in the 56Fe irradiated group 12 months after exposure.
Poulose et al., 2011	In vivo. 2-month-old male Sprague-Dawley rats were irradiated with 5, 50 and 100 cGy 16O particles. GFAP was measured by western blot in the hippocampus.	After 36 h, GFAP was increased 1.2-fold after 100 cGy. After 75 days, GFAP increased 1.2-fold after 5 and 50 cGy and 1.3-fold after 100 cGy.
Parihar et al., 2016	In vivo. Male Thy1-EGFP transgenic mice were irradiated with 600 MeV/amu charged particles (16O and 48Ti) (0.05 to 0.25 Gy/min) at 0.05 and 0.3 Gy. Activated glial cells were indicated by ED1 markers through immunostaining.	ED1+ cells increased ~1.2- to 1.6-fold 15 weeks post 16O irradiation and ~2-fold 27 weeks post irradiation in all 48Ti irradiated groups.
Parihar et al., 2018	In vivo. Male C57BL/6J mice were irradiated with He ions at 5 and 30 cGy (5 cGy/min). ED1 cells were used as markers for activated microglia by immunostaining and DAPI counterstaining.	52 weeks after radiation, ED1+ cells increased 3.5-fold and 3.8-fold, indicating microglial activation.
Parihar et al., 2020	In vivo. Mice were irradiated with low doses ( ≤≤ 30 cGy) of helium ions. Brain tissue sections were stained to identify microglia activation by CD68+ cells.	The number of activated microglia increased by 2.5-fold in the male irradiated group 15 weeks after 30 cGy 4He irradiation.
Allen et al., 2020	In vivo. Mice were exposed to 4He irradiation (400 MeV/amu) at 30 cGy. CD68+ cells and Iba-1 immunochemistry were used to measure activated microglia. GFAP was measured to determine astrogliosis.	An increase in CD68+ cells was observed 7-8 weeks post-irradiation.
Rola et al., 2008	In vivo. Male mice were irradiated with 0.5-4 Gy 56Fe ions. CD68+ cells determined microglia activation and BrdU identified neurogenesis.	2 months post-irradiation, BrdU/CD68+ cells increased up to 14-fold.
Cummings et al., 2007	In vivo. Sprague-Dawley rats were irradiated with 56Fe ions (600 MeV/amu) with 4 Gy dose. GFAP immunochemistry was used to identify astrogliosis.	There was a significant increase in GFAP+ cells 6 and 12 months post irradiation. A maximum 1.7-fold change was observed 12 months post irradiation compared to the control.
Raber et al., 2019	In vivo. Mice were irradiated with 1 GeV protons, 16O or 28Si (0, 25, 50, or 200 cGy). ELISA was used to detect levels of CD68 for activated microglia.	1.7-fold increase in CD68 levels in female mice was seen 3 months following 200 cGy exposure.
Hwang et al., 2006	In vivo. Sprague-Dawley rats were irradiated with X-rays at 2-10 Gy and 15 Gy. Immunostaining, RT-PCR and western blot were used to analyze GFAP protein levels.	GFAP levels were slightly higher at 6 h post irradiation compared to the initial levels and significantly increased 24 h post-irradiation.
Mizumatsu et al., 2003	In vivo. 2-month-old male C57BL/J6 mice were irradiated with 10 Gy X-rays at 175 cGy/min. New activated microglia in the hippocampus were determined with BrdU and CD68 staining.	No cells were activated without irradiation or 48 h after irradiation, while up to 50% of cells were activated 2 months after irradiation.
Hua et al., 2012	In vivo. Male FxBN rats were irradiated with 10 Gy of 137Cs gamma rays. CD68 was labelled with ED-1 in the hippocampus to show activated microglia.	The density of ED-1+ microglia increased 2- to 3-fold after 1 week, and was just slightly increased after 10 weeks.
Chen et al., 2016	In vitro. Human CHME5 microglia were irradiated with 8 Gy gamma rays (LET 0.9 keV/µm) delivered over 1-3 min. Activated cells were determined by morphology as well as western blot for CR3/43 and Glut-5 activation markers.	Cells demonstrated a normal morphology until 6 days then an activated morphology starting 7 days post-irradiation. Glut-5 was observed after 7,10 and 14 days , while CR3/43 was observed after 2 weeks.
Monje et al., 2002	In vivo. Adult female Fischer 344 rats were irradiated with X-rays at 175 cGy/min with two fractions of 5 Gy. Activated astrocytes and microglia were determined in the hippocampus through GFAP and ED-1 (labels CD68) staining, respectively.	The percent of GFAP+ cells increased from 5.4% to 7.4% after 2 months. The percent of ED-1+ cells increased from 0% to 22% after 2 months.
Casciati et al., 2016	In vivo. Female and male C57BL/6 mice were irradiated with 2 Gy X-rays. Activated astrocytes and microglia were determined in the hippocampus through GFAP and Iba-1 staining, respectively.	After 1 day, Iba-1+ cells increased 1.5-fold, while after 6 months, GFAP+ cells increased 1.3-fold.
Acharya et al., 2016	In vivo. 6-month-old male C57Bl/6J mice were irradiated with 9 Gy X-rays. Microglia activation was determined by CD68 staining.	In the hippocampus, CD68+ cells increased 1.75-fold after 2 and 6 weeks, while in the medial prefrontal cortex they increased 1.25-fold after 6 weeks.
Rola et al., 2004	In vivo. 21-day-old male C57BL/6J mice were irradiated with 5 Gy X-rays at 1.75 Gy/min. Microglial and astrocyte activation was determined by CD68 and GFAP staining, respectively, double-stained with BrdU for gliogenesis in the subgranular zone.	Both 1 and 3 months post-irradiation, CD68+ cells increased 2.5-fold, while GFAP+ cells increased 2-fold 3 months post-irradiation.
Dey et al., 2020	In vivo. 6-month-old male C57BL/6J mice received X-ray irradiation in fractions of 8.67 Gy/day at a dose rate of 1.10 Gy/min on alternating days for a total dose of 26 Gy. Activated microglia were determined through CD68 staining in the hippocampus.	Measured 5 weeks post-irradiation, in the CA1 region, CD68+ cells increased 3-fold, while in the CA3 region they increased 5-fold. No significant changes in these areas were observed 15 weeks post-irradiation.
Chiang, McBride & Withers, 1993	In vivo. 12-week-old male C3Hf/Sed/Kam mice were irradiated with X-rays (238 cGy/min). Activated astrocytes and microglia were determined through GFAP and Mac-1 immunohistochemistry, respectively. ELISA was also used to measure GFAP.	From 30-45 Gy, GFAP was significantly increased 1.2-fold 15 days after irradiation, as well as 120-180 days after irradiation. Similarly, 150 days after irradiation, Mac-1 was increased 1.2- to 3-fold from 2 to 45 Gy.
Kyrkanides et al., 1999	In vivo. Male C3H/HeN mice were irradiated with 60Co gamma rays (35 Gy, 0.9 Gy/min). Activated astrocytes and microglia were determined through GFAP and Mac-1 immunohistochemistry, respectively.	Mac-1 was first seen increased after 4 h, but peaked at 24 h. GFAP was also first increased after 4 h, and increased throughout the 7 days measured.
Moravan et al., 2011	In vivo. 8- to 10-week-old male C57BL/6J mice were irradiated with 137Cs gamma rays at 1.25 Gy/min. GFAP expression was measured by RT-qPCR.	GFAP increased 2- to 3-fold after 25 and 35 Gy, but not significantly after 5 and 15 Gy. The significant increases were observed after 1, 30 and 180 days.

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

N/A

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

The domain of applicability is related to any vertebrates and invertebrates with an innate immune system regardless of sex (Beck & Habicht, 1996, Sonetti et al., 1994, Rowley, 1996). The deposition of energy is most detrimental in utero because tissue resident cells and their pro-inflammatory responses can cause permanent tissue damage (Heiervang et al., 2010, McCollough et al., 2007, Kannan et al., 2007).

References

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

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