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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	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
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 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

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 minutes. 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 minutes. 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).