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Relationship: 2780

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, Endothelial Dysfunction

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, Endothelial Dysfunction

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 leads to vascular remodeling	non-adjacent	Moderate	Low	Cataia Ives (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
rabbit	Oryctolagus cuniculus	Moderate	NCBI

Sex Applicability

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

Sex	Evidence
Male	Moderate
Female	Moderate
Unspecific	Low

Life Stage Applicability

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

Term	Evidence
Adult	Moderate
Juvenile	Low
Not Otherwise Specified	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

Energy deposition can lead to ionization events that can directly interact with molecules within the cell and can subsequently lead to biological changes such as the formation of free radicals and the initiation of DNA damage repair mechanisms. Different radiation types have different physical properties and as a result the biological effects on cells may differ. Dose and dose rate of the deposited energy also play a role as these factors affect the amount and rate of energy deposited (Donaubauer et al., 2020). Repeated or prolonged exposure to radiation can exhaust the protective effect of the endothelium and lead to endothelial dysfunction (Baselet et al., 2019). Consequently, cells within the vascular endothelium may lose their integrity and become senescent or apoptotic via alterations to signaling pathways related to cell survival, leading to dysregulation of vasodilation and eventual endothelial dysfunction (Deanfield et al., 2007; Bonetti et al., 2003). Activation of the endothelium, consisting of inflammation, proliferation, thrombosis and low nitric oxide, occurs as a normal response to pathological conditions and oxidative stress from deposited energy (Krüger-Genge et al., 2019).

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 on radiation stressors 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

Much evidence for this relationship comes from high dose studies (>2 Gy); further work is needed at varying doses and dose rates to better understand the relationship.

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	Oxypurinol (Oxp) (a xanthine oxidase inhibitor)	Treatment led to increased endothelial relaxation response to ACh after irradiation.	(Soucy et al., 2011)
Drug	Vitamin C	Treatment increased the relaxation response to ACh after irradiation.	(On et al., 2001)
Drug	MnTBAP	Treatment restored vasodilation ability after irradiation.	(Hatoum et al., 2006)
Drug	Tempol	Treatment restored vasodilation ability after irradiation.	(Hatoum et al., 2006)
Drug	Human bone marrow stem cells	Both low and high doses decreased apoptosis after irradiation.	(Shen et al., 2018)

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

Examples of quantitative understanding of the relationship are shown in the table below. All data represented is statistically significant unless otherwise indicated.

Response-response Relationship

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

Dose Concordance 

Reference	Experiment Description	Result
Baselet et al., 2017	In vitro. X-ray radiation was delivered to human endothelial cells at a dose rate of 0.5 Gy/min for total doses of 0.05, 0.1, 0.5 and 2 Gy. SA-β-gal activity was used as a marker for senescence and endothelial dysfunction and was measured 14 days post exposure.	SA-β-gal activity for all radiation doses was significantly elevated above the non-irradiated control and increased with an increase in radiation dose. At the highest dose of 2 Gy, there was a 1.7-fold increase compared to control.
Soucy et al., 2011	In vivo. 3-4 months-old rats were whole body irradiated with 0.5 or 1 Gy of ⁵⁶Fe ions before their aortas were harvested and the endothelium dependent vasodilation response to ACh was evaluated at 4 months post-irradiation.	A 0.5 Gy dose did not show significant changes to maximum relaxation response to ACh compared to non-irradiated control. Following a 1 Gy dose there was a 0.8-fold decrease in maximum relaxation response to ACh compared to non-irradiated control.
Soucy et al., 2010	In vivo. 4-months-old rats were irradiated with 5 Gy of ¹³⁷Cs, and the endothelium dependent vasodilation response to ACh of harvested aortas was evaluated.	There was a 0.6-fold decrease in maximum relaxation response to ACh in the aorta compared to the non-irradiated control.
Soloviev et al., 2003	In vivo. The endothelium dependent vasorelaxation response to ACh of aortas from rabbits exposed to 6 Gy of ⁶⁰Co whole body irradiation was evaluated 9 days post exposure. Furthermore, endothelium dependent relaxation response following exposure to 1, 2, and 4 Gy on the 7th day post exposure were also evaluated.	9 days after exposure to 6 Gy, there was a 0.5-fold decrease in maximum relaxation response to ACh. At 7 days post irradiation, maximum relaxation response to ACh decreased with an increase in radiation dose, with 60% maximum relaxation at 0 Gy dropping down to 30% after 4 Gy.
Shen et al., 2018	In vivo. 18 Gy of X-ray radiation was delivered to 8-week-old mice. Apoptosis was evaluated using TUNEL assays at 3-, 7-, 14-, 28- and 84-days post irradiation.	Apoptosis levels in 18 Gy irradiated groups were significantly elevated above sham irradiated control at all time points tested. The difference peaked 7-days post irradiation at a 5-fold increase compared to control.
Hatoum et al., 2006	In vivo. Rats were whole body irradiated with up to 2250 cGy via 9 fractions of 250 cGy X-rays at a dose rate of 243 cGy/min. Endothelium dependent vasodilation response to ACh of harvested submucosal vessels was evaluated at various radiation doses.	After the final dose (total 22.5 Gy) there was a 0.03-fold decrease in maximum relaxation response to ACh in irradiated rat microvessels compared to non-irradiated controls. Following dose 1 and 2 (250 cGy and 500 cGy total dose), maximum dilation remained similar to non-irradiated control (~90% maximum dilation). However, following the third dose (750 cGy total), maximum dilation dropped below 10% and remained significantly below non-irradiated control levels for all remaining doses tested.

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

Time Concordance

Reference	Experiment Description	Result
Yentrapalli et al., 2013a	In vitro. Chronic gamma irradiation (¹³⁷Cs) was delivered to human umbilical vein endothelial cells (HUVECs) at a dose rate of 1.4 mGy/h or 2.4 mGy/h. SA-β-gal activity was used as a marker for premature endothelial cell senescence and was evaluated at 1-, 3-, 6-, 10- and 12-weeks post irradiation.	Between 1 to 6 weeks post irradiation no significant differences were observed between either of the irradiated groups and the sham irradiated control. At the 10- and 12-week time points, the 1.4 mGy/h exposure continued to show no significant changes from control, while the 2.4 mGy/h group showed a 1.7-fold increase at 10-weeks and 1.9-fold increase at 12-weeks.
Yentrapalli et al., 2013b	In vitro. Chronic gamma (¹³⁷Cs) of HUVECs at a dose rate of 4.1 mGy/h for up to 6 weeks for final doses of 0.69, 2.07 and 4.13 Gy. SA-β-gal activity was used as a marker for premature endothelial cell senescence and was evaluated at 1-, 3- and 6-weeks post exposure.	No significant changes in SA-β-gal activity were observed between irradiated and sham irradiated groups in the first week. SA-β-gal activity was significantly elevated in irradiated HUVECs at the 3- and 6-week timepoints, showing a 2-fold and 3-fold elevation above control respectively.
Soucy et al., 2011	In vivo. 3-4 months-old rats were whole body irradiated with 0.5 or 1 Gy of ⁵⁶Fe ions before their aortas were harvested and the endothelium dependent vasodilation response to ACh was evaluated.	At 4 months post radiation there was a 0.8-fold decrease in maximum relaxation response to ACh with a return to control levels by 6 months.
Soloviev et al., 2003	In vivo. The maximum endothelium dependent vasorelaxation response to ACh of aortas from rabbits having been whole body irradiated to 6 Gy ⁶⁰Co gamma-rays was evaluated 9- and 30-days post exposure.	At both 9- and 30-days post-irradiation there was a ~0.5-fold decrease in maximum relaxation response to ACh compared to non-irradiated control. There was no significant difference in maximum relaxation between the 9- and 30-day timepoints.
Shen et al., 2018	In vivo. 18 Gy of X-ray radiation was delivered to 8-week-old mice with apoptosis levels being measured for up to 84 days post-irradiation in the aorta.	There was a significant increase of 3-fold in apoptosis as soon as 3 days post-irradiation with a peak of 7-fold after 7 days. There was a gradual return to a 3-fold increase by 84 days.

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

Not identified.

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 evidence for the taxonomic applicability to humans is low as the majority of the evidence is from in vitro human-derived cells. The relationship is supported by both sexes of mouse, rat, and rabbit models. The in vivo studies were mostly undertaken in adolescent or adult rats and mice. In addition, the relationship is likely at any life stage.