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Relationship: 2769

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 Oxidative Stress

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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 adjacent High High Cataia Ives (send email) Open for citation & comment
Deposition of Energy Leading to Learning and Memory Impairment adjacent High Moderate Brendan Ferreri-Hanberry (send email) Open for citation & comment
Deposition of energy leading to occurrence of bone loss adjacent High Moderate Cataia Ives (send email) Open for citation & comment
Deposition of energy leading to occurrence of cataracts adjacent High High Arthur Author (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 Moderate NCBI
mouse Mus musculus Moderate NCBI
rat Rattus norvegicus High NCBI
rabbit Oryctolagus cuniculus Low NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male High
Female Moderate
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Juvenile High
Adult 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 deposited onto biomolecules stochastically in the form on ionizing and non-ionizing radiation can cause direct and indirect molecular-level damage. As energy is deposited in an aqueous solution, water molecules can undergo radiolysis, breaking bonds to produce reactive oxygen species (ROS) (Ahmadi et al., 2021; Karimi et al., 2017) or directly increase function of enzymes involved in ROS generation (i.e. catalaze). Various species of ROS can be generated with differing degrees of biological effects. For example, singlet oxygen, superoxide, and hydroxyl radical are highly unstable, with short half-lives and react close to where they are produced, while species like H2O2 are much more stable and membrane permeable, meaning they can travel from the site of production, reacting elsewhere as a much weaker oxidant (Spector, 1990). In addition, enzymes involved in reactive oxygen and nitrogen species (RONS) production can be directly upregulated following the deposition of energy (de Jager, Cockrell and Du Plessis, 2017). Although less common than ROS, reactive nitrogen species (RNS) can also be produced by energy deposition resulting in oxidative stress (Cadet et al., 2012; Tangvarasittichai & Tangvarasittichai, 2019), a state in which the amount of ROS and RNS, collectively known as RONS, overwhelms the cell’s antioxidant defense system. This loss in redox homeostasis can lead to oxidative damage to macromolecules including proteins, lipids, and nucleic acids (Schoenfeld et al., 2012; Tangvarasittichai & Tangvarasittichai, 2019; Turner et al., 2002). 

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 are several uncertainties and inconsistencies in this KER.  

  • Chen et al. (2021) found that radiation can have adaptive responses. The study used three neutron radiation doses, 0.4 and 1.2 Sv, and 3.6 Sv. After 0.4 and 1.2 Sv, the activity of antioxidant enzymes GSH and SOD increased, and the concentration of malondialdehyde, a product of oxidative stress, decreased. After 3.6 Sv, the opposite was true. 

  • While the concentration of most antioxidant enzymes decreases after energy deposition, there is some uncertainty with SOD. Certain papers have found that its concentration decreases with dose (Chen et al., 2021; Hua et al., 2019; Ji et al., 2015; Kang et al., 2020) while others found no difference after irradiation (Rogers et al., 2004; Zigman et al., 1995). Several studies have also found that higher levels of SOD do not increase resistance to UV radiation (Eaton, 1994; Hightower, 1995). 

  • At 1-week post-irradiation with 10 Gy of 60Co gamma rays, TICAE cells experienced a significant increase in levels of the antioxidant, PRDX5, contrary to the decrease generally seen in antioxidant levels following radiation exposure (Philipp et al., 2020). 

  • Various studies found an increase in antioxidant SOD levels within the brain after radiation exposure (Acharya et al., 2010; Baluchamy et al., 2012; Baulch et al., 2015; Veeraraghan et al., 2011). 

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 Factors

MF details

Effects on the KER

References

Antioxidants

CAT, GSH-Px, SOD, PRDX, vitamin E, C, carotene, lutein, zeaxanthin, selenium, zinc, alpha-lipoic acid, melatonin, gingko biloba leaf, fermented gingko biloba leaf, Nigella sativa oil, thymoquinone, and ferulic acid 

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

Zigman et al., 1995; Belkacémi et al., 2001; Chitchumroonchokchai et al., 2004; Fatma et al., 2005; Jiang et al., 2006; Fletcher, 2010; Karimi et al., 2017; Hua et al., 2019; Kang et al., 2020; Yang et al., 2020; Manda et al., 2008; Limoli et al., 2007; Manda et al., 2007; Taysi et al., 2012; Ismail et al., 2016; Demir et al., 2020; Chen et al., 2021

Age

Increased age

Antioxidant levels are lower and show a greater decrease after radiation in older organisms. This compromises their defense system, resulting in ROS increases and therefore, an increased likelihood of oxidative stress 

Marshall, 1985; Spector, 1990; Giblin et al., 2002; Kubo et al., 2010; Pendergrass et al., 2010; Zhang et al., 2012; Hamada et al., 2014; Tangvarasittichai & Tangvarasittichai, 2019

Oxygen

Increased oxygen levels

Higher oxygen concentrations increase sensitivity to ROS

Hightower et al., 1992; Eaton, 1994; Huang et al., 2006; Zhang et al., 2010; Schoenfeld et al., 2012

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

Most evidence is derived from in vitro studies, predominately using rabbit models. Evidence in humans and mice is moderate, while there is considerable available data using rat models. The relationship is applicable in both sexes, however, males are used more often in animal studies. No studies demonstrate the relationship in preadolescent animals, while adolescent animals were used very often, and adults were used occasionally in in vivo studies.