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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 Increase, Oxidative Stress

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, Oxidative Stress

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 abnormal vascular remodeling	adjacent	High	High	Vinita Chauhan (send email)	Open for citation & comment	WPHA/WNT Endorsed
Deposition of Energy Leading to Learning and Memory Impairment	adjacent	High	Moderate	Vinita Chauhan (send email)	Open for citation & comment	WPHA/WNT Endorsed
Deposition of energy leading to occurrence of bone loss	adjacent	High	Moderate	Vinita Chauhan (send email)	Open for citation & comment	WPHA/WNT Endorsed
Deposition of energy leading to occurrence of cataracts	adjacent	High	High	Vinita Chauhan (send email)	Open for citation & comment	WPHA/WNT Endorsed

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 defence 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 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: High

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

A large body of literature supports the linkage between the deposition of energy and oxidative stress. Multiple reviews describe the relationship in the context of ROS production (Marshall, 1985; Balasubramanian, 2000; Jurja et al., 2014), antioxidant depletion (Cabrera et al., 2011; Fletcher, 2010; Ganea & Harding, 2006; Hamada et al., 2014; Spector, 1990; Schoenfeld et al., 2012; Wegener, 1994), and overall oxidative stress (Eaton, 1994, Tangvarasittichai & Tangvarasittichain, 2019). This includes investigations into the mechanism behind the relationship (Ahmadi et al., 2021; Balasubramanian, 2000; Cencer et al., 2018; Eaton, 1994; Fletcher, 2010; Jiang et al., 2006; Jurja et al., 2014; Padgaonkar et al., 2015; Quan et al., 2021; Rong et al., 2019; Slezak et al., 2015; Soloviev & Kizub, 2019; Tian et al., 2017; Tahimic & Globus, 2017; Varma et al., 2011; Venkatesulu et al., 2018; Wang et al., 2019a; Yao et al., 2008; Yao et al., 2009; Zigman et al., 2000).

Water radiolysis is a main source of free radicals. Energy ionizes water and free radicals are produced that combine to create more stable ROS, such as hydrogen peroxide, hydroxide, superoxide, and hydroxyl (Eaton, 1994; Rehman et al., 2016; Tahimic & Globus, 2017; Tian et al., 2017; Varma et al., 2011; Venkatesulu et al., 2018). ROS formation causes ensuing damage to the body, as ~80% of tissues are comprised of water (Wang et al., 2019a). Ionizing radiation (IR) is a source of energy deposition, it can also interact with molecules, such as nitric oxide (NO), to produce less common free radicals, including RNS (Slezak et al., 2015; Tahimic & Globus, 2017; Wang et al., 2019a). Free radicals can diffuse throughout the cell and damage vital cellular components, such as proteins, lipids, and DNA, as well as dysregulate cellular processes, such as cell signaling (Slezak et al., 2015; Tian et al., 2017).

ROS are also commonly produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). Deposition of energy can activate NOX and induce expression of its catalytic and cytosolic components, resulting in increased intracellular ROS (Soloviev & Kizub, 2019). Intracellular ROS production can also be initiated through the expression of protein kinase C, which in turn activates NOX through phosphorylation of its cytosolic components (Soloviev & Kizub, 2019). Alternatively, ROS are often formed at the electron transport chain (ETC) of the mitochondria, due to IR-induced electron leakage leading to ionization of the surrounding O2 to become superoxide (Soloviev & Kizub, 2019). Additionally, energy reaching a cell can be absorbed by an unstable molecule, often NADPH, known as a chromophore, which leads to the production of ROS (Balasubramanian, 2000; Cencer et al., 2018; Jiang et al., 2006; Jurja et al., 2014; Padgaonkar et al., 2015; Yao et al., 2009; Zigman et al., 2000).

Energy deposition can also weaken a cell’s antioxidant defence system through the depletion of certain antioxidant enzymes, such as superoxide dismutase (SOD) and catalase (CAT). Antioxidants are consumed during the process of neutralizing ROS, so as energy deposition stimulates the formation of ROS it begins to outpace the rate at which antioxidants are replenished; this results in an increased risk of oxidative stress when their concentrations are low (Belkacémi et al., 2001; Giblin et al., 2002; Ji et al., 2014; Kang et al., 2020; Karimi et al., 2017; Padgaonkar et al., 2015; Rogers et al., 2004; Slezak et al., 2015; Tahimic & Globus, 2017; Wang et al., 2019a; Wegener, 1994; Weinreb & Dovrat, 1996; Zhang et al., 2012; Zigman et al., 1995; Zigman et al., 2000). When the amount of ROS overwhelms the antioxidant defence system, the cell will enter oxidative stress leading to macromolecular and cellular damage (Tangvarasittichai & Tangvarasittichai, 2019).

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 relationship between energy deposition and oxidative stress is strongly supported by primary research on the effects of IR on ROS and antioxidant levels (Bai et al., 2020; Cervelli et al., 2017; Hatoum et al., 2006; Huang et al., 2018; Huang et al., 2019; Karam & Radwan, 2019; Kook et al., 2015; Liu et al., 2018; Liu et al., 2019; Mansour, 2013; Philipp et al., 2020; Ramadan et al., 2020; Sharma et al., 2018; Shen et al., 2018; Soltani et al., 2016; Soucy et al., 2010; Soucy et al., 2011; Ungvari et al., 2013; Wang et al., 2016; Wang et al., 2019b; Zhang et al., 2018; Zhang et al., 2020). Of note is that the relationship is demonstrated across studies conducted using various cell types, models and using broad dose ranges as summarized below. Much evidence is available and described to help discern the quantitative understanding of the relationship, since it is well established.

Dose Concordance

It is well-accepted that any dose of radiation will deposit energy onto matter. Doses as low as 1 cGy support this relationship (Tseung et al., 2014). Following the deposition of energy, markers of oxidative stress are observed in the form of RONS, a change in levels of antioxidants, and oxidative damage to macromolecules. These effects have been shown across various organs/tissues and cell types as described below.

RONS

Cardiovascular tissue:

There is a considerable amount of evidence to support this relationship in cell types and tissues of relevance to the cardiovascular system. Recent studies have shown a linear increase in ROS in human umbilical vein endothelial cells (HUVECs) following 0-5 Gy gamma irradiation (Wang et al., 2019b). HUVECs irradiated with 0.25 Gy X-rays (Cervelli et al., 2017) and 9 Gy 250kV photons (Sharma et al., 2018) show increased ROS. Gamma ray irradiated rats at 5 Gy display increased ROS levels in the aorta (Soucy et al., 2010). A study using cerebromicrovascular endothelial cell (CMVECs) showed a dose-dependent increase in ROS from 0-8 Gy gamma irradiation (Ungvari et al., 2013). Additionally, telomerase-immortalized coronary artery endothelial (TICAE) and telomerase-immortalized microvascular endothelial (TIME) cells irradiated with 0.1 and 5 Gy of X-rays displayed increased ROS production (Ramadan et al., 2020). Gut arterioles of rats showed increased ROS following multiple fractions of 2.5 Gy X-ray rat irradiation (Hatoum et al., 2006). Additionally, rats irradiated with 1 Gy of 56Fe expressed increased ROS levels in the aorta (Soucy et al., 2011).

Brain tissue:

Markers of oxidative stress have also been consistently observed in brain tissue. Human neural stem cells subjected to 1, 2 or 5 Gy gamma rays showed a dose-dependent increase in RONS production (Acharya et al., 2010). A dose-dependent increase in ROS was observed in rat brains following 1-10 Gy gamma rays (Collins-Underwood et al., 2008). Neural precursor cells exposed to 0-10 Gy of X-irradiation showed increased ROS levels (Giedzinski et al., 2005; Limoli et al., 2004). Mice brain tissue displayed increased ROS following proton irradiation (Baluchamy et al., 2012; Giedzinski et al., 2005). Neural processor cells expressed linearly increased ROS levels following doses of 56Fe (Limoli et al., 2007). A dose-dependent increase in RONS was also observed after exposure to 1-15 cGy 56Fe irradiation in mice neural stem/precursor cell (Tseng et al., 2014). Human neural stem cells exposed to 5-100 cGy of various ions demonstrated a dose-dependent increase in RONs (Baulch et al., 2015).

Eye tissue:

The eye is also sensitive to the accumulation of free radicals, in a state of antioxidant decline. It has been shown in human lens epithelial cells (HLECs) and HLE-B3 following gamma irradiation of 0.25 and 0.5 Gy that ROS levels are markedly increased (Ahmadi et al., 2021). Exposure to non-ionizing radiation, such as ultraviolet (UV)-B, has also led to increased ROS in HLECs and mice lenses (Ji et al., 2015; Kubo et al., 2010; Rong et al., 2019; Yang et al., 2020)

Bone tissue:

Rat bone marrow-derived mesenchymal stem cell (bmMSCs) irradiated with 2, 5 and 10 Gy gamma rays and murine MC3T3-E1 osteoblast cells irradiated with 2, 4, and 8 Gy of X-rays have shown a dose-dependent increase in ROS levels (Bai et al., 2020; Kook et al., 2015). Murine RAW264.7 cells and rat bmMSC irradiated with 2 Gy of gamma rays displayed increased ROS levels (Huang et al., 2019; Huang et al., 2018; hang et al., 2020). Human bone marrow-derived mesenchymal stem cell (hBMMSCs) irradiated with 2 or 8 Gy X-rays showed increased ROS (Liu et al., 2018; Zhang et al., 2018). Similarly, murine MC3T3-E1 osteoblast-like cells irradiated with 6 Gy of X-rays also displayed increased ROS (Wang et al., 2016). Finally, whole-body irradiation of mice with 2 Gy of 31.6 keV although LET 12C heavy ions showed increased ROS (Liu et al., 2019)

Antioxidants

Blood:

Workers exposed to X-rays at less than 1 mSv/year for an average of 15 years showed around 20% decreased antioxidant activity compared to unexposed controls (Klucinski et al., 2008). Similarly, adults exposed to high background irradiation of 260 mSv/year showed about 50% lower antioxidant activity power compared to controls (Attar, Kondolousy and Khansari, 2007).

Cardiovascular tissue:

Heart tissue of rats following gamma irradiation of rats at 5 and 6 Gy resulted in a decrease in antioxidant levels (Karam & Radwan, 2019; Mansour, 2013). Similarly, HUVECs (Soltani, 2016) and TICAE cells (Philipp et al., 2020) irradiated at 2 Gy and 0.25-10 Gy gamma rays, respectively, displayed decreased antioxidant levels. Mice exposed to 18 Gy of X-ray irradiation showed decreased antioxidants in the aorta (Shen et al., 2018).

Brain tissue:

Mice brain tissue following 2, 10 and 50 cGy whole-body gamma irradiation revealed a dose-dependent change in SOD2 activity (Veeraraghan et al., 2011). Mice brain tissue showed decreased glutathione (GSH) and SOD levels following proton irradiation (Baluchamy et al., 2012)

Eye tissue:

Rats exposed to 15 Gy gamma rays demonstrated decreased antioxidants in the lens tissue (Karimi et al, 2017). Neutron irradiation of rats at 3.6 Sv resulted in a decrease in antioxidants in lens (Chen et al., 2021). A few studies found a dose concordance between UV irradiation and decreased antioxidant levels (Hua et al, 2019; Ji et al, 2015; Zigman et al., 2000; Zigman et al, 1995). HLECs following UVB exposure from 300 J/m2 to 14,400 J/m2 in HLECs showed linear decreases in antioxidant activity (Ji et al., 2015). Similarly, HLEC exposed to 4050, 8100 and 12,150 J/m2 found decreased antioxidant levels (Hua et al., 2019). Following UV irradiation of rabbit and squirrel lens epithelial cells (LECs) showed a linear decrease of antioxidant level, CAT (Zigman et al., 2000; Zigman et al., 1995). Mice exposed to UV irradiation found decreased antioxidant levels in lens (Zhang et al., 2012). Similarly, SOD levels decreased following 0.09 mW/cm 2 UVB exposure of HLECs (Kang et al., 2020).

Bone tissue:

Rat bmMSCs irradiated with 2, 5 and 10 Gy gamma rays and Murine MC3T3-E1 osteoblast cells irradiated with 2, 4, and 8 Gy of X- rays showed a dose-dependent decrease in antioxidant levels (Bai et al., 2020; Kook et al., 2015). hBMMSCs irradiated with 8 Gy X-rays also showed a decrease in antioxidant, SOD, levels (Liu et al., 2018).

Oxidative Damage

Cardiovascular tissue:

HUVECs and rat hearts irradiated by gamma rays at 2 and 6 Gy, respectively, resulted in increased levels of oxidative stress markers, such as malondialdehyde (MDA), and thiobarbituric reactive substances (TBARS) (Mansour, 2013; Soltani, 2016).

Brain tissue:

Mice brain tissue were shown to have increased lipid peroxidation (LPO) as determined by MDA measurements, following proton irradiation at 1 and 2 Gy (Baluchamy et al., 2012). Neural precursor cells from rat hippocampus exposed to 0, 1, 5 and 10 Gy of X- irradiation resulted in increased lipid peroxidation (Limoli et al., 2004).

Eye tissue:

Rats exposed to 15 Gy gamma rays demonstrated increased MDA in lens tissue (Karimi et al, 2017). Neutron irradiation of rats at 3.6 Sv resulted in an initial decrease, followed by an increase in MDA in lens (Chen et al., 2021). Following UV irradiation at 300, 4050, 8100 and 12,150 J/m2, there was an increase in LPO in human lens (Chitchumroonchokchai et al., 2004; Hua et al., 2019). Similarly, LPO increased following 0.09 mW/cm2 UVB exposure of HLECs (Kang et al., 2020).

Time Concordance

It is well-accepted that deposition of energy into matter results in immediate vibrational changes to molecules or ionization events. Deposition of energy is therefore an upstream event to all follow-on latent events like oxidative stress.

RONS

Cardiovascular tissue:

In TICAE and TIME cells, ROS increased at 45 minutes after X-ray irradiation (Ramadan et al., 2020). Superoxide and peroxide production were increased 1 day after 2-8 Gy of gamma irradiation in CMVECs (Unvari et al., 2013).

Bone tissue:

hBMMSCs irradiated with X-rays at 2 Gy showed peak ROS production at 2-8h post-irradiation (Zhang et al., 2018). Murine RAW264.7 cells (can undergo osteoclastogenesis) irradiated with 2 Gy of gamma rays showed increased ROS at 2-8h post- irradiation (Huang et al., 2018).

Brain tissue:

In human lymphoblast cells exposed to 2 Gy of X-rays, ROS were increased at various times between 13 and 29 days post- irradiation (Rugo and Schiestl, 2004). RONS were increased in human neural stem cells at 12-48h post-irradiation with 2 and 5 Gy of gamma rays (Acharya et al., 2010). ROS levels were increased in rat neural precursor cells at 6-24h after irradiation with 1-10 Gy of protons (Giedzinksi et al., 2005). Both 56Fe (1.3 Gy) and gamma ray (2 Gy) irradiation of mice increased ROS levels after 2 months post-irradiation in the cerebral cortex (Suman et al., 2013). ROS were also increased 12 months after 56Fe irradiation (Suman et al., 2013). RONS increased as early as 12h post-irradiation continuing to 8 weeks with 2-200 cGy doses of 56Fe irradiation of mouse neural stem/precursor cells (Tseng et al., 2014). The same cell type irradiated with 1 and 5 Gy of 56Fe irradiation showed increased ROS at 6h post-irradiation, with the last increase observed 25 days post-irradiation (Limoli et al., 2004).

Eye tissue:

Mice exposed to 11 Gy of X-rays showed increased ROS at 9 months post-irradiation in lenses (Pendergrass et al., 2010). In human lens cells, ROS were found increased at 1h after 0.25 Gy gamma ray irradiation (Ahmadi et al., 2021), 15 minutes after 30 mJ/cm2 UV radiation (Jiang et al., 2006), 2.5-120 minutes after 0.014 and 0.14 J/cm2 UV radiation (Cencer et al., 2018), and 24h after 30 mJ/cm2 UVB-radiation (Yang et al., 2020).

Antioxidants

Cardiovascular tissue:

CAT antioxidant enzyme was decreased in mice aortas as early as 3 days post-irradiation, remaining decreased until 84 days after irradiation with 18 Gy of X-rays (Shen et al., 2018). The antioxidant enzymes peroxiredoxin 5 (PRDX5) and SOD were both shown to have the greatest decrease at 24h after 2 Gy gamma irradiation of TICAE cells (Philipp et al., 2020).

Eye tissue:

Bovine lenses irradiated with 44.8 J/cm2 of UVA radiation showed decreased CAT levels at 48-168h post-irradiation (Weinreb and Dovrat, 1996). UV irradiation of mice at 20.6 kJ/m2 led to decreased GSH at both 1 and 16 months post-irradiation in the lens (Zhang et al., 2012). Bovine lens cells exposed to 10 Gy of X-rays showed decreased levels of the antioxidant GSH at 24 and 120h after exposure (Belkacemi et al., 2001).

Oxidative damage markers

Cardiovascular tissue:

Oxidative damage markers 4-hydroxynonemal (4-HNE) and 3-Nitrotyosine (3-NT) were both significantly increased in the aorta of mice at 3 days post-irradiation, remaining increased until 84 days after irradiation with 18 Gy of X-rays (Shen et al., 2018).

Essentiality

Radiation has been found to induce oxidative stress above background levels. Many studies have shown that lower doses of ionizing radiation resulted in decreased levels in markers of oxidative stress in multiple cell types (Acharya et al., 2010; Ahmadi et al., 2021; Bai et al., 2020; Baluchamy et al., 2012 Chen et al., 2021; Collins-Underwood et al., 2008; Giedzinski et al., 2005; Kook et al., 2015; Kubo et al., 2010; Philipp et al., 2020; Ramadan et al., 2020; Ungvari et al., 2013; Veeraraghan et al., 2011; Wang et al., 2019b; Zigman et al., 2000; Zigman et al., 1995). The essentiality of deposition of energy can be assessed through the removal of deposited energy, a physical stressor that does not require to be metabolized in order to elicit downstream effects on a biological system. 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 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).
Chien et al. (2015) found no changes to ROS levels in hippocampal neurons five days after 0.2 Gy of electron radiation.
Antioxidants that increase in expression are indicative of the presence of RONS. When antioxidants decrease in expression/activity, this is most likely due to the overwhelming of the antioxidant defence mechanisms
There is limited data to support an understanding of deposition of energy leading to oxidative stress at low doses.

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, ginko biloba leaf, fermented ginkobiloba 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 defence 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)

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.

Response-response Relationship

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

Dose Concordance

Reference	Experiment Description	Result
Attar, Kondolousy and Khansari, 2007	In vivo. One hundred individuals between 20 and 50 years old in two villages in Iran exposed to background IR at 260 mSv/year had antioxidant levels measured. The control group was from two villages not exposed to the high background radiation. The total antioxidant levels in the blood were determined by the ferric reducing/antioxidant power assay.	The total antioxidant level was significantly reduced from 1187±199 µmol in the control to 686±170 µmol in the exposed group.
Klucinski et al., 2008	In vivo. A group of 14 men and 31 women aged 25–54 years working X-ray equipment (receiving doses of less than 1 mSv/year) for an average of 15.3 years (range of 2-33 years) were compared to a control group for antioxidant activity. Antioxidant activity of SOD, glutathione peroxidase (GSH-Px), and CAT in erythrocytes were measured in U/g of hemoglobin.	Enzymes (SOD, GSH, CAT) showed significantly decreased antioxidant activity in the workers. In the controls (U/g of Hb): SOD: 1200 ± 300 GSH-Px: 39 ± 7 CAT: 300 ± 60 In the workers (U/g of Hb): SOD: 1000 ± 200 GSH-Px: 29 ± 4 CAT: 270 ± 50
Limoli et al., 2007	In vitro. Neural precursor cells isolated from rat hippocampi was exposed to 0.25-5 Gy of 56Fe irradiation at dose rates of 0.5-1.0 Gy/min. ROS were measured 6h post-irradiation.	At a low dose of 0.25 Gy and 0.5 Gy, relative ROS levels were significantly elevated and showed a linear dose response (from ~1 to ~2.25 relative ROS levels) until 1 Gy, where it reached its peak (~3 relative ROS levels). At higher doses, the relative ROS levels decreased.
Tseng et al., 2014	In vitro. Neural stem/precursor cells isolated from mouse subventricular and hippocampal dentate subgranular zones were exposed to 1-15 cGy of 56Fe irradiation at dose rates ranging from 5-50 cGy/min. RONS levels were measured.	A dose-dependent and significant rise in RONS levels was detected after 56Fe irradiation. 12 h post-irradiation, a steady rise was observed and reached a 6-fold peak after 15 cGy.
Limoli et al., 2004	In vitro. Neural precursor cells from rat hippocampus were exposed to 0, 1, 5 and 10 Gy of X-irradiation at a dose rate of 4.5 Gy/min. ROS levels were measured. In vivo. MDA was used to quantify oxidative stress.	A dose-dependent increase in ROS levels was seen in the first 12 h post-irradiation, with relative maximums at 12 h after 5 Gy (35% increase) and 24 h after 1 Gy (31% increase). ROS levels measured 1 week after 5 Gy were increased by 180% relative to sham-irradiated controls. MDA levels increased significantly (approximately 1.3-fold) after exposure to 10 Gy.
Collins-Underwood et al., 2008	In vitro. Immortalized rat brain microvascular endothelial cells were exposed to 1-10 Gy of 137Cs-irradiation at a dose rate of 3.91 Gy/min. Intracellular ROS and O2- production were both measured.	Irradiation resulted in a significant dose-dependent increase in intracellular ROS generation from 1-10 Gy. At 5 Gy, there was an approximate 10-fold increase in ROS levels, and at 10 Gy there was an approximate 20-fold increase.
Giedzinski et al., 2005	In vitro. Neural precursor cells were irradiated with 1, 2, 5 and 10 Gy of 250 MeV protons (1.7-1.9 Gy/min) and X-irradiation (4.5 Gy/min). ROS levels were measured.	There was a rapid increase in ROS at 6, 12, 18 and 24h after proton irradiation, with an exception at the 1 Gy 18h point. Most notably, at 6h post-irradiation, a dose-dependent increase in relative ROS levels from 1 to 10 Gy was seen that ranged from 15% (at 1 Gy) to 65% (at 10 Gy). Linear regression analysis showed that at ≤2 Gy, ROS levels increased by 16% per Gy. The linear dose response obtained at 24h showed that proton irradiation increased the relative ROS levels by 3% per Gy.
Veeraraghan et al., 2011	In vivo. Adult mice were exposed to 2, 10 or 50 cGy of whole-body gamma irradiation at 0.81 Gy/min. Brain tissues were harvested 24h post-irradiation. SOD2 levels and activity were measured.	Compared to the controls, the levels of SOD2 expression increased in the brain after 2, 10 and 50 cGy. Analysis revealed a significant and dose-dependent change in SOD2 activity. More specifically, SOD2 activity showed significant increases after 10 (~25% increase above control) and 50 cGy (~60% increase above control), but not 2 cGy.
Baluchamy et al., 2012	In vivo. Male mice were exposed to whole-body irradiation with 250 MeV protons at 0.01, 1 and 2 Gy and the whole brains were dissected out. ROS, LPO, GSH and total SOD were measured.	Dose-dependent increases in ROS levels was observed compared to controls, with a two-fold increase at 2 Gy. A 2.5 to 3-fold increase in LPO levels was also seen at 1 and 2 Gy, respectively, which was directly correlated with the increase in ROS levels. Additionally, results showed a significant reduction in GSH (~70% decrease at 2 Gy) and SOD activities (~2-fold decrease) following irradiation that was dose-dependent.
Acharya et al., 2010	In vitro. Human neural stem cells were subjected to 1, 2 or 5 Gy of gamma irradiation at a dose rate of 2.2 Gy/min. RONS and superoxide levels were determined.	Intracellular RONS levels increased by approximately 1.2 to 1.3-fold compared to sham-irradiated controls and was found to be reasonable dose-responsive. At 12h, levels of superoxide increased 2 and 4-fold compared to control for 2 and 5 Gy, respectively. At 24h and 48h, there was a dose-dependent increase in RONS levels. At 7 days, levels of RONS increased approximately 3 to 7-fold for 2 and 5 Gy, respectively.
Baulch et al., 2015	In vitro. Human neural stem cells were exposed to 5-100 cGy of 16O, 28Si, 48Ti or 56Fe particles (600 MeV) at 10-50 cGy/min. RONS and superoxide levels were determined.	3 days post-irradiation, oxidative stress was found to increase after particle irradiation. Most notably, exposure to 56Fe resulted in a dose-dependent increase with 100% increase in RONS levels at 100 cGy. Dose-dependent increase was also seen in superoxide levels after 56Fe irradiation. At 7 days post-irradiation, 56Fe irradiation induced significantly lower nitric oxide levels by 47% (5 cGy), 55% (25 cGy) and 45% (100 cGy).
Bai et al., 2020	In vitro. bmMSCs were taken from 4-week-old, male Sprague-Dawley rats. After extraction, cells were then irradiated with 2, 5, and 10 Gy of 137Cs gamma rays. Intracellular ROS levels and relative mRNA expression of the antioxidants, SOD1, SOD2, and CAT2, were measured to assess the extent of oxidative stress induced by IR.	Cellular ROS levels increased significantly in a dose-dependent manner from 0-10 Gy. Compared to sham-irradiated controls, ROS levels increased by ~15%, ~55%, and ~105% after exposure to 2, 5, and 10 Gy, respectively. Antioxidant mRNA expression decreased in a dose-dependent manner from 0-10 Gy, with significant increases seen at doses 2 Gy for SOD1 and CAT2 and 5 Gy for SOD2. Compared to sham-irradiated controls, SOD1 expression decreased by ~9%, ~18%, and ~27% after exposure to 2, 5, and 10 Gy, respectively. SOD2 expression decreased by ~31% and ~41% after exposure to 5 and 10 Gy, respectively. CAT2 expression decreased by ~15%, ~33%, and ~58% after exposure to 2, 5, and 10 Gy, respectively.
Liu et al., 2018	In vitro. hBMMSCs were irradiated with 8 Gy of X-rays at a rate of 1.24 Gy/min. Intracellular ROS levels and SOD activity were measured to analyze IR-induced oxidative stress.	Compared to sham-irradiated controls, hBMMSCs irradiated with 8 Gy of X-rays experienced a significant increase to intracellular ROS levels. hBMMSCs irradiated with 8 Gy of X-rays experienced a ~46% reduction in SOD activity.
Kook et al., 2015	In vitro. Murine MC3T3-E1 osteoblast cells were irradiated with 2, 4, and 8 Gy of X-rays at a rate of 1.5 Gy/min. Intracellular ROS levels and the activity of antioxidant enzymes, including GSH, SOD, CAT, were measured to assess the extent of oxidative stress induced by IR exposure.	Compared to sham-irradiated controls, irradiated MC3T3-E1 cells experienced a dose-dependent increase in ROS levels, with significant increases at 4 and 8 Gy (~26% and ~38%, respectively). Antioxidant enzyme activity initially increased by a statistically negligible amount from 0-2 Gy and then decreased in a dose-dependent manner from 2-8 Gy. SOD activity decreased significantly at 4 and 8 Gy by ~29% and ~59%, respectively. GSH activity similarly decreased significantly at 4 and 8 Gy by ~30% and ~48%, respectively. CAT activity did not change by a statistically significant amount.
Liu et al., 2019	In vivo. 8–10-week-old, juvenile, female SPF BALB/c mice underwent whole-body irradiation with 2 Gy of 31.6 keV/µm 12C heavy ions at a rate of 1 Gy/min. ROS levels were measured from femoral bone marrow mononuclear cells of the irradiated mice to analyze IR-induced oxidative stress.	Compared to sham-irradiated controls, irradiated mice experienced a ~120% increase in ROS levels.
Zhang et al., 2020	In vitro. Murine RAW264.7 osteoclast precursor cells were irradiated with 2 Gy of 60Co gamma rays at a rate of 0.83 Gy/min. ROS levels were measured to determine the extent of oxidative stress induced by IR exposure.	Compared to sham-irradiated controls, ROS levels in irradiated RAW264.7 cells increased by ~100%.
Wang et al., 2016	In vitro. Murine MC3T3-E1 osteoblast-like cells were irradiated with 6 Gy of X-rays. Intracellular ROS production was measured to assess oxidative stress from IR exposure.	Compared to sham-irradiated controls, intracellular ROS production increased by ~81%.
Huang et al., 2018	In vitro. Murine RAW264.7 osteoblast-like cells were irradiated with 2 Gy of gamma rays at a rate of 0.83 Gy/min. ROS levels were measured to analyze IR-induced oxidative stress.	Compared to sham-irradiated controls, ROS levels in RAW264.7 cells increased by ~138% by 2 h post-irradiation.
Zhang et al., 2018	In vitro. hBMMSCs were irradiated with 2 Gy of X-rays at a rate of 0.6 Gy/min. Relative ROS concentration was measured to assess the extent of oxidative stress induced by IR.	Compared to sham-irradiated controls, irradiated hBMMSCs experienced a maximum increase of ~90% to ROS levels at 3 h post-irradiation.
Huang et al., 2019	In vitro. Rat bmMSC were irradiated with 2 Gy of 60Co gamma rays at a rate of 0.83 Gy/min. ROS levels were measured to assess IR-induced oxidative stress.	Compared to sham-irradiated controls, ROS levels in irradiated bone marrow stromal cells increased by approximately 2-fold.
Soucy et al., 2011	In vivo. 7- to 12-month-old, adult, male Wistar rats underwent whole-body irradiation with 1 Gy of 56Fe heavy ions. ROS production in the aorta was measured along with changes in activity of the ROS-producing enzyme xanthine oxidase (XO) to assess IR-induced oxidative stress.	Compared to sham-irradiated controls, irradiated mice experienced a 74.6% increase in ROS production (from 4.84 to 8.45) and XO activity increased by 36.1% (6.12 to 8.33).
Soucy et al., 2010	In vivo. 4-month-old, adult, male Sprague-Dawley rats underwent whole-body irradiation with 5 Gy of 137Cs gamma rays. Changes in XO activity and ROS production were measured in the aortas of the mice to assess IR-induced oxidative stress.	Compared to sham-irradiated controls, irradiated mice experienced a ~68% increase in ROS production and a ~46% increase in XO activity.
Karam & Radwan, 2019	In vivo. Adult male Albino rats underwent irradiation with 5 Gy of 137Cs gamma rays at a rate of 0.665 cGy/s. Activity levels of the antioxidants, SOD and CAT, present in the heart tissue were measured to assess IR-induced oxidative stress.	Compared to the sham-irradiated controls, SOD and CAT activity decreased by 57% and 43%, respectively, after irradiation.
Cervelli et al., 2017	In vitro. HUVECs were irradiated with 0.25 Gy of X-rays at a rate of 91 mGy/min. ROS production was measured to analyze IR-induced oxidative stress.	Compared to the sham-irradiated controls, irradiated mice experienced a ~171% increase in ROS production (not significant).
Mansour, 2013	In vivo. Male Wistar rats underwent whole-body irradiation with 6 Gy of 137Cs gamma rays at a rate of 0.012 Gy/s. MDA was measured from heart homogenate, along with the antioxidants: SOD, GSH, and GSH-Px.	Compared to sham-irradiated controls, MDA increased by 65.9%. SOD, GSH-Px, and GSH decreased by 33.8%, 42.4%, and 50.0%, respectively.
Soltani, 2016	In vitro. HUVECs were irradiated with 2 Gy of ⁶⁰Co gamma rays at a dose rate of 0.6 Gy/min. Markers of oxidative stress, including reduced GSH and TBARS, were measured to assess GSH depletion and LPO, respectively.	Compared to non-irradiated controls, sham-irradiated cells experienced a ~28% decrease in GSH and a ~433% increase in TBARS.
Wang et al., 2019b	In vitro. HUVECs were irradiated with 0.2, 0.5, 1, 2, and 5 Gy of 137Cs gamma rays. ROS production was measured to assess IR-induced oxidative stress.	Compared to sham-irradiated controls, ROS production increase significantly ~32% at 5 Gy. While changes to ROS production were insignificant at doses <2 Gy, following a linear increase from 0-5 Gy.
Sharma et al., 2018	In vitro. HUVECs were irradiated with 9 Gy of photons. ROS production was measured to determine the effects of IR on oxidative stress.	Compared to sham-irradiated controls, irradiated HUVECs displayed ~133% increase in ROS production.
Hatoum et al., 2006	In vivo. Sprague-Dawley rats were irradiated with 9 fractions of 2.5 Gy of X-rays for a cumulative dose of 22.5 Gy at a rate of 2.43 Gy/min. Production of the ROS superoxide and peroxide in gut arterioles were measured to determine the level of oxidative stress caused by irradiation.	ROS production started increasing compared to the sham-irradiated control after the second dose and peaked at the fifth dose. By the ninth dose, superoxide production increased by 161.4% and peroxide production increased by 171.3%.
Phillip et al., 2020	In vitro. Human TICAE cells were irradiated with 0.25, 0.5, 2, and 10 Gy of 60Co gamma rays at a rate of 0.4 Gy/min. Levels of the antioxidants, SOD1 and PRDX5 were measured to assess oxidative stress from IR exposure.	While SOD1 levels did not follow a dose-dependent pattern. At 2 Gy, SOD1 decreased about 0.5-fold. At 1 week post-irradiation, PRDX5 remained at approximately control levels for doses <2 Gy but increased by ~60% from 2-10 Gy. PRDX5 only decreased at 2 Gy and 24h post-irradiation.
Ramadan et al., 2020	In vitro. Human TICAE/TIME cells were irradiated with 0.1 and 5 Gy of X-rays at a dose rate of 0.5 Gy/min. Intracellular ROS production was measured to determine the extent of IR-induced oxidative stress.	ROS production saw a dose-dependent increase in both TICAE and TIME cells. By 45 min post-irradiation, 0.1 Gy of IR had induced increases to ROS production of ~3.6-fold and ~8-fold in TICAE and TIME cells, respectively, compared to sham-irradiated controls. 5 Gy of IR caused more significant increases to ROS production of ~18-fold and ~17-fold in TICAE and TIME cells, respectively, compared to sham-irradiated controls.
Shen et al., 2018	In vivo. 8-week-old, female, C57BL/6 mice were irradiated with 18 Gy of X-rays. Levels of the oxidative markers, 4-HNE and 3-NT, and the antioxidants, CAT and heme oxygenase 1 (HO-1) were measured in the aortas of the mice.	Compared to sham-irradiated controls, irradiated mice saw maximum increases of ~1.75-fold on day 14 and ~2.25-fold on day 7 to 4-HNE and 3-NT levels, respectively. While CAT levels decreased up to 0.33-fold on day 7, HO-1 levels increased by ~1.9-fold on day 7.
Ungvari et al., 2013	In vitro. The CMVECs of adult male rats were irradiated with 2, 4, 6, and 8 Gy of 137Cs gamma rays. Production of the reactive oxygen species, peroxide and O2.-, were measured to assess the extent of IR-induced oxidative stress.	Compared to sham-irradiated controls, production of peroxide in CMVECs of irradiated mice 1 day post exposure increased in a dose-dependent manner from 0-8 Gy, with significant changes observed at doses >4 Gy. At 8 Gy, peroxide production had increased ~3.25-fold. Production of O2.- followed a similar dose-dependent increase with significant observed at doses >6 Gy. At 8 Gy, O2.- production increased ~1.6-fold. 14 days post-exposure, IR-induced changes to ROS production were not significant for either peroxide or O2.- and did not show a dose-dependent pattern. ROS production progressively decreased from 0-4 Gy and then recovered from 6-8 Gy back to control levels.
Ahmadi et al., 2021	In vitro. HLEC and HLE-B3 cells were exposed to 0.1, 0.25 and 0.5 Gy of gamma irradiation at 0.3 and 0.065 Gy/min. Intracellular ROS levels were measured.	In HLE-B3 cells, there were about 7 and 17% ROS-positive cells 1 h after exposure to 0.25 and 0.5 Gy respectively at 0.3 Gy/min. 24 h after exposure there were about 10% ROS-positive cells after 0.5 Gy at 0.3 Gy/min. 1 h after exposure there were about 13 and 17% ROS-positive cells at 0.25 and 0.5 Gy and 0.065 Gy/min. 24 h after exposure there were 8% ROS-positive cells after 0.5 Gy and 0.065 Gy/min. In human lens epithelial cells 1 h after exposure there were about 10 and 19% ROS-positive cells after 0.25 and 0.5 Gy at 0.3 Gy/min. After exposure to 0.5 Gy at 0.065 Gy/min there were about 16 and 9% ROS-positive cells one and 24 h after exposure.
Ji et al, 2015	In vitro. HLECs were exposed to UVB irradiation (297 nm; 2 W/m2) for 0 – 120 min. Total antioxidative capability (T-AOC), ROS levels, MDA, and SOD were measured at various time points at 5-120 min.	HLECs exposed to 1 W/m2 UVB for 0 - 120 min (representative of dose) showed a gradual increase in ROS levels that began to plateau 105 min post-irradiation at an ROS level 750 000x control.
Hua et al, 2019	In vitro. HLECs were exposed to 4050, 8100 and 12,150 J/m2 of UVB-irradiation at 1.5, 3.0 and 4.5 W/m2. MDA, SOD, GSH-Px, and GSH were measured.	MDA activity as a ratio of the control increased about 1.5 at 3.0 W/m2 and about 3 at 4.5 W/m2. SOD activity as a ratio of the control decreased about 0.1 at 1.5 W/m2, 0.2 at W/m2, and 0.3 at 4.5 W/m2. GSH-Px activity as a ratio of the control decreased about 0.02 at 3.0 W/m2 and 0.2 at 4.5 W/m2. GSH activity as a ratio of the control decreased about 0.2 at 3.0 W/m2 and 0.7 at 4.5 W/m2.
Chen et al, 2021	In vivo. Male rats were irradiated with 0, 0.4, 1.2 and 3.6 Sv of neutron-irradiation at 14, 45 and 131 mSv/h. In rat lenses, MDA, GSH, and SOD, were measured.	MDA concentration decreased by about 1.5 nmol/mg protein at 1.2 Sv and increased by about 7.5 nmol/mg protein relative to the control at 3.6 Sv. GSH concentration increased by about 3.5 µg/mg protein and decreased by about 1 µg/mg protein relative to the control at 3.6 Sv (neutron radiation). SOD activity decreased by about 0.08 U/mg protein relative to the control at 3.6 Sv. It should be noted that Sv is not the correct unit when investigating animals and cultured cells, radiation should have been measured in Gy (ICRU, 1998).
Zigman et al., 2000	In vitro. Rabbit LECs were exposed to 3-12 J/cm2 of UVA-irradiation (300-400 nm range, 350 nm peak). CAT activity was assayed to demonstrate oxidative stress.	Rabbit LECs exposed to 3 – 12 J/cm2 UVA showed an approximately linear decrease in catalase activity (indicative of increased oxidative stress) with the maximum dose displaying a 3.8x decrease.
Chitchumroonchokchai et al, 2004	In vitro. HLECs were exposed to 300 J/m2 of UVB-irradiation at 3 mW/cm2. MDA and HAE were used to measure oxidative stress.	The concentration of MDA and HAE increased by about 900 pmol/mg protein compared to the control after irradiation with 300 J/m2 UVB.
Zigman et al, 1995	In vitro. Rabbit and squirrel LECs were exposed to 6, 9, 12, 15 and 18 J/m2 of UV-irradiation at 3 J/cm2/h (300-400 nm range, 350 nm peak). CAT was used to measure oxidative stress levels.	The CAT activity was 10% of the control activity at 6 J/cm2, and then decreased to 0% of the control activity at 18 J/cm2 (99.9% UV-A and 0.1% UV-B).
Karimi et al, 2017	In vivo. Adult rats were exposed to 15 Gy of gamma 60Co-irradiation at a dose rate of 98.5 cGy/min. In lens tissue, MDA, thiobarbituric acid (TBA), and GSH levels were used to indicate oxidative stress.	MDA concentration increased from 0.37 +/- 0.03 to 1.60 +/- 0.16 nmol/g of lens after irradiation. GSH concentration decreased from 0.99 +/- 0.06 to 0.52 +/- 0.16 µmol/g of lens after exposure.
Rong et al., 2019	In vitro. HLECs were exposed to UVB-irradiation (297 nm; 2 W/m² for 10 min). Intracellular H₂O₂ and superoxide levels were measured.	The amount of ROS was measured as the dicholofluoroscein (DCFH-DA) fluorescence density, which increased about 10-fold relative to the control. A similar test but with dihydroethidium (DHE) staining showed a fluorescence density increase of about 3-fold relative to the control.
Kubo et al., 2010	In vitro. Lenses isolated from mice were exposed to 400 or 800 J/m2 of UVB-irradiation. ROS levels were measured.	The ratio of ROS level/survived LECs increased from about 175 to 250% after exposure to 400 and 800 J/m2 UVB respectively.
Kang et al., 2020	In vitro. HLECs were exposed to 0.09 mW/cm2 UVB-irradiation (275-400 nm range, 310 nm peak) for 15 min. MDA and SOD activity were measured.	MDA activity increased about 30% compared to control after 15 min of 0.09 mW/cm2 UVB exposure. SOD activity decreased about 50% compared to control under the same conditions.
Yang et al., 2020	In vitro. HLEs were irradiated with 30 mJ/cm2 of UVB-irradiation. ROS levels were determined.	The level of ROS production in HLEs increased approximately 5-fold as determined by 2’,7’-dichlorofluorescein diacetate after exposure to 30 mJ/cm2 UVB.
Zhang et al., 2012	In vivo. Adult mice were exposed to 20.6 kJ/m2 UV-irradiation (313 nm peak; 1.6 mW/cm2). GSH levels were measured in lens homogenates.	Decrease in GSH of about 1 and 2 µmol/g wet weight compared to control after 1 and 16 months respectively after 20.6 kJ/m2 UV (313 nm peak) at 1.6 mW/cm2.

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
Tseng et al., 2014	In vitro. Neural stem/precursor cells isolated from mouse subventricular and hippocampal dentate subgranular zones were exposed to 1-200 cGy of 56Fe irradiation at dose rates ranging from 5-50 cGy/min. RONS were measured from 1 to 8 weeks post-irradiation.	Compared to sham-irradiated controls, a trend toward increasing oxidative stress was seen, particularly at 1- and 4-weeks post-irradiation where RONS levels showed dose-responsive increases. The greatest rise was also seen at 10 cGy where relative RONS levels increased ~2-fold from 1 to 4 weeks, ~3-fold from 4 to 6 weeks and ~2 fold from 6 to 8 weeks. RONS were also found increased at doses as low as 2 cGy at 12 and 24h post-irradiation.
Suman et al., 2013	In vivo. Female mice were exposed to either 1.3 Gy of 56Fe irradiation (1 GeV/nucleon; dose rate of 1 Gy/min) or 2 Gy of gamma irradiation (dose rate of 1 Gy/min). ROS were measured in cerebral cortical cells at 2 and 12 months.	ROS levels showed statistically significant increases after 56Fe irradiation at both 2 and 12 months, while gamma irradiation led to an increase at only 2 months. The percent fluorescence intensity of ROS levels for control, gamma irradiated and 56Fe-irradiated were approximately 100, 115 and 140 at 2 months, and 100, 90 and 125 at 12 months, respectively.
Limoli et al., 2004	In vitro. Neural stem/precursor cells isolated from mouse subventricular and hippocampal dentate subgranular zones were exposed to 1 or 5 Gy of 56Fe irradiation at dose rates ranging from 4.5 Gy/min. RONS were measured at various time points until 33 days post-exposure.	ROS levels exhibited statistically significant fluctuations, increasing over the first 12h before dropping at 18h and rising again at 24h. At 5 Gy, ROS levels fluctuated with a peak at 7 days, a decrease at 13 days, an increase at 25 days, and a decrease below control levels at 33 days. At 1 Gy, ROS levels peaked at 25 days and also decreased below control at 33 days.
Gledzinski et al., 2005	In vitro. Neural precursor cells derived from rats were irradiated with 1, 2, 5 and 10 Gy of proton (1.7-1.9 Gy/min). ROS levels were determined at 5-25h post-irradiation.	Proton irradiation led to a rapid rise in ROS levels, with the increase most marked at 6h (approximately 10-70% for 1 and 10 Gy, respectively). The increase in ROS persisted for 24h, mainly for 10 Gy where the ROS levels were around 30% above control at the 12, 18 and 24h mark.
Acharya et al., 2010	In vitro. Human neural stem cells were subjected to 1, 2 or 5 Gy of gamma irradiation at a dose rate of 2.2 Gy/min. RONS and superoxide levels were measured at various time points until 7 days.	Intracellular RONS and superoxide levels showed significant increase from 2- to 4-fold at 12h. At 7 days, levels of RONS increased and were dose-responsive, elevated by ~3- to 7-fold and 3- to 5-fold, respectively, over sham-irradiated controls.
Rugo and Schiestl, 2004	In vitro. Human lymphoblast cell lines (TK6 and TK6 E6) were irradiated with 2 Gy of X-irradiation at a dose rate of 0.72 Gy/min. ROS levels were measured at various time points until 29 days.	In the TK6 E6 clones, there was only a significant ROS increase at day 29 (45.7 DCF fluorescence units). In the TK6 clones, there were significant ROS increases at days 13 (26.0 DCF fluorescence units), 15 (26.3 DCF fluorescence units) and 20 (38.1 DCF fluorescence units), with a strong trend of increased ROS in the treated group at day 25. On day 18, ROS levels decreased in the irradiated group, and there was no significant difference at day 29.
Huang et al., 2018	In vitro. Murine RAW264.7 cells were irradiated with 2 Gy of gamma rays at a rate of 0.83 Gy/min. ROS levels were measured at 2 and 8 h post-irradiation.	ROS levels in irradiated RAW264.7 cells decreased by ~10% from 2 h post-exposure to 8 h post-exposure (from ~138% above control at 2 h to ~98% above control at 8).
Zhang et al., 2018	In vitro. hBMMSCs were irradiated with 2 Gy of X-rays at a rate of 0.6 Gy/min. Relative ROS concentration was measured at 0, 0.5, 2, 3, 6, 8, and 12 h post-irradiation.	ROS levels increased in time dependent manner until a peak of ~90% above control level at 3 h-post irradiation, and then steadily declined back to approximately control levels at 12 h post-irradiation.
Phillip et al., 2020	In vitro. Human TICAE cells were irradiated with 0.25, 0.5, 2, and 10 Gy of 60Co gamma rays at a rate of 400 mGy/min. Levels of the antioxidants, SOD1 and PRDX5 were measured at 4 h, 24 h, 48 h, and 1-week post-irradiation to assess oxidative stress from IR exposure.	SOD1 levels did not follow a time-dependent pattern. However, SOD1 decreased at 2 Gy for every timepoint post-irradiation. While PRDX5 levels stayed at approximately baseline levels for the first two days after exposure to 10 Gy of radiation, levels elevated by ~1.6-fold after 1 week.
Ramadan et al., 2020	In vitro. Human TICAE/TIME cells were irradiated with 0.1 and 5 Gy of X-rays at a rate of 0.5 Gy/min. Intracellular ROS production was measured at 45 min, 2 h, and 3 h post-irradiation.	After irradiation, ROS production saw time-dependent decreases in both TICAE and TIME cells from 45 min to 3 h post-exposure. ROS production was elevated at 45 min but returned to approximately baseline levels at 2 and 3 h.
Shen et al., 2018	In vivo. 8-week-old, female, C57BL/6 mice were irradiated with 18 Gy of X-rays. Levels of the oxidative markers, 4-HNE and 3-NT, and the antioxidants, CAT and heme HO-1 were measured the aortas of the mice at 3, 7, 14, 28, and 84 days post-irradiation.	Significant changes were observed in 4-HNE, 3-NT, CAT, and HO-1 levels of irradiated mice after 3 days. 3-NT and HO-1 levels increased from days 3 to 7 and then progressively decreased, while 4-HNE levels followed the same pattern but with a peak at day 14. CAT levels were at their lowest at day 3 and followed a time dependent increase until day 84.
Ungvari et al., 2013	In vitro. The CMVECs of adult male rats were irradiated with 2, 4, 6, and 8 Gy of 137Cs gamma rays. Production of the reactive oxygen species, peroxide and superoxide, were measured at 1- and 14-days post-irradiation.	ROS production was generally higher at day 1 than day 14, with the difference becoming progressively more significant from 2-8 Gy. Peroxide production was reduced from a ~3.25-fold increase compared to controls at day 1 back to baseline levels at day 14. Superoxide production had a ~1.6-fold increase at day 1 recover to baseline levels at day 14.
Ahmadi et al., 2021	In vitro. HLEC and HLE-B3 cells were exposed to 0.1, 0.25 and 0.5 Gy of gamma irradiation at 0.3 and 0.065 Gy/min. ROS levels were measured.	In human LECs immediately exposed to 0.25 Gy gamma rays, the level of ROS positive cells increased by 5%, relative to control, 1 h post-irradiation.
Jiang et al., 2006	In vitro. HLECs were exposed to UV-irradiation at a wavelength over 290 nm (30 mJ/cm2). ROS levels were measured.	Approximately 10-fold increase in ROS generation 15 min after exposure to 30 mJ/cm2 UV.
Pendergrass et al., 2010	In vivo. Female mice were irradiated with 11 Gy of X-irradiation at a dose rate of 2 Gy/min. ROS levels in the lenses were used to represent oxidative stress.	9 months after irradiation with 11 Gy X-rays at 2 Gy/min there’s 2250% cortical ROS relative to the control. 3 months after there was no significant change.
Belkacemi et al., 2001	In vitro. Bovine lens cells were exposed to 10 Gy of X-irradiation at 2 Gy/min. GSH levels were measured.	The intracellular GSH pool was measured by a decrease of about 15% monobromobimane fluorescence relative to the control 24 h after exposure to 10 Gy X-rays at 2 Gy/min and there was a decrease of about 40% relative to the control by 120 h.
Weinreb and Dovrat, 1996	In vitro. Bovine lenses were irradiated with 22.4 J/cm2 (10 min) and 44.8 J/cm2 (100 min) of UVA-irradiation at 8.5 mW/cm2. CAT levels were determined.	CAT activity decreased from 1.75 (control) to 0.5 U/mg protein at 48-168 h after exposure to 44.8 J/cm2 UV-A.
Cencer et al., 2018	In vitro. HLECs were exposed to 0.014 and 0.14 J/cm² of UVB-irradiation at 0.09, 0.9 mW/cm² for 2 and 5 min. ROS levels (mainly H₂O₂) were measured.	About 5 min after exposure to both 0.09 and 0.9 mW/cm2 UVB for 2.5 min there is an increase of about 4 average brightness minus control (densitometric fluorescence scanning for ROS, mostly indicating H₂O₂). About 90 and 120 min after exposure to 0.9 mW/cm² the average brightness minus control is about 35 and 20 respectively.
Yang et al., 2020	In vitro. HLECs were irradiated with 30 mJ/cm2 of UVB-irradiation. Intracellular ROS levels were measured.	The level of ROS production in HLECs increased approximately 5-fold as determined by 2’,7’-dichlorofluorescein diacetate 24 h after exposure to 30 mJ/cm2 UVB.
Zhang et al., 2012	In vivo. Adult mice were exposed to 20.6 kJ/m2 UV-irradiation (313 nm peak; 1.6 mW/cm2). GSH levels were measured in lens homogenates.	Decrease in GSH of about 1 and 2 µmol/g wet weight compared to control after 1 and 16 months respectively after 20.6 kJ/m2 UV (313 nm peak) at 1.6 mW/cm2.

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

The relationship between deposition of energy and increased oxidative stress leads to several feedforward loops. Firstly, ROS activates the transforming growth factor beta (TGF)-β, which increases the production of ROS. This process is modulated in normal cells containing PRDX-6, or cells with added MnTBAP, which will both prevent TGF-β from inducing ROS formation (Fatma et al., 2005). Secondly, ROS can damage human mitochondrial DNA (mtDNA), this can then cause changes to the cellular respiration mechanisms, leading to increased ROS production (Turner et al., 2002; Zhang et al., 2010; Tangvarasittichai & Tangvarasittichai, 2019, Ahmadi et al., 2021; Yves, 2000). Some other feedback loops through which deposition of energy causes oxidative stress are discussed by Soloviev & Kizub (2019).

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.

References

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

Acharya, M. M. et al. (2010), “Consequences of ionizing radiation-induced damage in human neural stem cells”, Free radical biology & medicine, Vol. 49/12, Elsevier, Amsterdam, https://doi.org/10.1016/j.freeradbiomed.2010.08.021.

Ahmadi, M. et al. (2021), “Early responses to low-dose ionizing radiation in cellular lens epithelial models”, Radiation research, Vol. 197/1, Radiation Research Society, Bozeman, https://doi.org/10.1667/RADE-20-00284.1

Attar, M., Y. M. Kondolousy, N. Khansari, (2007), “Effect of High Dose Natural Ionizing Radiation on the Immune System of the Exposed Residents of Ramsar Town, Iran”, Iranian Journal of Allergy, Asthma and Immunology, Vol. 6/2, pp. 73-78.

Bai, J. et al. (2020), “Irradiation-induced senescence of bone marrow mesenchymal stem cells aggravates osteogenic differentiation dysfunction via paracrine signaling”, American Journal of Physiology - Cell Physiology, Vol. 318/5, American Physiological Society, Rockville, https://doi.org/10.1152/ajpcell.00520.2019.

Balasubramanian, D (2000), “Ultraviolet radiation and cataract”, Journal of ocular pharmacology and therapeutics, Vol. 16/3, Mary Ann Liebert Inc., Larchmont, https://doi.org/10.1089/jop.2000.16.285.

Baluchamy, S. et al. (2012), “Reactive oxygen species mediated tissue damage in high energy proton irradiated mouse brain”, Molecular and cellular biochemistry, Vol. 360/1-2, Springer, London, https://doi.org/10.1007/s11010-011-1056-2.

Baulch, J. E. et al. (2015), “Persistent oxidative stress in human neural stem cells exposed to low fluences of charged particles Redox biology, Vol. 5, Elsevier, Amsterdam, https://doi.org/10.1016/j.redox.2015.03.001.

Belkacémi, Y. et al. (2001), “Lens epithelial cell protection by aminothiol WR-1065 and anetholedithiolethione from ionizing radiation”, International journal of cancer, Vol. 96, John Wiley & Sons, Ltd., Hoboken, https://doi.org/10.1002/ijc.10346.

Cabrera M., R. Chihuailaf and F. Wittwer Menge (2011), “Antioxidants and the integrity of ocular tissues”, Veterinary medicine international, Vol. 2011, Hindawi, London, https://doi.org/10.4061/2011/905153.

Cadet, J. et al. (2012), “Oxidatively generated complex DNA damage: tandem and clustered lesions”, Cancer letters, Vol. 327, Elsevier, Amsterdam, https://doi.org/10.1016/j.canlet.2012.04.005.

Cencer, C. et al. (2018), “PARP-1/PAR activity in cultured human lens epithelial cells exposed to tow levels of UVB light”, Photochemistry and photobiology, Vol. 94, John Wiley & Sons, Ltd., Hoboken, https://doi.org/10.1111/php.12814.

Cervelli, T. et al. (2017), “A New Natural Antioxidant Mixture Protects against Oxidative and DNA Damage in Endothelial Cell Exposed to Low-Dose Irradiation”, Oxidative medicine and cellular longevity, Vol. 2017, Hindawi, London, https://doi.org/10.1155/2017/9085947.

Chen, Y. et al. (2021), “Effects of neutron radiation on Nrf2-regulated antioxidant defence systems in rat lens”, Experimental and therapeutic medicine, Vol. 21/4, Spandidos Publishing Ltd, Athens, https://doi.org/10.3892/etm.2021.9765.

Chien, L. et al. (2015) “Low-dose ionizing radiation induces mitochondrial fusion and increases expression of mitochondrial complexes I and III in hippocampal neurons”, Oncotarget, Vol. 6/31, Impact Journals, Orchard Park, https://doi.org/10.18632/oncotarget.5790

Chitchumroonchokchai, C. et al. (2004), “Xanthophylls and α-tocopherol decrease UVB-induced lipid peroxidation and stress signaling in human lens epithelial cells”, The Journal of Nutrition, Vol. 134/12, American Society for Nutritional Sciences, Bethesda, https://doi.org/10.1093/jn/134.12.3225.

Collins-Underwood, J. R. et al. (2008), “NADPH oxidase mediates radiation-induced oxidative stress in rat brain microvascular endothelial cells”, Free radical biology & medicine, Vol. 45/6, Elsevier, Amsterdam, https://doi.org/10.1016/j.freeradbiomed.2008.06.024.

de Jager, T.L., Cockrell, A.E., Du Plessis, S.S. (2017), “Ultraviolet Light Induced Generation of Reactive Oxygen Species”, in Ultraviolet Light in Human Health, Diseases and Environment. Advances in Experimental Medicine and Biology, Springer, Cham, https://doi.org/10.1007/978-3-319-56017-5_2

Demir, E. et al. (2020), “Nigella sativa oil and thymoquinone reduce oxidative stress in the brain tissue of rats exposed to total head irradiation”, International journal of radiation biology, Vol. 96/2, Informa, London, https://doi.org/10.1080/09553002.2020.1683636.

Eaton, J. W. (1994), “UV-mediated cataractogenesis: A radical perspective”, Documenta ophthalmologica, Vol. 88, Springer, London, https://doi.org/10.1007/BF01203677.

Fatma, N. et al. (2005), “Impaired homeostasis and phenotypic abnormalities in Prdx6-/- mice lens epithelial cells by reactive oxygen species: Increased expression and activation of TGFβ”, Cell death and differentiation, Vol. 12, Nature Portfolio, London, https://doi.org/10.1038/sj.cdd.4401597.

Fletcher, A. E (2010), “Free radicals, antioxidants and eye diseases: evidence from epidemiological studies on cataract and age-related macular degeneration”, Ophthalmic Research, Vol. 44, Karger International, Basel, https://doi.org/10.1159/000316476.

Ganea, E. and J. J. Harding (2006), “Glutathione-related enzymes and the eye”, Current eye research, Vol. 31/1, Informa, London, https://doi.org/10.1080/02713680500477347.

Giblin, F. J. et al. (2002), “UVA light in vivo reaches the nucleus of the guinea pig lens and produces deleterious, oxidative effects”, Experimental eye research, Vol. 75/4, Elsevier, Amsterdam, https://doi.org/10.1006/exer.2002.2039.

Giedzinski, E. et al. (2005), “Efficient production of reactive oxygen species in neural precursor cells after exposure to 250 MeV protons”, Radiation research, Vol. 164/4, Radiation Research Society, Bozeman, https://doi.org/10.1667/rr3369.1.

Hamada, N. et al. (2014), “Emerging issues in radiogenic cataracts and cardiovascular disease”, Journal of radiation research, Vol. 55/5, Oxford University Press, Oxford, https://doi.org/10.1093/jrr/rru036.

Hatoum, O. A. et al. (2006), “Radiation induces endothelial dysfunction in murine intestinal arterioles via enhanced production of reactive oxygen species”, Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 26/2, Lippincot Williams & Wilkins, Philadelphia, https://doi.org/10.1161/01.ATV.0000198399.40584.8C.

Hightower, K. and J. McCready (1992), “Mechanisms involved in cataract development following near-ultraviolet radiation of cultured lenses”, Current eye research, Vol. 11/7, Informa, London, https://doi.org/10.3109/02713689209000741.

Hightower, K. R. (1995), “The role of the lens epithelium in development of UV cataract”, Current eye research, Vol. 14/1, Informa, London, https://doi.org/10.3109/02713689508999916.

Hua, H. et al. (2019), “Protective effects of lanosterol synthase up-regulation in UV-B-induced oxidative stress”, Frontiers in pharmacology, Vol. 10, Frontiers Media SA, Lausanne, https://doi.org/10.3389/fphar.2019.00947.

Huang, L. et al. (2006), “Oxidation-induced changes in human lens epithelial cells 2. Mitochondria and the generation of reactive oxygen species”, Free radical biology & medicine, Vol. 41/6, Elsevier, Amsterdam, https://doi.org/10.1016/j.freeradbiomed.2006.05.023.

Huang, B. et al. (2019), “Amifostine suppresses the side effects of radiation on BMSCs by promoting cell proliferation and reducing ROS production”, Stem Cells International, Vol. 2019, Hindawi, London, https://doi.org/10.1155/2019/8749090.

Huang, B. et al. (2018), “Sema3a inhibits the differentiation of raw264.7 cells to osteoclasts under 2gy radiation by reducing inflammation”, PLoS ONE, Vol. 13/7, PLOS, San Francisco, https://doi.org/10.1371/journal.pone.0200000.

ICRU (1998), “ICRU report 57: conversion coefficients for use in radiological protection against external radiation”, Journal of the ICRU, Vol. 29/2, SAGE Publishing

Ismail, A. F. and S. M. El-Sonbaty (2016), “Fermentation enhances Ginkgo biloba protective role on gamma-irradiation induced neuroinflammatory gene expression and stress hormones in rat brain”, Journal of photochemistry and photobiology. B, Biology, Vol. 158, Elsevier, Amsterdam, https://doi.org/10.1016/j.jphotobiol.2016.02.039.

Ji, Y. et al. (2015), “The mechanism of UVB irradiation induced-apoptosis in cataract”, Molecular and cellular biochemistry, Vol. 401, Springer, London, https://doi.org/10.1007/s11010-014-2294-x.

Jiang, Q. et al. (2006), “UV radiation down-regulates Dsg-2 via Rac/NADPH oxidase-mediated generation of ROS in human lens epithelial cells”, International Journal of Molecular Medicine, Vol. 18/2, Spandidos Publishing Ltd, Athens, https://doi.org/10.3892/ijmm.18.2.381.

Jurja, S. et al. (2014), “Ocular cells and light: harmony or conflict?”, Romanian Journal of Morphology & Embryology, Vol. 55/2, Romanian Academy Publishing House, Bucharest, pp. 257–261.

Kang, L. et al. (2020), “Ganoderic acid A protects lens epithelial cells from UVB irradiation and delays lens opacity”, Chinese journal of natural medicines, Vol. 18/12, Elsevier, Amsterdam, https://doi.org/10.1016/S1875-5364(20)60037-1.

Karam, H. M. and R. R. Radwan (2019), “Metformin modulates cardiac endothelial dysfunction, oxidative stress and inflammation in irradiated rats: A new perspective of an antidiabetic drug”, Clinical and Experimental Pharmacology and Physiology, Vol. 46/12, Wiley-Blackwell, Hoboken, https://doi.org/10.1111/1440-1681.13148.

Karimi, N. et al. (2017), “Radioprotective effect of hesperidin on reducing oxidative stress in the lens tissue of rats”, International Journal of Pharmaceutical Investigation, Vol. 7/3, Phcog Net, Bengaluru, https://doi.org/10.4103/jphi.JPHI_60_17.

Kłuciński, P. et al. (2008), “Erythrocyte antioxidant parameters in workers occupationally exposed to low levels of ionizing radiation”, Annals of Agricultural and Environmental Medicine, Vol. 15/1, pp. 9-12.

Kook, S. H. et al. (2015), “Irradiation inhibits the maturation and mineralization of osteoblasts via the activation of Nrf2/HO-1 pathway”, Molecular and Cellular Biochemistry, Vol. 410/1-2, Springer, London, https://doi.org/10.1007/s11010-015-2559-z.

Kubo, E. et al. (2010), “Protein expression profiling of lens epithelial cells from Prdx6-depleted mice and their vulnerability to UV radiation exposure”, American Journal of Physiology, Vol. 298/2, American Physiological Society, Rockville, https://doi.org/10.1152/ajpcell.00336.2009.

Lee, J. et al. (2004), “Reactive oxygen species, aging, and antioxidative nutraceuticals”, Comprehensive reviews in food science and food safety, Vol. 3/1, Blackwell Publishing Ltd, Oxford, http://doi.org/10.1111/j.1541-4337.2004.tb00058.x.

Limoli, C. L. et al. (2007), “Redox changes induced in hippocampal precursor cells by heavy ion irradiation”, Radiation and environmental biophysics, Vol. 46/2, Springer, London, https://doi.org/10.1007/s00411-006-0077-9.

Limoli, C. L. et al. (2004), “Radiation response of neural precursor cells: linking cellular sensitivity to cell cycle checkpoints, apoptosis and oxidative stress”, Radiation research, Vol. 161/1, Radiation Research Society, Bozeman, https://doi.org/10.1667/rr3112.

Liu, F. et al. (2019), “Transcriptional response of murine bone marrow cells to total-body carbon-ion irradiation”, Mutation Research - Genetic Toxicology and Environmental Mutagenesis, Vol. 839, Elsevier, Amsterdam, https://doi.org/10.1016/j.mrgentox.2019.01.014.

Liu, Y. et al. (2018), “Protective effects of α2macroglobulin on human bone marrow mesenchymal stem cells in radiation injury”, Molecular Medicine Reports, Vol. 18/5, Spandidos Publishing Ltd, Athens, https://doi.org/10.3892/mmr.2018.9449.

Manda, K. et al. (2007), “Melatonin attenuates radiation-induced learning deficit and brain oxidative stress in mice”, Acta neurobiologiae experimentalis, Vol. 67/1, Nencki Institute of Experimental Biology, Warsaw, pp. 63 –70.

Manda, K., M. Ueno and K. Anzai (2008), “Memory impairment, oxidative damage and apoptosis induced by space radiation: ameliorative potential of alpha-lipoic acid”, Behavioural brain research, Vol. 187/2, Elsevier, Amsterdam, https://doi.org/10.1016/j.bbr.2007.09.033.

Mansour, H. H. (2013), “Protective effect of ginseng against gamma-irradiation-induced oxidative stress and endothelial dysfunction in rats”, EXCLI Journal, Vol. 12, Leibniz Research Centre for Working Environment and Human Factors, Dortmund, pp. 766-777.

Marshall, J. (1985), “Radiation and the ageing eye”, Ophthalmic & physiological optics, Vol. 5, Wiley-Blackwell, Hoboken, https://doi.org.10.1111/j.1475-1313.1985.tb00666.x.

Padgaonkar, V. A. et al. (2015) “Thioredoxin reductase activity may be more important than GSH level in protecting human lens epithelial cells against UVA light”, Photochemistry and photobiology, Vol. 91/2, Wiley-Blackwell, Hoboken, https://doi.org/10.1111/php.12404.

Pendergrass, W. et al. (2010), “X-ray induced cataract is preceded by LEC loss, and coincident with accumulation of cortical DNA, and ROS; similarities with age-related cataracts”, Molecular Vision, Vol. 16, Emory University, Atlanta, pp. 1496-513.

Philipp, J. et al. (2020), “Radiation Response of Human Cardiac Endothelial Cells Reveals a Central Role of the cGAS-STING Pathway in the Development of Inflammation”, Proteomes, Vol. 8/4, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/proteomes8040030.

Quan, Y. et al. (2021), “Connexin hemichannels regulate redox potential via metabolite exchange and protect lens against cellular oxidative damage”, Redox biology, Vol. 46, Elsevier, Amsterdam, https://doi.org/10.1016/j.redox.2021.102102.

Ramadan, R. et al. (2020), “Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage”, Frontiers in Pharmacology, Vol. 11, Frontiers Media SA, Lausanne, https://doi.org/10.3389/fphar.2020.00212

Rehman, M. U. et al. (2016), “Comparison of free radicals formation induced by cold atmospheric plasma, ultrasound, and ionizing radiation”, Archives of biochemistry and biophysics, Vol. 605, Elsevier, Amsterdam, https://doi.org/10.1016/j.abb.2016.04.005.

Rogers, C. S. et al. (2004), “The effects of sub-solar levels of UV-A and UV-B on rabbit corneal and lens epithelial cells”, Experimental eye research, Vol. 78, Elsevier, Amsterdam, https://doi.org/10.1016/j.exer.2003.12.011.

Rong, X. et al. (2019), “TRIM69 inhibits cataractogenesis by negatively regulating p53”, Redox biology, Vol. 22, Elsevier, Amsterdam, https://doi.org/10.1016/j.redox.2019.101157.

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