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Relationship: 2769
Title
Energy Deposition leads to Oxidative Stress
Upstream event
Downstream event
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
Sex Applicability
| Sex | Evidence |
|---|---|
| Male | High |
| Female | Moderate |
| Unspecific | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| Juvenile | High |
| Adult | Moderate |
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).
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.
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| 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
There are several uncertainties and inconsistencies in this KER.
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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).
|
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 |
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
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. |
All three enzymes showed significantly decreased antioxidant activity in the workers. In the controls (U/g of Hb):
In the workers (U/g of Hb):
|
|
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 saw a significant, ~32% increase at 5 Gy. While changes to ROS production were insignificant at doses <2 Gy, they followed 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 saw a significant, ~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 mins 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 mins. MDA and SOD activity were measured. |
MDA activity increased about 30% compared to control after 15 mins 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. HLECs were irradiated with 30 mJ/cm2 of UVB-irradiation. ROS levels were determined. |
The level of ROS production in HLECs 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
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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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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). |
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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. |
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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. |
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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 mins, 2 h, and 3 h post-irradiation. |
After irradiation, ROS production saw time-dependent decreases in both TICAE and TIME cells from 45 mins to 3 h post-exposure. ROS production was elevated at 45 mins but returned to approximately baseline levels at 2 and 3 h. |
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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. |
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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. |
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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.
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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. |
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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 mins after exposure to 30 mJ/cm2 UV. |
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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.
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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. |
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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.
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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.
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About 5 min after exposure to both 0.09 and 0.9 mW/cm2 UVB for 2.5 mins 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.
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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. |
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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
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).
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.