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Event: 1392
Key Event Title
Oxidative Stress
Short name
Biological Context
Level of Biological Organization |
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Molecular |
Cell term
Organ term
Key Event Components
Process | Object | Action |
---|---|---|
oxidative stress | increased |
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
Cyp2E1 Activation Leading to Liver Cancer | KeyEvent | Agnes Aggy (send email) | Open for citation & comment | WPHA/WNT Endorsed |
Oxidative stress and Developmental impairment in learning and memory | KeyEvent | Brendan Ferreri-Hanberry (send email) | Open for citation & comment | WPHA/WNT Endorsed |
Oxidative stress in chronic kidney disease | KeyEvent | Brendan Ferreri-Hanberry (send email) | Under development: Not open for comment. Do not cite | |
TLR9 activation leading to Multi Organ Failure and ARDS | KeyEvent | Cataia Ives (send email) | Under development: Not open for comment. Do not cite | |
Oxidative stress Leading to Decreased Lung Function | MolecularInitiatingEvent | Brendan Ferreri-Hanberry (send email) | Open for comment. Do not cite | |
Ox stress-mediated CFTR/ASL/CBF/MCC impairment | MolecularInitiatingEvent | Arthur Author (send email) | Open for comment. Do not cite | |
ox stress-mediated FOXJ1/cilia/CBF/MCC impairment | MolecularInitiatingEvent | Agnes Aggy (send email) | Open for comment. Do not cite | |
tau-AOP | KeyEvent | Brendan Ferreri-Hanberry (send email) | Under development: Not open for comment. Do not cite | |
PM-induced respiratory toxicity | KeyEvent | Cataia Ives (send email) | Under development: Not open for comment. Do not cite | |
Calcium overload driven development of parkinsonian motor deficits | KeyEvent | Cataia Ives (send email) | Under development: Not open for comment. Do not cite | |
Deposition of energy leads to vascular remodeling | KeyEvent | Cataia Ives (send email) | Open for citation & comment | |
Deposition of energy leading to cataracts | KeyEvent | Arthur Author (send email) | Open for citation & comment | |
Mitochondrial complexes inhibition leading to LV function decrease | KeyEvent | Agnes Aggy (send email) | Under development: Not open for comment. Do not cite | Under Development |
AOPs of SiNPs: ROS-mediated oxidative stress increased respiratory toxicity. | KeyEvent | Evgeniia Kazymova (send email) | Under development: Not open for comment. Do not cite | |
Deposition of energy leading to bone loss | KeyEvent | Cataia Ives (send email) | Open for citation & comment | |
Deposition of Energy Leading to Learning and Memory Impairment | KeyEvent | Brendan Ferreri-Hanberry (send email) | Open for citation & comment | |
ROS formation leads to cancer via inflammation pathway | KeyEvent | Evgeniia Kazymova (send email) | Under development: Not open for comment. Do not cite | |
Essential element imbalance leads to reproductive failure via oxidative stress | KeyEvent | Agnes Aggy (send email) | Under development: Not open for comment. Do not cite | |
CYP450 upregulation leads to Chronic kidney disease | KeyEvent | Arthur Author (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Life Stages
Life stage | Evidence |
---|---|
All life stages | High |
Sex Applicability
Term | Evidence |
---|---|
Mixed | High |
Key Event Description
Oxidative stress is defined as an imbalance in the production of reactive oxygen species (ROS) and antioxidant defenses. High levels of oxidizing free radicals can be very damaging to cells and molecules within the cell (Pizzino et al., 2017; Sharifi-Rad et al., 2020; Jena et al., 2023). As a result, the cell has important defense mechanisms to protect itself from ROS. For example, Nrf2 is a transcription factor and master regulator of the oxidative stress response. During periods of oxidative stress, Nrf2-dependent changes in gene expression are important in regaining cellular homeostasis (Nguyen, et al. 2009) and can be used as indicators of the presence of oxidative stress in the cell.
In addition to the directly damaging actions of ROS, cellular oxidative stress also changes cellular activities on a molecular level. Redox sensitive proteins have altered physiology in the presence and absence of ROS, which is caused by the oxidation of sulfhydryls to disulfides (2SH àSS) on neighboring amino acids (Antelmann and Helmann 2011). Importantly Keap1, the negative regulator of Nrf2, is regulated in this manner (Itoh, et al. 2010).
ROS also undermine the mitochondrial defense system from oxidative damage. The antioxidant systems consist of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, as well as antioxidants such as α-tocopherol and ubiquinol, or antioxidant vitamins and minerals including vitamin E, C, carotene, lutein, zeaxanthin, selenium, and zinc (Fletcher, 2010). The enzymes, vitamins and minerals catalyze the conversion of ROS to non-toxic molecules such as water and O2. However, these antioxidant systems are not perfect and endogenous metabolic processes and/or exogenous oxidative influences can trigger cumulative oxidative injuries to the mitochondria, causing a decline in their functionality and efficiency, which further promotes cellular oxidative stress (Balasubramanian, 2000; Ganea & Harding, 2006; Guo et al., 2013; Karimi et al., 2017).
However, an emerging viewpoint suggests that ROS-induced modifications may not be as detrimental as previously thought, but rather contribute to signaling processes (Foyer et al., 2017).
Protection against oxidative stress is relevant for all tissues and organs, although some tissues may be more susceptible. For example, the brain possesses several key physiological features, such as high O2 utilization, high polyunsaturated fatty acids content, presence of autooxidable neurotransmitters, and low antioxidant defenses as compared to other organs, that make it highly susceptible to oxidative stress (Halliwell, 2006; Emerit and al., 2004; Frauenberger et al., 2016).
Sources of ROS Production
Direct Sources: Direct sources involve the deposition of energy onto water molecules, breaking them into active radical species. When ionizing radiation hits water, it breaks it into hydrogen (H*) and hydroxyl (OH*) radicals by destroying its bonds. The hydrogen will create hydroxyperoxyl free radicals (HO2*) if oxygen is available, which can then react with another of itself to form hydrogen peroxide (H2O2) and more O2 (Elgazzar and Kazem, 2015). Antioxidant mechanisms are also affected by radiation, with catalase (CAT) and peroxidase (POD) levels rising as a result of exposure (Seen et al. 2018; Ahmad et al. 2021).
Indirect Sources: An indirect source of ROS is the mitochondria, which is one of the primary producers in eukaryotic cells (Powers et al., 2008). As much as 2% of the electrons that should be going through the electron transport chain in the mitochondria escape, allowing them an opportunity to interact with surrounding structures. Electron-oxygen reactions result in free radical production, including the formation of hydrogen peroxide (H2O2) (Zhao et al., 2019). The electron transport chain, which also creates ROS, is activated by free adenosine diphosphate (ADP), O2, and inorganic phosphate (Pi) (Hargreaves et al. 2020; Raimondi et al. 2020; Vargas-Mendoza et al. 2021). The first and third complexes of the transport chain are the most relevant to mammalian ROS production (Raimondi et al., 2020). The mitochondria have its own set of DNA and it is a prime target of oxidative damage (Guo et al., 2013). ROS are also produced through nicotinamide adenine dinucleotide phosphate oxidase (NOX) stimulation, an event commenced by angiotensin II, a product/effector of the renin-angiotensin system (Nguyen Dinh Cat et al. 2013; Forrester et al. 2018). Other ROS producers include xanthine oxidase, immune cells (macrophage, neutrophils, monocytes, and eosinophils), phospholipase A2 (PLA2), monoamine oxidase (MAO), and carbon-based nanomaterials (Powers et al. 2008; Jacobsen et al. 2008; Vargas-Mendoza et al. 2021).
How It Is Measured or Detected
Oxidative Stress. Direct measurement of ROS is difficult because ROS are unstable. The presence of ROS can be assayed indirectly by measurement of cellular antioxidants, or by ROS-dependent cellular damage. Listed below are common methods for detecting the KE, however there may be other comparable methods that are not listed
- Detection of ROS by chemiluminescence (https://www.sciencedirect.com/science/article/abs/pii/S0165993606001683)
- Detection of ROS by chemiluminescence is also described in OECD TG 495 to assess phototoxic potential.
- Glutathione (GSH) depletion. GSH can be measured by assaying the ratio of reduced to oxidized glutathione (GSH:GSSG) using a commercially available kit (e.g., http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html).
- TBARS. Oxidative damage to lipids can be measured by assaying for lipid peroxidation using TBARS (thiobarbituric acid reactive substances) using a commercially available kit.
- 8-oxo-dG. Oxidative damage to nucleic acids can be assayed by measuring 8-oxo-dG adducts (for which there are a number of ELISA based commercially available kits),or HPLC, described in Chepelev et al. (Chepelev, et al. 2015).
Molecular Biology: Nrf2. Nrf2’s transcriptional activity is controlled post-translationally by oxidation of Keap1. Assay for Nrf2 activity include:
- Immunohistochemistry for increases in Nrf2 protein levels and translocation into the nucleus
- Western blot for increased Nrf2 protein levels
- Western blot of cytoplasmic and nuclear fractions to observe translocation of Nrf2 protein from the cytoplasm to the nucleus
- qPCR of Nrf2 target genes (e.g., Nqo1, Hmox-1, Gcl, Gst, Prx, TrxR, Srxn), or by commercially available pathway-based qPCR array (e.g., oxidative stress array from SABiosciences)
- Whole transcriptome profiling by microarray or RNA-seq followed by pathway analysis (in IPA, DAVID, metacore, etc.) for enrichment of the Nrf2 oxidative stress response pathway (e.g., Jackson et al. 2014)
- OECD TG422D describes an ARE-Nrf2 Luciferase test method
- In general, there are a variety of commercially available colorimetric or fluorescent kits for detecting Nrf2 activation
Assay Type & Measured Content | Description | Dose Range Studied |
Assay Characteristics (Length / Ease of use/Accuracy) |
ROS Formation in the Mitochondria assay (Shaki et al., 2012) |
“The mitochondrial ROS measurement was performed flow cytometry using DCFH-DA. Briefly, isolated kidney mitochondria were incubated with UA (0, 50, 100 and 200 μM) in respiration buffer containing (0.32 mM sucrose, 10 mM Tris, 20 mM Mops, 50 μM EGTA, 0.5 mM MgCl2, 0.1 mM KH2PO4 and 5 mM sodium succinate) [32]. In the interval times of 5, 30 and 60 min following the UA addition, a sample was taken and DCFH-DA was added (final concentration, 10 μM) to mitochondria and was then incubated for 10 min. Uranyl acetate-induced ROS generation in isolated kidney mitochondria were determined through the flow cytometry (Partec, Deutschland) equipped with a 488-nm argon ion laser and supplied with the Flomax software and the signals were obtained using a 530-nm bandpass filter (FL-1 channel). Each determination is based on the mean fluorescence intensity of 15,000 counts.” | 0, 50, 100 and 200 μM of Uranyl Acetate |
Long/ Easy High accuracy |
Mitochondrial Antioxidant Content Assay Measuring GSH content (Shaki et al., 2012) |
“GSH content was determined using DTNB as the indicator and spectrophotometer method for the isolated mitochondria. The mitochondrial fractions (0.5 mg protein/ml) were incubated with various concentrations of uranyl acetate for 1 h at 30 °C and then 0.1 ml of mitochondrial fractions was added into 0.1 mol/l of phosphate buffers and 0.04% DTNB in a total volume of 3.0 ml (pH 7.4). The developed yellow color was read at 412 nm on a spectrophotometer (UV-1601 PC, Shimadzu, Japan). GSH content was expressed as μg/mg protein.” |
0, 50, 100, or 200 μM Uranyl Acetate |
|
H2O2 Production Assay Measuring H2O2 Production in isolated mitochondria (Heyno et al., 2008) |
“Effect of CdCl2 and antimycin A (AA) on H2O2 production in isolated mitochondria from potato. H2O2 production was measured as scopoletin oxidation. Mitochondria were incubated for 30 min in the measuring buffer (see the Materials and Methods) containing 0.5 mM succinate as an electron donor and 0.2 µM mesoxalonitrile 3‐chlorophenylhydrazone (CCCP) as an uncoupler, 10 U horseradish peroxidase and 5 µM scopoletin.” ( |
0, 10, 30 μM Cd2+ 2 μM antimycin A |
|
Flow Cytometry ROS & Cell Viability (Kruiderig et al., 1997) |
“For determination of ROS, samples taken at the indicated time points were directly transferred to FACScan tubes. Dih123 (10 mM, final concentration) was added and cells were incubated at 37°C in a humidified atmosphere (95% air/5% CO2) for 10 min. At t 5 9, propidium iodide (10 mM, final concentration) was added, and cells were analyzed by flow cytometry at 60 ml/min. Nonfluorescent Dih123 is cleaved by ROS to fluorescent R123 and detected by the FL1 detector as described above for Dc (Van de Water 1995)” |
Strong/easy medium |
|
DCFH-DA Assay Detection of hydrogen peroxide production (Yuan et al., 2016) |
Intracellular ROS production was measured using DCFH-DA as a probe. Hydrogen peroxide oxidizes DCFH to DCF. The probe is hydrolyzed intracellularly to DCFH carboxylate anion. No direct reaction with H2O2 to form fluorescent production. |
0-400 µM |
Long/ Easy High accuracy |
H2-DCF-DA Assay Detection of superoxide production (Thiebault et al., 2007) |
This dye is a stable nonpolar compound which diffuses readily into the cells and yields H2-DCF. Intracellular OH or ONOO- react with H2-DCF when cells contain peroxides, to form the highly fluorescent compound DCF, which effluxes the cell. Fluorescence intensity of DCF is measured using a fluorescence spectrophotometer. | 0–600 µM |
Long/ Easy High accuracy |
CM-H2DCFDA Assay | **Come back and explain the flow cytometry determination of oxidative stress from Pan et al. (2009)** |
Direct Methods of Measurement
Method of Measurement |
References |
Description |
OECD-Approved Assay |
Chemiluminescence |
(Lu, C. et al., 2006; Griendling, K. K., et al., 2016) |
ROS can induce electron transitions in molecules, leading to electronically excited products. When the electrons transition back to ground state, chemiluminescence is emitted and can be measured. Reagents such as uminol and lucigenin are commonly used to amplify the signal. |
No |
Spectrophotometry |
(Griendling, K. K., et al., 2016) |
NO has a short half-life. However, if it has been reduced to nitrite (NO2-), stable azocompounds can be formed via the Griess Reaction, and further measured by spectrophotometry. |
No |
Direct or Spin Trapping-Based Electron Paramagnetic Resonance (EPR) Spectroscopy |
(Griendling, K. K., et al., 2016) |
The unpaired electrons (free radicals) found in ROS can be detected with EPR, and is known as electron paramagnetic resonance. A variety of spin traps can be used. |
No |
Nitroblue Tetrazolium Assay |
(Griendling, K. K., et al., 2016) |
The Nitroblue Tetrazolium assay is used to measure O2•– levels. O2•– reduces nitroblue tetrazolium (a yellow dye) to formazan (a blue dye), and can be measured at 620 nm. |
No |
Fluorescence analysis of dihydroethidium (DHE) or Hydrocyans |
(Griendling, K. K., et al., 2016) |
Fluorescence analysis of DHE is used to measure O2•– levels. O2•– is reduced to O2 as DHE is oxidized to 2-hydroxyethidium, and this reaction can be measured by fluorescence. Similarly, hydrocyans can be oxidized by any ROS, and measured via fluorescence. |
No |
Amplex Red Assay |
(Griendling, K. K., et al., 2016) |
Fluorescence analysis to measure extramitochondrial or extracellular H2O2 levels. In the presence of horseradish peroxidase and H2O2, Amplex Red is oxidized to resorufin, a fluorescent molecule measurable by plate reader. |
No |
Dichlorodihydrofluorescein Diacetate (DCFH-DA) |
(Griendling, K. K., et al., 2016) |
An indirect fluorescence analysis to measure intracellular H2O2 levels. H2O2 interacts with peroxidase or heme proteins, which further react with DCFH, oxidizing it to dichlorofluorescein (DCF), a fluorescent product. |
No |
HyPer Probe |
(Griendling, K. K., et al., 2016) |
Fluorescent measurement of intracellular H2O2 levels. HyPer is a genetically encoded fluorescent sensor that can be used for in vivo and in situ imaging. |
No |
Cytochrome c Reduction Assay |
(Griendling, K. K., et al., 2016) |
The cytochrome c reduction assay is used to measure O2•– levels. O2•– is reduced to O2 as ferricytochrome c is oxidized to ferrocytochrome c, and this reaction can be measured by an absorbance increase at 550 nm. |
No |
Proton-electron double-resonance imagine (PEDRI) |
(Griendling, K. K., et al., 2016) |
The redox state of tissue is detected through nuclear magnetic resonance/magnetic resonance imaging, with the use of a nitroxide spin probe or biradical molecule. |
No |
Glutathione (GSH) depletion |
(Biesemann, N. et al., 2018) |
A downstream target of the Nrf2 pathway is involved in GSH synthesis. As an indication of oxidation status, GSH can be measured by assaying the ratio of reduced to oxidized glutathione (GSH:GSSG) using a commercially available kit (e.g., http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html). |
No |
Thiobarbituric acid reactive substances (TBARS) |
(Griendling, K. K., et al., 2016) |
Oxidative damage to lipids can be measured by assaying for lipid peroxidation with TBARS using a commercially available kit. |
No |
Protein oxidation (carbonylation) |
(Azimzadeh et al., 2017; Azimzadeh etal., 2015; Ping et al., 2020) |
Can be determined with enzyme-linked immunosorbent assay (ELISA) or a commercial assay kit. Protein oxidation can indicate the level of oxidative stress. |
No |
Seahorse XFp Analyzer | Leung et al. 2018 | The Seahorse XFp Analyzer provides information on mitochondrial function, oxidative stress, and metabolic dysfunction of viable cells by measuring respiration (oxygen consumption rate; OCR) and extracellular pH (extracellular acidification rate; ECAR). | No |
Molecular Biology: Nrf2. Nrf2’s transcriptional activity is controlled post-translationally by oxidation of Keap1. Assays for Nrf2 activity include:
Method of Measurement |
References |
Description |
OECD-Approved Assay |
Immunohistochemistry |
(Amsen, D., de Visser, K. E., and Town, T., 2009) |
Immunohistochemistry for increases in Nrf2 protein levels and translocation into the nucleus |
No |
Quantitative polymerase chain reaction (qPCR) |
(Forlenza et al., 2012) |
qPCR of Nrf2 target genes (e.g., Nqo1, Hmox-1, Gcl, Gst, Prx, TrxR, Srxn), or by commercially available pathway-based qPCR array (e.g., oxidative stress array from SABiosciences) |
No |
Whole transcriptome profiling via microarray or via RNA-seq followed by a pathway analysis |
(Jackson, A. F. et al., 2014) |
Whole transcriptome profiling by microarray or RNA-seq followed by pathway analysis (in IPA, DAVID, metacore, etc.) for enrichment of the Nrf2 oxidative stress response pathway |
No |
Domain of Applicability
Taxonomic applicability: Occurrence of oxidative stress is not species specific.
Life stage applicability: Occurrence of oxidative stress is not life stage specific.
Sex applicability: Occurrence of oxidative stress is not sex specific.
Evidence for perturbation by prototypic stressor: There is evidence of the increase of oxidative stress following perturbation from a variety of stressors including exposure to ionizing radiation and altered gravity (Bai et al., 2020; Ungvari et al., 2013; Zhang et al., 2009).
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