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Event: 1115
Key Event Title
Increase, Reactive oxygen species
Short name
Biological Context
Level of Biological Organization |
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Cellular |
Cell term
Cell term |
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cell |
Organ term
Organ term |
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organ |
Key Event Components
Process | Object | Action |
---|---|---|
reactive oxygen species biosynthetic process | reactive oxygen species | increased |
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
unknown MIE renal failure | KeyEvent | Kellie Fay (send email) | Under Development: Contributions and Comments Welcome | |
Inhibition fatty acid beta oxidation leading to nonalcoholic steatohepatisis (NASH) | KeyEvent | Lyle Burgoon (send email) | Open for adoption | |
Frustrated phagocytosis-induced lung cancer | KeyEvent | Carole Seidel (send email) | Under development: Not open for comment. Do not cite | Under Development |
ACE2 inhibition, liver fibrosis | KeyEvent | Young Jun Kim (send email) | Under development: Not open for comment. Do not cite | Under Development |
AT1R, lung fibrosis | KeyEvent | Young Jun Kim (send email) | Under development: Not open for comment. Do not cite | Under Development |
ACE/Ang-II/AT1R axis, chronic kidney disease (CKD) | KeyEvent | Young Jun Kim (send email) | Under development: Not open for comment. Do not cite | |
Deposition of ionizing energy leads to population decline via impaired meiosis | KeyEvent | Erica Maremonti (send email) | Under development: Not open for comment. Do not cite | |
Frustrated phagocytosis leads to malignant mesothelioma | KeyEvent | Penny Nymark (send email) | Under development: Not open for comment. Do not cite | |
Oxidation of Reduced Glutathione Leading to Mortality | KeyEvent | Zarin Hossain (send email) | Open for citation & comment | |
AHR activation leading to lung cancer via IL-6 tox path | KeyEvent | Dianke Yu (send email) | Under development: Not open for comment. Do not cite | |
AHR activation decreasing lung function via AHR-ARNT tox path | KeyEvent | Dianke Yu (send email) | Under development: Not open for comment. Do not cite | |
Deposition of ionizing energy leading to population decline via photosynthesis inhibition | KeyEvent | Knut Erik Tollefsen (send email) | Under development: Not open for comment. Do not cite | |
ROS production leading to population decline via mitochondrial dysfunction | KeyEvent | Knut Erik Tollefsen (send email) | Under development: Not open for comment. Do not cite | |
Binding to ACE2 leads to lung fibrosis | KeyEvent | Young Jun Kim (send email) | Open for comment. Do not cite | Under Development |
Interaction with lung cells leads to lung cancer | KeyEvent | Penny Nymark (send email) | Under development: Not open for comment. Do not cite | |
Adverse Outcome Pathways diagram related to PBDEs associated male reproductive toxicity | MolecularInitiatingEvent | Yue Zhang (send email) | Under development: Not open for comment. Do not cite | |
Glutathione conjugation leading to reproductive dysfunction | KeyEvent | Leonardo Vieira (send email) | Under Development: Contributions and Comments Welcome | |
ERa inactivation leads to insulin resistance in skeletal muscle and metabolic syndrome | KeyEvent | Min Ji Kim (send email) | Under development: Not open for comment. Do not cite | |
MEK-ERK1/2 activation leading to deficits in learning and cognition via ROS | KeyEvent | Travis Karschnik (send email) | Under development: Not open for comment. Do not cite | |
ROS formation leads to cancer via inflammation pathway | MolecularInitiatingEvent | John Frisch (send email) | Under development: Not open for comment. Do not cite | |
ROS formation leads to cancer via PPAR pathway | MolecularInitiatingEvent | John Frisch (send email) | Under development: Not open for comment. Do not cite | |
Essential element imbalance leads to reproductive failure via oxidative stress | KeyEvent | Travis Karschnik (send email) | Under development: Not open for comment. Do not cite | |
ROS in Fish Ovary Impairs Reproduction | MolecularInitiatingEvent | Kevin Brix (send email) | Under development: Not open for comment. Do not cite | |
Activation of ROS leading the atherosclerosis | MolecularInitiatingEvent | Hiromi Ohara (send email) | Under development: Not open for comment. Do not cite | |
Energy deposition leading to population decline via DNA oxidation and follicular atresia | KeyEvent | You Song (send email) | Under development: Not open for comment. Do not cite | |
Energy deposition leading to population decline via DNA oxidation and oocyte apoptosis | KeyEvent | You Song (send email) | Under development: Not open for comment. Do not cite | |
ROS leading to growth inhibition via LPO and cell death | MolecularInitiatingEvent | You Song (send email) | Under development: Not open for comment. Do not cite | |
ROS leading to growth inhibition via LPO and reduced cell proliferation | MolecularInitiatingEvent | You Song (send email) | Under development: Not open for comment. Do not cite | |
ROS leading to growth inhibition via DNA damage and cell death | MolecularInitiatingEvent | You Song (send email) | Under development: Not open for comment. Do not cite | |
ROS leading to growth inhibition via DNA damage and reduced proliferation | MolecularInitiatingEvent | You Song (send email) | Under development: Not open for comment. Do not cite | |
ROS leading to growth inhibition via protein oxidation and cell death | MolecularInitiatingEvent | You Song (send email) | Under development: Not open for comment. Do not cite | |
ROS leading to growth inhibition via OXPHOS uncoupling | MolecularInitiatingEvent | You Song (send email) | Under development: Not open for comment. Do not cite | |
Excessive ROS leading to mortality (1) | MolecularInitiatingEvent | You Song (send email) | Under development: Not open for comment. Do not cite | |
Excessive ROS leading to mortality (2) | MolecularInitiatingEvent | You Song (send email) | Under development: Not open for comment. Do not cite | |
Excessive ROS leading to mortality (3) | MolecularInitiatingEvent | You Song (send email) | Under development: Not open for comment. Do not cite | |
Excessive ROS leading to mortality (4) | MolecularInitiatingEvent | You Song (send email) | Under development: Not open for comment. Do not cite | |
Calcium-mediated neuronal ROS production and energy imbalance | KeyEvent | Lyle Burgoon (send email) | Open for adoption | |
SDH inhibition, oxidative stress and cancer | KeyEvent | Xavier COUMOUL (send email) | Under development: Not open for comment. Do not cite | |
Mitochondrial complex inhibition leading to liver injury | KeyEvent | Wanda van der Stel (send email) | Under development: Not open for comment. Do not cite | |
Increased ROS and DNT | MolecularInitiatingEvent | Eliska Kuchovska (send email) | Under development: Not open for comment. Do not cite | |
Increase in ROS and chronic ROS leading to human treatment-resistant gastric cancer | MolecularInitiatingEvent | Shihori Tanabe (send email) | Open for comment. Do not cite | Under Review |
Cholestatic Liver Injury induced by Inhibition of the Bile Salt Export Pump (ABCB11) | KeyEvent | Mathieu Vinken (send email) | Under development: Not open for comment. Do not cite | Under Development |
The AOP framework on ROS-mediated oxidative stress induced vascular disrupting effects | MolecularInitiatingEvent | Yanhong Wei (send email) | Under development: Not open for comment. Do not cite | |
NADPH oxidase activation leading to reproductive failure | KeyEvent | Jinhee Choi (send email) | Under development: Not open for comment. Do not cite | |
hepatocyte apoptosis | MolecularInitiatingEvent | Fei Li (send email) | Under development: Not open for comment. Do not cite | |
AOPs of SiNPs: ROS-mediated oxidative stress increased respiratory toxicity. | MolecularInitiatingEvent | Hailin Xu (send email) | Under development: Not open for comment. Do not cite | |
ROS-mediated chemical phototoxicity | MolecularInitiatingEvent | Satomi Onoue (send email) | Under development: Not open for comment. Do not cite | Under Review |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
Vertebrates | Vertebrates | High | NCBI |
human | Homo sapiens | Moderate | NCBI |
human and other cells in culture | human and other cells in culture | Moderate | NCBI |
mouse | Mus musculus | Moderate | NCBI |
crustaceans | Daphnia magna | High | NCBI |
Lemna minor | Lemna minor | High | NCBI |
zebrafish | Danio rerio | High | NCBI |
Life Stages
Life stage | Evidence |
---|---|
All life stages | High |
Sex Applicability
Term | Evidence |
---|---|
Unspecific | High |
Mixed | High |
Key Event Description
Biological State: increased reactive oxygen species (ROS)
Biological compartment: an entire cell -- may be cytosolic, may also enter organelles.
Reactive oxygen species (ROS) are O2- derived molecules that can be both free radicals (e.g. superoxide, hydroxyl, peroxyl, alcoxyl) and non-radicals (hypochlorous acid, ozone and singlet oxygen) (Bedard and Krause 2007; Ozcan and Ogun 2015). ROS production occurs naturally in all kinds of tissues inside various cellular compartments, such as mitochondria and peroxisomes (Drew and Leeuwenburgh 2002; Ozcan and Ogun 2015). Furthermore, these molecules have an important function in the regulation of several biological processes – they might act as antimicrobial agents or triggers of animal gamete activation and capacitation (Goud et al. 2008; Parrish 2010; Bisht et al. 2017). However, in environmental stress situations (exposure to radiation, chemicals, high temperatures) these molecules have its levels drastically increased, and overly interact with macromolecules, namely nucleic acids, proteins, carbohydrates and lipids, causing cell and tissue damage (Brieger et al. 2012; Ozcan and Ogun 2015).
Reactive oxygen species (ROS) refers to the chemical species superoxide, hydrogen peroxide, and their secondary reactive products. In the biological context, ROS are signaling molecules with important roles in cell energy metabolism, cell proliferation, and fate. Therefore, balancing ROS levels at the cellular and tissue level is an important part of many biological processes. Disbalance, mainly an increase in ROS levels, can cause cell dysfunction and irreversible cell damage.
ROS are produced from both exogenous stressors and normal endogenous cellular processes, such as the mitochondrial electron transport chain (ETC). Inhibition of the ETC can result in the accumulation of ROS. Exposure to chemicals, heavy metal ions, or ionizing radiation can also result in increased production of ROS. Chemicals and heavy metal ions can deplete cellular antioxidants reducing the cell’s ability to control cellular ROS and resulting in the accumulation of ROS. Cellular antioxidants include glutathione (GSH), protein sulfhydryl groups, superoxide dismutase (SOD).
ROS are radicals, ions, or molecules that have a single unpaired electron in their outermost shell of electrons, which can be categorized into two groups: free oxygen radicals and non-radical ROS [Liou et al., 2010].
<Free oxygen radicals>
superoxide |
O2·- |
hydroxyl radical |
·OH |
nitric oxide |
NO· |
organic radicals |
R· |
peroxyl radicals |
ROO· |
alkoxyl radicals |
RO· |
thiyl radicals |
RS· |
sulfonyl radicals |
ROS· |
thiyl peroxyl radicals |
RSOO· |
disulfides |
RSSR |
<Non-radical ROS>
hydrogen peroxide |
H2O2 |
singlet oxygen |
1O2 |
ozone/trioxygen |
O3 |
organic hydroperoxides |
ROOH |
hypochlorite |
ClO- |
peroxynitrite |
ONOO- |
nitrosoperoxycarbonate anion |
O=NOOCO2- |
nitrocarbonate anion |
O2NOCO2- |
dinitrogen dioxide |
N2O2 |
nitronium |
NO2+ |
highly reactive lipid- or carbohydrate-derived carbonyl compounds |
Potential sources of ROS include NADPH oxidase, xanthine oxidase, mitochondria, nitric oxide synthase, cytochrome P450, lipoxygenase/cyclooxygenase, and monoamine oxidase [Granger et al., 2015]. ROS are generated through NADPH oxidases consisting of p47phox and p67phox. ROS are generated through xanthine oxidase activation in sepsis [Ramos et al., 2018]. Arsenic produces ROS [Zhang et al., 2011]. Mitochondria-targeted paraquat and metformin mediate ROS production [Chowdhury et al., 2020]. ROS are generated by bleomycin [Lu et al., 2010]. Radiation induces dose-dependent ROS production [Ji et al., 2019].
ROS are generated in the course of cellular respiration, metabolism, cell signaling, and inflammation [Dickinson and Chang 2011; Egea et al. 2017]. Hydrogen peroxide is also made by the endoplasmic reticulum in the course of protein folding. Nitric oxide (NO) is produced at the highest levels by nitric oxide synthase in endothelial cells and phagocytes. NO production is one of the main mechanisms by which phagocytes kill bacteria [Wang et al., 2017]. The other species are produced by reactions with superoxide or peroxide, or by other free radicals or enzymes.
ROS activity is principally local. Most ROS have short half-lives, ranging from nano- to milliseconds, so diffusion is limited, while reactive nitrogen species (RNS) nitric oxide or peroxynitrite can survive long enough to diffuse across membranes [Calcerrada et al. 2011]. Consequently, local concentrations of ROS are much higher than average cellular concentrations, and signaling is typically controlled by colocalization with redox buffers [Dickinson and Chang 2011; Egea et al. 2017].
Although their existence is limited temporally and spatially, ROS interact with other ROS or with other nearby molecules to produce more ROS and participate in a feedback loop to amplify the ROS signal, which can increase RNS. Both ROS and RNS also move into neighboring cells, and ROS can increase intracellular ROS signaling in neighboring cells [Egea et al. 2017].
In the primary event, photoreactive chemicals are excited by the absorption of photon energy. The energy of the photoactivated chemicals transfer to oxygen and then generates the reactive oxygen species (ROS), including superoxide (O2−) via type I reaction and singlet oxygen (1O2) via type II reaction, as principal intermediate species in phototoxic reaction (Foote, 1991, Onoue et al. , 2009).
How It Is Measured or Detected
Photocolorimetric assays (Sharma et al. 2017; Griendling et al. 2016) or through commercial kits purchased from specialized companies.
Yuan, Yan, et al., (2013) described ROS monitoring by using H2-DCF-DA, a redox-sensitive fluorescent dye. Briefly, the harvested cells were incubated with H2-DCF-DA (50 µmol/L final concentration) for 30 min in the dark at 37°C. After treatment, cells were immediately washed twice, re-suspended in PBS, and analyzed on a BD-FACS Aria flow cytometry. ROS generation was based on fluorescent intensity which was recorded by excitation at 504 nm and emission at 529 nm.
Lipid peroxidation (LPO) can be measured as an indicator of oxidative stress damage Yen, Cheng Chien, et al., (2013).
Chattopadhyay, Sukumar, et al. (2002) assayed the generation of free radicals within the cells and their extracellular release in the medium by addition of yellow NBT salt solution (Park et al., 1968). Extracellular release of ROS converted NBT to a purple colored formazan. The cells were incubated with 100 ml of 1 mg/ml NBT solution for 1 h at 37 °C and the product formed was assayed at 550 nm in an Anthos 2001 plate reader. The observations of the ‘cell-free system’ were confirmed by cytological examination of parallel set of explants stained with chromogenic reactions for NO and ROS.
On the basis of the pathogenesis of drug-induced phototoxicity, a reactive oxygen species (ROS) assay was proposed to evaluate the phototoxic risk of chemicals. The ROS assay can monitor generation of ROS, such as singlet oxygen and superoxide, from photoirradiated chemicals, and the ROS data can be used to evaluate the photoreactivity of chemicals (Onoue et al. , 2014, Onoue et al. , 2013, Onoue and Tsuda, 2006). The ROS assay is a recommended approach by guidelines to evaluate the phototoxic risk of chemicals (ICH, 2014, PCPC, 2014).
<Direct detection>
Many fluorescent compounds can be used to detect ROS, some of which are specific, and others are less specific.
・ROS can be detected by fluorescent probes such as p-methoxy-phenol derivative [Ashoka et al., 2020].
・Chemiluminescence analysis can detect the superoxide, where some probes have a wider range for detecting hydroxyl radical, hydrogen peroxide, and peroxynitrite [Fuloria et al., 2021].
・ROS in the blood can be detected using superparamagnetic iron oxide nanoparticles (SPION)-based biosensor [Lee et al., 2020].
・Hydrogen peroxide (H2O2) can be detected with a colorimetric probe, which reacts with H2O2 in a 1:1 stoichiometry to produce a bright pink colored product, followed by the detection with a standard colorimetric microplate reader with a filter in the 540-570 nm range.
・The levels of ROS can be quantified using multiple-step amperometry using a stainless steel counter electrode and non-leak Ag|AgCl reference node [Flaherty et al., 2017].
・Singlet oxygen can be measured by monitoring the bleaching of p-nitrosodimethylaniline at 440 nm using a spectrophotometer with imidazole as a selective acceptor of singlet oxygen [Onoue et al., 2014].
<Indirect Detection>
Alternative methods involve the detection of redox-dependent changes to cellular constituents such as proteins, DNA, lipids, or glutathione [Dickinson and Chang 2011; Wang et al. 2013; Griendling et al. 2016]. However, these methods cannot generally distinguish between the oxidative species behind the changes and cannot provide good resolution for the kinetics of oxidative activity.
Domain of Applicability
ROS is a normal constituent found in all organisms, lifestages, and sexes.
References
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Zhang, Z., et al. (2011). "Reactive oxygen species mediate arsenic induced cell transformation and tumorigenesis through Wnt/β-catenin pathway in human colorectal adenocarcinoma DLD1 cells. " Toxicology and Applied Pharmacology, 256(2), 114-121. doi:10.1016/j.taap.2011.07.016