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Event: 1632

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Increase in reactive oxygen and nitrogen species (RONS)

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help

Increase in RONS

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. More help

Organ term

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Increased DNA damage leading to breast cancer	KeyEvent	Allie Always (send email)	Under development: Not open for comment. Do not cite	Under Development
RONS leading to breast cancer	MolecularInitiatingEvent	Evgeniia Kazymova (send email)	Under development: Not open for comment. Do not cite	Under Development

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Name
Ionizing Radiation

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Reactive oxygen and nitrogen species (RONS) are highly reactive oxygen- and nitrogen-based molecules that often contain or generate free radicals. Key molecules include superoxide ([O2]•−), hydrogen peroxide (H2O2), hydroxyl radical ([OH]•), lipid peroxide (ROOH), nitric oxide ([NO]•, and peroxynitrite ([ONOO-]) (Dickinson and Chang 2011; Egea, Fabregat et al. 2017)

RONS are generated in the course of cellular respiration, metabolism, cell signaling, and inflammation (Dickinson and Chang 2011; Egea, Fabregat et al. 2017). Superoxide and hydrogen peroxide are commonly produced by the mitochondrial electron transport chain and cytochrome c and by membrane bound NADPH oxidases and related molecules. Hydrogen peroxide is also made by the endoplasmic reticulum in the course of protein folding. Nitric oxide is produced at the highest levels by nitric oxide synthase in endothelial cells and phagocytes. The other species are produced by reactions with superoxide or peroxide, or by other free radicals or enzymes.

RONS activity is principally local. Most reactive oxygen species (ROS) have short half-lives, ranging from nano- to milliseconds, so diffusion is limited, while reactive nitrogen species (RNS) nitric oxide or peroxynitrate can survive long enough to diffuse across membranes (Calcerrada, Peluffo 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, Fabregat et al. 2017). The effects of ROS and RNS are countered by cellular antioxidants, with glutathione and peroxiredoxins playing a major role (Dickinson and Chang 2011). Glutathione is slower but broad acting, while peroxiredoxins act quickly and are specific to peroxides. Peroxiredoxins are effective at low peroxide concentrations but can be deactivated at higher concentrations, suggesting the cellular response to peroxides may sometimes be non-linear.

Although their existence is limited temporally and spatially, reactive oxygen species (ROS) interact with other RONS or with other nearby molecules to produce more ROS and participate in a feedback loop to amplify the ROS signal, which can increase Reactive Nitrogen Species (RNS). Both ROS and RNS also move into neighboring cells and ROS can increase intracellular RONS signaling in neighboring cells (Egea, Fabregat et al. 2017).

RONS can modify a range of targets including amino acids, lipids, and nucleic acids to inactivate or alter target functionality (Calcerrada, Peluffo et al. 2011; Dickinson and Chang 2011; Go and Jones 2013; Ravanat, Breton et al. 2014; Egea, Fabregat et al. 2017). For example, phosphatases including the tumor suppressor PTEN can be reversibly deactivated by oxidation, and the movement of HDAC4 is peroxide dependent. Elevated ROS are implicated in proliferation and maintenance of stem cell population size (Dickinson and Chang 2011) and conversely in differentiation of stem cells and oncogene-induced senescence (Egea, Fabregat et al. 2017).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

RONS is typically measured using fluorescent or other probes that react with RONS to change state, or by measuring the redox state of proteins or DNA (Dickinson and Chang 2011; Wang, Fang et al. 2013; Griendling, Touyz et al. 2016). Optimal methods for RONS detection have high sensitivity, selectivity, and spatiotemporal resolution to distinguish transient and localized activity, but most methods lack one or more of these parameters.

Molecular probes that indicate the presence of RONS species vary in specificity and kinetics (Dickinson and Chang 2011; Wang, Fang et al. 2013; Griendling, Touyz et al. 2016). Small molecule fluorescent probes can be applied to any tissue in vitro, but cannot be finely targeted to different cellular compartments. The non-selective probe DCHF was widely used in the past, but can produce false positive signals and is no longer recommended. Newer more selective small molecule probes such as boronate-based molecules are being developed but are not yet widely used. Alternatively, fluorescent protein-based probes can be genetically engineered, expressed in vivo, and targeted to cellular compartments and specific cells. However, these probes are very sensitive to pH in the physiological range and must be carefully controlled. EPR (electron paramagnetic resonance spectroscopy) provide the most direct and specific detection of free radicals, but requires specialized equipment.

Alternative methods involve the detection of redox-dependent changes to cellular constituents such as proteins, DNA, lipids, or glutathione (Dickinson and Chang 2011; Wang, Fang et al. 2013; Griendling, Touyz et al. 2016). However, these methods cannot generally distinguish between the oxidative species behind the changes, and cannot provide good resolution for kinetics of oxidative activity.

Table 1. Common methods for detecting oxidative activity

Target	Name	Method	Strengths/Weaknesses
Hydrogen peroxide- extracellular	AmplexRed	Small molecule fluorescent probes	Can be applied to any tissue in vitro.
Hydrogen peroxide- mitochondrial	MitoPy1	Small molecule fluorescent probes	Can be applied to any tissue in vitro.
Hydrogen peroxide	HyPer	Protein-based fluorescent probes	Sensitive, can be targeted to specific cells and compartments. Slower and pH sensitive.
Hydrogen peroxide	HyPer3	Protein-based fluorescent probes	Rapid kinetics and larger dynamic range, can be targeted to specific cells and compartments. Sensitive to pH, less sensitive to H2O2.
Hydrogen peroxide	Boronate-based indicators	Small molecule fluorescent probe	Selective for H2O2 but can interact with peroxynitrite.
Superoxide- intracellular	DHE (dihydroethidium)	Small molecule fluorescent probe	Can be applied to any tissue in vitro, but not targeted to different compartments.
Superoxide- intracellular	cpYFP	Protein-based fluorescent probes	Reversible. Can be targeted to specific cells and compartments.
Superoxide- mitochondrial	MitoSox	Small molecule fluorescent probe	Can be applied to any tissue in vitro.
Superoxide- mitochondrial	mt-cpYFP	Protein-based fluorescent probes	Reversible. Can be targeted to specific cells and compartments.
Superoxide- extracellular	nitroblue tetrazolium	Small molecule fluorescent probe	Can be applied to any tissue in vitro.
Superoxide- intracellular or extracelluar	various trityl probes	EPR	Very specific, but requires specialized equipment, not as sensitive in tissue.
Nitric oxide	Fe[DETC]2 and Fe[MGD]2,	EPR	Very specific, but requires specialized equipment, not as sensitive in tissue.
Nitric oxide	DAF-FM	Small molecule fluorescent probe	Can be applied to any tissue in vitro, but not targeted to different compartments
Peroxynitrite	EMPO	EPR	Very specific, but requires specialized equipment, not as sensitive in tissue.
Peroxynitrite	Boronate-based indicators	Small molecule fluorescent probe	Selective for H2O2 but can interact with (is inhibited by) peroxynitrite.
Peroxynitrite	8-nitroguanine (DNA) content	HPLC-MS/MS	Destruction of sample required for measurement.
Non-specific oxidation	DCHF	Small molecule fluorescent probe	Very non selective, and can produce false positive signals.
Non-specific oxidation	roGFP or FRET	Protein-based fluorescent probes	Slow acting. Good to look at steady state activity.
Non-specific oxidation	ratio of reduced to oxidized glutathione or cysteine	Redox state detectors	Slow acting. Good to look at steady state activity. Destruction of sample required for measurement.
Non-specific oxidation	8-oxoguanine (DNA) or protein carbonyl content	HPLC-MS/MS	Destruction of sample required for measurement.
Non-specific oxidation	TBARS (thiobarbituric acid reactive substance)	Lipid peroxidation	Destruction of sample required for measurement.

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information. More help

This KE is broadly applicable across species.

Evidence for Perturbation by Stressor

Overview for Molecular Initiating Event

When a specific MIE can be defined (i.e., the molecular target and nature of interaction is known), in addition to describing the biological state associated with the MIE, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to list stressors known to trigger the MIE and provide evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). Depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). Known stressors should be included in the MIE description, but it is not expected to include a comprehensive list. Rather initially, stressors identified will be exemplary and the stressor list will be expanded over time. For more information on MIE, please see pages 32-33 in the User Handbook.

The following stressors increase this key event: ionizing radiation.

Ionizing Radiation

Reactive oxygen and nitrogen species are created by the interaction of ionizing radiation with tissue. When ionizing radiation encounters water or extracellular or intracellular components, it releases energy. This energy ejects electrons from atoms and molecules, and the ejected electrons pass energy on to neighboring molecules. Since the majority of biological tissue is composed of water molecules, ionizing radiation results in the radiolysis of water to hydroxyl radicals, which can interact to form additional reactive molecules. This reaction is generally accepted. Because RONS have such a short half-life, their appearance has been historically measured by their effect on the cell (e.g. in terms of DNA damage), and only more recently characterized using molecular probes that directly reflect their occurrence.

The time course of RONS following ionizing radiation has been described using molecular probes- primarily the non-specific fluorescent probe for ROS DCHF as well as non-specific lipid peroxidation. ROS levels increase at multiple time points: in vitro immediately following radiation (Denissova, Nasello et al. 2012; Yoshida, Goto et al. 2012; Martin, Nakamura et al. 2014), around 15 minutes later (Narayanan, Goodwin et al. 1997; Saenko, Cieslar-Pobuda et al. 2013), hours to days (Lyng, Seymour et al. 2001; Yang, Asaad et al. 2005; Choi, Kang et al. 2007; Du, Gao et al. 2009; Das, Manna et al. 2014; Werner, Wang et al. 2014; Ameziane-El-Hassani, Talbot et al. 2015; Manna, Das et al. 2015; Zhang, Zhu et al. 2017), and in vivo intestinal epithelial cells and bone marrow stem cells showed elevated ROS up to a year after IR exposure of the animal (Pazhanisamy, Li et al. 2011; Datta, Suman et al. 2012). In intestinal epithelial cells, widespread ROS expression over a period of weeks would require transgenerational expression of ROS, indicating that a cell with increased RONS can pass that characteristic to its daughter cells.

Multiple mechanisms underlie the increase in RONS after IR. The early (15 minute) and later (days to weeks) elevation in ROS is associated with increased NADPH-oxidase production of superoxide and H2O2 (Narayanan, Goodwin et al. 1997; Ameziane-El-Hassani, Talbot et al. 2015), and intermediate (hours to days) and chronic ROS elevation has been associated with mitochondrial respiration (Dayal, Martin et al. 2009; Datta, Suman et al. 2012; Saenko, Cieslar-Pobuda et al. 2013). The increase in mitochondrial respiration may be supported by nitric oxide, which increases around 8 hours after IR and remains elevated through at least day 2. A chronic (1 year) ROS effect of IR was not observed in cell culture when cell divisions were limited, potentially implicating cell division in sustaining chronic RONS (Suzuki, Kashino et al. 2009). RONS can also be indirectly initiated by ionizing radiation in neighboring cells via unknown soluble factors, possibly including extracellular H2O2, which is elevated immediately and in the first week following IR (Driessens, Versteyhe et al. 2009; Ameziane-El-Hassani, Boufraqech et al. 2010; Ameziane-El-Hassani, Talbot et al. 2015). Elevated intracellular ROS was observed in cells after exposure to media from IR-exposed cells (Narayanan, Goodwin et al. 1997; Lyng, Seymour et al. 2001; Yang, Asaad et al. 2005), and protein carbonylation and lipid oxidation reflecting RONS activity was elevated in cells 20 passages after exposure to media from IR cells (Buonanno, de Toledo et al. 2011), suggesting that the effect of IR on RONS can penetrate well beyond the directly exposed cells in both space and time.

Few studies have measured RONS at multiple doses of ionizing radiation, and the time points, doses, and cell types tested for dose response vary between studies along with the dose-dependence. Two studies report dose-dependence of RONS measured with lipid peroxidation or DCHF in response to a few doses between 0.5 and 12 Gy IR (Jones, Riggs et al. 2007; Saenko, Cieslar-Pobuda et al. 2013), dose-dependence of ROS only at lower doses below 1 Gy (Werner, Wang et al. 2014), or non-linear dose-dependence (Narayanan, Goodwin et al. 1997). Dose-dependent RONS responses are also reported in extracellular media (Driessens, Versteyhe et al. 2009), and in bystander cells not directly exposed to IR (Narayanan, Goodwin et al. 1997), even after multiple generations in culture (Buonanno, de Toledo et al. 2011). ROS appears to be more dose-dependent immediately after IR and after 24 hours following IR with less dose-dependence at times in between (Narayanan, Goodwin et al. 1997; Saenko, Cieslar-Pobuda et al. 2013; Zhang, Zhu et al. 2017), possibly reflecting different mechanisms of ROS generation. These studies use probes for ROS or indicators of oxidation, but none that we are aware of explicitly measures indicators of RNS at different doses of IR.

Ameziane-El-Hassani, R., M. Boufraqech, et al. (2010). "Role of H2O2 in RET/PTC1 chromosomal rearrangement produced by ionizing radiation in human thyroid cells." Cancer Res 70(10): 4123-4132.

Ameziane-El-Hassani, R., M. Talbot, et al. (2015). "NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation." Proceedings of the National Academy of Sciences of the United States of America 112(16): 5051-5056.

Buonanno, M., S. M. de Toledo, et al. (2011). "Long-term consequences of radiation-induced bystander effects depend on radiation quality and dose and correlate with oxidative stress." Radiation research 175(4): 405-415.

Choi, K. M., C. M. Kang, et al. (2007). "Ionizing radiation-induced micronucleus formation is mediated by reactive oxygen species that are produced in a manner dependent on mitochondria, Nox1, and JNK." Oncol Rep 17(5): 1183-1188.

Das, U., K. Manna, et al. (2014). "Role of ferulic acid in the amelioration of ionizing radiation induced inflammation: a murine model." PLoS One 9(5): e97599.

Datta, K., S. Suman, et al. (2012). "Exposure to heavy ion radiation induces persistent oxidative stress in mouse intestine." PLoS One 7(8): e42224.

Dayal, D., S. M. Martin, et al. (2009). "Mitochondrial complex II dysfunction can contribute significantly to genomic instability after exposure to ionizing radiation." Radiation research 172(6): 737-745.

Denissova, N. G., C. M. Nasello, et al. (2012). "Resveratrol protects mouse embryonic stem cells from ionizing radiation by accelerating recovery from DNA strand breakage." Carcinogenesis 33(1): 149-155.

Driessens, N., S. Versteyhe, et al. (2009). "Hydrogen peroxide induces DNA single- and double-strand breaks in thyroid cells and is therefore a potential mutagen for this organ." Endocrine-related cancer 16(3): 845-856.

Du, C., Z. Gao, et al. (2009). "Mitochondrial ROS and radiation induced transformation in mouse embryonic fibroblasts." Cancer Biol Ther 8(20): 1962-1971.

Jones, J. A., P. K. Riggs, et al. (2007). "Ionizing radiation-induced bioeffects in space and strategies to reduce cellular injury and carcinogenesis." Aviat Space Environ Med 78(4 Suppl): A67-78.

Lyng, F. M., C. B. Seymour, et al. (2001). "Oxidative stress in cells exposed to low levels of ionizing radiation." Biochemical Society transactions 29(Pt 2): 350-353.

Manna, K., U. Das, et al. (2015). "Naringin inhibits gamma radiation-induced oxidative DNA damage and inflammation, by modulating p53 and NF-kappaB signaling pathways in murine splenocytes." Free Radic Res 49(4): 422-439.

Martin, N. T., K. Nakamura, et al. (2014). "Homozygous mutation of MTPAP causes cellular radiosensitivity and persistent DNA double-strand breaks." Cell Death Dis 5: e1130.

Narayanan, P. K., E. H. Goodwin, et al. (1997). "Alpha particles initiate biological production of superoxide anions and hydrogen peroxide in human cells." Cancer research 57(18): 3963-3971.

Pazhanisamy, S. K., H. Li, et al. (2011). "NADPH oxidase inhibition attenuates total body irradiation-induced haematopoietic genomic instability." Mutagenesis 26(3): 431-435.

Saenko, Y., A. Cieslar-Pobuda, et al. (2013). "Changes of reactive oxygen and nitrogen species and mitochondrial functioning in human K562 and HL60 cells exposed to ionizing radiation." Radiation research 180(4): 360-366.

Suzuki, K., G. Kashino, et al. (2009). "Long-term persistence of X-ray-induced genomic instability in quiescent normal human diploid cells." Mutation research 671(1-2): 33-39.

Werner, E., H. Wang, et al. (2014). "Opposite roles for p38MAPK-driven responses and reactive oxygen species in the persistence and resolution of radiation-induced genomic instability." PLoS One 9(10): e108234.

Yang, H., N. Asaad, et al. (2005). "Medium-mediated intercellular communication is involved in bystander responses of X-ray-irradiated normal human fibroblasts." Oncogene 24(12): 2096-2103.

Yoshida, T., S. Goto, et al. (2012). "Mitochondrial dysfunction, a probable cause of persistent oxidative stress after exposure to ionizing radiation." Free Radic Res 46(2): 147-153.

Zhang, Q., L. Zhu, et al. (2017). "Ionizing radiation promotes CCL27 secretion from keratinocytes through the cross talk between TNF-alpha and ROS." J Biochem Mol Toxicol 31(3)

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Calcerrada, P., G. Peluffo, et al. (2011). "Nitric oxide-derived oxidants with a focus on peroxynitrite: molecular targets, cellular responses and therapeutic implications." Curr Pharm Des 17(35): 3905-3932.

Dickinson, B. C. and C. J. Chang (2011). "Chemistry and biology of reactive oxygen species in signaling or stress responses." Nature chemical biology 7(8): 504-511.

Egea, J., I. Fabregat, et al. (2017). "European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)." Redox biology 13: 94-162.

Go, Y. M. and D. P. Jones (2013). "The redox proteome." J Biol Chem 288(37): 26512-26520.

Griendling, K. K., R. M. Touyz, et al. (2016). "Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement From the American Heart Association." Circulation research 119(5): e39-75.

Ravanat, J. L., J. Breton, et al. (2014). "Radiation-mediated formation of complex damage to DNA: a chemical aspect overview." Br J Radiol 87(1035): 20130715.

Wang, X., H. Fang, et al. (2013). "Imaging ROS signaling in cells and animals." Journal of molecular medicine 91(8): 917-927.