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Relationship: 2966


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increased, Reactive oxygen species leads to Apoptosis

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis adjacent Not Specified Not Specified Travis Karschnik (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Rattus norvegicus Rattus norvegicus Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

ROS generation in normal cells, including neurons, occurs within homeostatic control. When ROS levels exceed the antioxidant capacity of a cell, a deleterious condition known as oxidative stress occurs (Klein and Ackerman 2003). Unchecked, excessive ROS can lead to the destruction of cellular components including lipids, protein, and DNA, and ultimately cell death via apoptosis or necrosis (Kannan and Jain 2000).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. The KER is referenced in publications which were cited in the originating work for the putative AOP "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis", Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework, Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Reactive oxygen species (ROS) can be derived from exogenous sources or produced in vivo; these include the superoxide anion (O 2), the hydroxyl radical (OH), and hydrogen  peroxide (H 2O2). ROS at low levels participate in cell signaling while higher ROS concentrations are deleterious due to the oxidation of proteins, lipids, and DNA. Additionally,  persistent ROS production compromises the cellular antioxidant defense systems and results in oxidative stress and apoptosis (337). ROS can initiate apoptosis via the  mitochondrial and death receptor pathways. In the former, ROS have been shown to induce loss of the m, release of mitochondrial pro-apoptotic proteins, and activation of caspase 3 (49).

ROS signaling has been shown to mediate cytokine-induced apoptosis (Okouchi et al., 2007). TNF is a pro-inflammatory cytokine produced by macrophages and is the most studied cytokine in  apoptosis and the pathophysiology of various diseases, including neurodegenerative disorders (Jackson et al., 1999). Mechanistically, the binding of TNF to its receptor activates the NF-B and JNK signaling pathways believed to be mediated by ROS (Okouchi et al., 2007).  A role for ROS has also been implicated in death receptor-mediated apoptosis induced by apoptosis signal-regulating kinase 1 (ASK1), an ubquitiously expressed MAP kinase kinase kinase (MAPKKK), that activates JNK and p38 MAP kinase pathways (Okouchi et al., 2007).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

ROS and/or oxidative damage can activate gene transcription and transcribed genes may be implicated in either cell survival or cell death (Klein and Ackerman 2003).

The increase in reactive oxygen species at As(III) concentrations of 0.5 mg/l or more may play an apoptogenic role and/or be a consequence of events occurring during apoptosis (Rocha et al. 2011). It is generally reported that ROS cause an increase in [Ca2+]i of various cell types, which might be one of the causes for the C17.2 cells to enter apoptosis (Rocha et al. 2011). According to Hool and Corry (2007), the redox control of Ca2+ transport is due to the fact that ROS can react with the thiol groups of protein that form part of the Ca2+ transporters or channels. Alternatively, mitochondrial matrix Ca2+ overload can lead to enhanced generation of reactive oxygen species, triggering the permeability transition pore, dissipation of transmembrane mithocondrial potential, and cytochrome c release (Brookes et al., 2004). In any case, the fact that treatment with various antioxidants (vitamin E, tocopherol, and quercetin) did not rescue the cells from death by apoptosis indicates that oxidative stress was not the main cause of the observed cell death (Rocha et al. 2011).

Superoxides and lipid peroxidation are increased during apoptosis induced by myriad stimuli (Bredesen 1995). However, generation of ROS may be a relatively late event, occurring after cells have embarked on a process of caspase activation (Green and Reed 1998). In this regard, attempts to study apoptosis under conditions of anoxia have demonstrated that at least some proapoptotic stimuli function in the absence or near absence of oxygen, which implies that ROSs are not the sine qua non of apoptosis (Jacobson and Raff 1995). However, ROSs can be generated under conditions of virtual anaerobiosis (Degli Esposti and McLennan 1998), and thus their role in apoptosis cannot be excluded solely on this basis (Green and Reed 1998).

Okouchi et. al. (2007) found that PC12 apoptosis can be initiated by GSH/GSSG redox imbalance alone independently of ROS generation (Pias et al., 2003), suggesting that a loss of cellular  redox homeostasis is downstream of ROS signaling in neuronal cell apoptosis.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


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

A.H. Poliandri, J.P. Cabilla, M.O. Velardez, C.C. Bodo, B.H. Duvilanski Cadmium induces apoptosis in anterior pituitary cells that can be reversed by treatment with antioxidants Toxicol. Appl. Pharmacol., 190 (2003), pp. 17-24

Asit Rai et al., Characterization of Developmental Neurotoxicity of As, Cd, and Pb Mixture: Synergistic Action of Metal Mixture in Glial and Neuronal Functions, Toxicological Sciences, Volume 118, Issue 2, December 2010, Pages 586–601

Bharathi, Ravid R, Jagannathan Rao KS (2006) Role of metals in neuronal apoptosis: challenges associated with neurodegeneration. Curr Alzheimer Res 3:311–326

Bredesen, Dale E. "Neural apoptosis." Annals of neurology 38.6 (1995): 839-851.

Chen, Long, Lei Liu, and Shile Huang. "Cadmium activates the mitogen-activated protein kinase (MAPK) pathway via induction of reactive oxygen species and inhibition of protein phosphatases 2A and 5." Free Radical Biology and Medicine 45.7 (2008): 1035-1044.

Degli Esposti, Mauro, and Holly McLennan. "Mitochondria and cells produce reactive oxygen species in virtual anaerobiosis: relevance to ceramide-induced apoptosis." FEBS letters 430.3 (1998): 338-342.

Flora SJ, Bhatt K, Mehta A (2009) Arsenic moiety in gallium arsenide is responsible for neuronal apoptosis and behavioral alterations in rats. Toxicol Appl Pharmacol 240:236–244

Gharibzadeh S, Hoseini SS (2008) Arsenic exposure may be a risk factor for Alzheimer’s disease. J Neuropsychiatr Clin Neurosci 20:501

Green, Douglas R., and John C. Reed. "Mitochondria and apoptosis." science 281.5381 (1998): 1309-1312.

Han D, Hanawa N, Saberi B, and Kaplowitz N. Hydrogen peroxide and redox modulation sensitize primary mouse hepatocytes to TNF-induced apoptosis. Free Rad Biol Med 41: 627–639, 2006.

J. Kim, R.P. Sharma Calcium-mediated activation of c-Jun NH2-terminal kinase (JNK) and apoptosis in response to cadmium in murine macrophages Toxicol. Sci., 81 (2004), pp. 518-527

Jackson CE, Fisher RE, Hsu AP, Anderson SM, Choi YN, Wang J, Dale JK, Fleisher TA, Middelton LA, Sneller MC, Leonardo MJ, Straus SE, and Puck JM. Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. Am J Hum Genet 64: 1002–1014, 1999

Jacobson, Michael D., and Martin C. Raff. "Programmed cell death and Bcl-2 protection in very low oxygen." Nature 374.6525 (1995): 814-816.

K. Takuma, E. Lee, M. Kidawara, K. Mori, Y. Kimura, A. Baba, T. Matsuda Apoptosis in Ca2+ reperfusion injury of cultured astrocytes: roles of reactive oxygen species and NF-κB  activation Eur. J. Neurosci., 11 (1999), pp. 4204-4212

Kannan, K, Jain, SK. Oxidative stress and apoptosis. Pathophysiology. 2000. 7:153-163.

Klein, Jeffrey A., and Susan L. Ackerman. "Oxidative stress, cell cycle, and neurodegeneration." The Journal of clinical investigation 111.6 (2003): 785-793.

L.C. Hool, B. Corry Redox control of calcium channels: from mechanisms to therapeutic opportunities Antioxid. Redox Signal, 9 (2007), pp. 409-435

Lu, Tien-Hui, et al. "Arsenic induces reactive oxygen species-caused neuronal cell apoptosis through JNK/ERK-mediated mitochondria-dependent and GRP 78/CHOP-regulated pathways." Toxicology letters 224.1 (2014): 130-140.

O.I. Aruoma, B. Halliwell, B.M. Hoey, J. Butler The antioxidant action of N-acetylcysteine: itS reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid Free Radic. Biol. Med., 6 (1989), pp. 593-597

Okouchi, Masahiro, et al. "Neuronal apoptosis in neurodegeneration." Antioxidants & redox signaling 9.8 (2007): 1059-1096.

P.S. Brookes, Y. Yoon, J.L. Robotham, M.W. Anders, S.-S. Shen Calcium ATP and ROS: a mitochondrial love-hate triangle Am. J. Physiol. Cell Physiol., 287 (2004), pp.  817-833

Pias EK and Aw TY. Apoptosis in mitotic competent undifferentiated cells is induced by cellular redox imbalance independent of reactive oxygen species production. FASEB J 16:781–790, 2002

Pias EK and Aw TY. Early redox imbalance mediates hydroperoxide-induced apoptosis in mitotic competent undifferentiated PC-12 cells. Cell Death Differ 9: 1007–1016, 2002.

Pias EK, Ekshyyan OY, Rhoads CA, Fuseler J, Harrison L, and Aw TY. Differential effects of superoxide dismutase isoform expression on hydroperoxide-induced apoptosis in PC-12 cells. J Biol Chem 278: 13294–13301, 2003.

Pias EK, Ekshyyan OY, Rhoads CA, Fuseler J, Harrison L, and Aw TY. Differential effects of superoxide dismutase isoform expression on hydroperoxide-induced apoptosis in PC-12 cells. J Biol Chem 278: 13294–13301, 2003

Rocha, R. A., et al. "Arsenic and fluoride induce neural progenitor cell apoptosis." Toxicology letters 203.3 (2011): 237-244.

Schulze–Osthoff K, Bakker AC, Vanhaesebroeck B, Beyaert R, Jacob WA, and Fiers W. Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial function. J Biol Chem 267: 5317–5323, 1992.

Takuma, Kazuhiro, Akemichi Baba, and Toshio Matsuda. "Astrocyte apoptosis: implications for neuroprotection." Progress in neurobiology 72.2 (2004): 111-127.