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Increased, Reactive oxygen species leads to Apoptosis
Key Event Relationship Overview
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 Do not cite|
|Rattus norvegicus||Rattus norvegicus||Moderate||NCBI|
Life Stage Applicability
Key Event Relationship Description
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
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
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
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
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.