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Oxidative Stress leads to Cell injury/death
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins involved in protection against oxidative stress during brain development leads to impairment of learning and memory||non-adjacent||High||High||Marie-Gabrielle Zurich (send email)||Under development: Not open for comment. Do not cite||EAGMST Approved|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Oxidative stress (OS) as a concept in redox biology and medicine has been formulated in 1985 (Sies, 2015). OS is intimately linked to cellular energy balance and comes from the imbalance between the generation and detoxification of reactive oxygen and nitrogen species (ROS/RNS) or from a decay of the antioxidant protective ability. OS is characterized by the reduced capacity of endogenous systems to fight against the oxidative attack directed towards target biomolecules (Wang and Michaelis, 2010; Pisoschi and Pop, 2015). Glutathione, the most important redox buffer in cells (antioxidant), cycles between reduced glutathione (GSH) and oxidized glutathione disulfide (GSSG), and serves as a vital sink for control of ROS levels in cells (Reynolds et al., 2007). Several case-control studies have reported the link between lower concentrations of GSH, higher levels of GSSG and the development of diseases (Rossignol and Frye, 2014). OS can cause cellular damage and subsequent cell death because the ROS oxidize vital cellular components such as lipids, proteins, and nucleic acids (Gilgun-Sherki, Melamed and Offen, 2001; Wang and Michaelis, 2010).
The central nervous system is especially vulnerable to free radical damage since it has a high oxygen consumption rate, an abundant lipid content and reduced levels of antioxidant enzymes (Coyle and Puttfarcken, 1993; Markesbery, 1997). It has been show that the developing brain is particularly vulnerable to neurotoxicants and OS due to differentiation processes, changes in morphology, lack of physiological barriers and less intrinsic capacity to cope with cellular stress (Grandjean and Landrigan, 2014; Sandström et al., 2017). However, it has to be noted that neural stem cells distinguish themeselves from post-mitotic neural cells by their lower ROS levels and higher expression of the key antioxidant enzymes glutathione peroxidase. This increased "vigilance" of antioxidant mechanisms might represent an innate characteristic of NSCs, which not only defines their cell fate, but also helps them to encounter oxidative stress (Madhavan et al., 2006).
OS has been linked to brain aging, neurodegenerative diseases, and other related adverse conditions. There is evidence that free radicals play a role in cerebral ischemia-reperfusion, head injury, Parkinson’s disease, amyotrophic lateral sclerosis, Down’s syndrome, and Alzheimer’s disease due to cellular damage (Markesbery, 1997; Gilgun-Sherki, Melamed and Offen, 2001; Wang and Michaelis, 2010). OS has also been linked to neurodevelopmental diseases and deficits like autism spectrum disorder and postnatal motor coordination deficits (Wells et al., 2009; Rossignol and Frye, 2014; Bhandari and Kuhad, 2015).
Evidence Supporting this KER
A noteworthy insight, early on, was the perception that oxidation-reduction (redox) reactions in living cells are utilized in fundamental processes of redox regulation, collectively termed ‘redox signaling’ and ‘redox control’ (Sies, 2015).
Free radical-induced damage in OS has been confirmed as a contributor to the pathogenesis and patho-physiology of many chronic diseases, such as Alzheimer, atherosclerosis, Parkinson, but also in traumatic brain injury, sepsis, stroke, myocardial infraction, inflammatory diseases, cataracts and cancer (Bar-Or et al., 2015; Pisoschi and Pop, 2015). It has been assessed that oxidative stress is correlated with over 100 diseases, either as source or outcome (Pisoschi and Pop, 2015).
Therefore, the fact that ROS over-production can kill neurons is well accepted (Brown and Bal-Price, 2003; Taetzsch and Block, 2013). This ROS over-production can occur in the neurons themselves or can also have a glial origin (Yuste et al., 2015).
Uncertainties and Inconsistencies
Mercury-induced upregulation of GSH level and GR activity as an adaptive mechanism following lactational exposure to methylmercury (10 mg/L in drinking water) associated with motor deficit, suggesting neuronal impairment (Franco et al., 2006).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Rat, Mouse: (Sarafian et al., 1994; Castoldi et al., 2000; Kaur et al., 2006; Franco et al., 2007; Lu et al., 2011; Polunas et al., 2011)
(Richetti et al., 2011) - Adult and healthy zebrafish of both sexes (12 animals and housed in 3 L) mercury chloride final concentration of 20 mg/L. Mercury chloride promoted a significant decrease in acetylcholinesterase activity and the antioxidant competence was also decreased.
(Berntssen, Aatland and Handy, 2003) - Atlantic salmon (Salmo salar L.) were supplemented with mercuric chloride (0, 10, or 100 mg Hg per kg) or methylmercury chloride (0, 5, or 10 mg Hg per kg) for 4 months.
- accumulated significantly in the brain of fish fed 5 or 10 mg/kg
- No mortality or growth reduction
- - 2-fold increase in the antioxidant enzyme super oxide dismutase (SOD) in the brain
- 10 mg/kg - 7-fold increase of lipid peroxidative products (thiobarbituric acid reactive substances, TBARS) and a subsequently 1.5-fold decrease in anti oxidant enzyme activity (SOD and glutathione peroxidase, GSH-Px). Fish also had pathological damage (vacoulation and necrosis), significantly reduced neural enzyme activity (5-fold reduced monoamine oxidase, MAO, activity), and reduced overall post-feeding activity behaviour.
- accumulated significantly in the brain only at 100 mg/kg
- No mortality or growth reduction
- 100 mg/kg - significant reduced neural MAO activity and pathological changes (astrocyte proliferation) in the brain, however, neural SOD and GSH-Px enzyme activity, lipid peroxidative products (TBARS), and post feeding behaviour did not differ from controls.
Allam, a et al. (2011) ‘Prenatal and perinatal acrylamide disrupts the development of cerebellum in rat: Biochemical and morphological studies.’, Toxicology and industrial health, 27, pp. 291–306. doi: 10.1177/0748233710386412.
Bar-Or, D. et al. (2015) ‘Oxidative stress in severe acute illness’, Redox Biology. Elsevier, 4, pp. 340–345. doi: 10.1016/j.redox.2015.01.006.
Berntssen, M. H. G., Aatland, A. and Handy, R. D. (2003) ‘Chronic dietary mercury exposure causes oxidative stress, brain lesions, and altered behaviour in Atlantic salmon (Salmo salar) parr’, Aquatic Toxicology, 65(1), pp. 55–72. doi: 10.1016/S0166-445X(03)00104-8.
Bhandari, R. and Kuhad, A. (2015) ‘Neuropsychopharmacotherapeutic efficacy of curcumin in experimental paradigm of autism spectrum disorders’, Life Sciences. Elsevier Inc., 141, pp. 156–169. doi: 10.1016/j.lfs.2015.09.012.
Brown, G.C. and Bal-Price, A. (2003) ‘Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria’, Molecular Biology, 27(3), pp. 325-355.
Castoldi, A. F. et al. (2000) ‘Early acute necrosis, delayed apoptosis and cytoskeletal breakdown in cultured cerebellar granule neurons exposed to methylmercury’, Journal of Neuroscience Research, 59(6), pp. 775–787. doi: 10.1002/(SICI)1097-4547(20000315)59:6<775::AID-JNR10>3.0.CO;2-T.
Coyle, J. and Puttfarcken, P. (1993) ‘Glutamate Toxicity’, Science, 262, pp. 689–95.
Franco, J. L. et al. (2006) ‘Cerebellar thiol status and motor deficit after lactational exposure to methylmercury’, Environmental Research, 102(1), pp. 22–28. doi: 10.1016/j.envres.2006.02.003.
Franco, J. L. et al. (2007) ‘Mercurial-induced hydrogen peroxide generation in mouse brain mitochondria: Protective effects of quercetin’, Chemical Research in Toxicology, 20(12), pp. 1919–1926. doi: 10.1021/tx7002323.
Gilgun-Sherki, Y., Melamed, E. and Offen, D. (2001) ‘Oxidative stress induced-neurodegenerative diseases: The need for antioxidants that penetrate the blood brain barrier’, Neuropharmacology, 40(8), pp. 959–975. doi: 10.1016/S0028-3908(01)00019-3.
Grandjean, P. and Landrigan, P. J. (2014) ‘Neurobehavioural effects of developmental toxicity’, The Lancet Neurology, 13(3), pp. 330–338. doi: 10.1016/S1474-4422(13)70278-3.
Kaur, P., Aschner, M. and Syversen, T. (2006) ‘Glutathione modulation influences methyl mercury induced neurotoxicity in primary cell cultures of neurons and astrocytes’, NeuroToxicology, 27(4), pp. 492–500. doi: 10.1016/j.neuro.2006.01.010.
Lakshmi, D. et al. (2012) ‘Ameliorating effect of fish oil on acrylamide induced oxidative stress and neuronal apoptosis in cerebral cortex’, Neurochemical Research, 37(9), pp. 1859–1867. doi: 10.1007/s11064-012-0794-1.
Lu, T. H. et al. (2011) ‘Involvement of oxidative stress-mediated ERK1/2 and p38 activation regulated mitochondria-dependent apoptotic signals in methylmercury-induced neuronal cell injury’, Toxicology Letters. Elsevier Ireland Ltd, 204(1), pp. 71–80. doi: 10.1016/j.toxlet.2011.04.013.
Madhavan, L. et al. (2006) ‘Increased "vigilance" of antioxidant mechanisms in neural stem cells potentiates their capability to resist oxidative stress’, Stem Cells 24(2) pp. 2110-2119.
Markesbery, W. R. (1997) ‘Oxidative stress hypothesis in Alzheimer’s disease’, Free Radical Biology and Medicine, 23(1), pp. 134–147. doi: 10.1016/S0891-5849(96)00629-6.
Pisoschi, A. M. and Pop, A. (2015) ‘The role of antioxidants in the chemistry of oxidative stress: A review’, European Journal of Medicinal Chemistry. Elsevier Masson SAS, 97, pp. 55–74. doi: 10.1016/j.ejmech.2015.04.040.
Polunas, M. et al. (2011) ‘Role of oxidative stress and the mitochondrial permeability transition in methylmercury cytotoxicity’, NeuroToxicology. Elsevier B.V., 32(5), pp. 526–534. doi: 10.1016/j.neuro.2011.07.006.
Reynolds, A. et al. (2007) ‘Oxidative Stress and the Pathogenesis of Neurodegenerative Disorders’, International Review of Neurobiology, 82(7), pp. 297–325. doi: 10.1016/S0074-7742(07)82016-2.
Richetti, S. K. et al. (2011) ‘Acetylcholinesterase activity and antioxidant capacity of zebrafish brain is altered by heavy metal exposure’, NeuroToxicology. Elsevier B.V., 32(1), pp. 116–122. doi: 10.1016/j.neuro.2010.11.001.
Rossignol, D. A. and Frye, R. E. (2014) ‘Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism’, Frontiers in Physiology, 5 APR(April), pp. 1–15. doi: 10.3389/fphys.2014.00150.
Sandström, J. et al. (2016) ‘Toxicology in Vitro Development and characterization of a human embryonic stem cell-derived 3D neural tissue model for neurotoxicity testing’, Tiv, pp. 1–12. doi: 10.1016/j.tiv.2016.10.001.
Sandström, J. et al. (2017) ‘Potential mechanisms of development-dependent adverse effects of the herbicide paraquat in 3D rat brain cell cultures’, NeuroToxicology, 60, pp. 116–124. doi: 10.1016/j.neuro.2017.04.010.
Sarafian, T. A. et al. (1994) ‘Bcl-2 Expression Decreases Methyle Mercury-Induced Free-Radical Generation and Cell Killing in a Neural Cell Line’, Toxicol. Lett., 74(2), pp. 149–155.
Sies, H. (2015) ‘Oxidative stress: A concept in redox biology and medicine’, Redox Biology. Elsevier, 4, pp. 180–183. doi: 10.1016/j.redox.2015.01.002.
Taetzsch, T. and Block, M.L. (2013) ‘Pesticides, microglial NOX2, and Parkinson's disease’, J Biochem Molecular Toxicology, 27(2), pp. 137-149.
Wang, X. and Michaelis, E. K. (2010) ‘Selective neuronal vulnerability to oxidative stress in the brain’, Frontiers in Aging Neuroscience, 2(MAR), pp. 1–13. doi: 10.3389/fnagi.2010.00012.
Wells, P. G. et al. (2009) ‘Oxidative stress in developmental origins of disease: Teratogenesis, neurodevelopmental deficits, and cancer’, Toxicological Sciences, 108(1), pp. 4–18. doi: 10.1093/toxsci/kfn263.
Yuste, J.E., et al., 2015. Implications of glial nitric oxide in neurodegenerative diseases. Front Cell Neurosci. 9, 322.