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Relationship: 1766
Title
Protection against oxidative stress, decreased leads to Oxidative Stress
Upstream event
Downstream event
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 | adjacent | High | High | Marie-Gabrielle Zurich (send email) | Open for citation & comment | WPHA/WNT Endorsed |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Male | High |
Female | High |
Life Stage Applicability
Term | Evidence |
---|---|
All life stages | High |
Key Event Relationship Description
High levels of oxidizing free radicals can be very damaging to cells and molecules within the cell. As a result, the cell has important defense mechanisms to protect itself from ROS, including reducing agents, glutathione peroxidases, thioredoxin reductases. Oxidative stress is defined as an imbalance in the production of reactive oxygen species (ROS) and antioxidant defenses. Ensuing from this definition, a decrease in cellular antioxidant protection will lead to the increase of oxidative stress.
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility
The cell has important defense mechanisms to protect itself from oxidative stress. The cellular defense mechanisms are numerous and include repair mechanisms, prevention mechanisms, physical defenses, as well as antioxidant defense such as antioxidant enzymes, low-molecular-weight antioxidants and chelating agents (Kohen, 2002). Whenever one or many of these mechanisms are decreased, the balance will tilt towards the production of ROS, and thus generate oxidative stress. In this KER we focus on the decreased protection due to interference with the antioxidant defense system.
Empirical Evidence
Decreased protection against oxidative stress |
KEdown Oxidative stress |
species; in vivo / in vitro |
Stressor |
Dose/ conc. + Duration of exp. |
Protective/ aggravating evidence |
Reference |
Post-transcriptional effects on GPx1 and TrxR1 expression and activity TrxR1 – 2-fold GPx1 – 0.6-fold |
Disturbance of redox-response and induction of oxidative stress SOD – 2-fold ROS – increased |
Mouse myoblast C2C12, |
MeHg |
0.4 µM 9 h |
Treatment with ebselen suppressed MeHg-induced oxidative stress |
(Usuki, 2011) |
Inhibition of TrxR and GSH activities TrxR1&2 – 0.6-fold GSH – 0.7-fold |
Oxidative stress shown by shift in GSSG/GSH ratio GSSG/GSH – 1.5-fold |
Human neuroblastoma cells (SH-SY5Y) |
MeHg |
1 µM |
Se supplementation gave some extent of oxidative stress protection |
(Branco, 2017) |
Inhibition of GPx activity GPx – 0.4-fold |
Increased ROS formation and lipid peroxidation ROS – 1.75-fold Total peroxidase – 4.5-fold Lipid perox. – 3-fold |
Mouse brain |
MeHg |
40 mg/L in drinking water 21-days |
Incubation of mitochondrial-enriched fractions with exogenous GPx completely blocked MeHg-induced mitochondrial lipid peroxidation |
(Franco, 2009) |
Inhibition of GPx activity GPx – 0.7-fold |
Increased ROS formation and lipid peroxidation Total H2O2 – 1.5-fold |
Human neuro-blastoma SH-SY5Y cells. |
MeHg |
1 µM (nominal) |
Inhibition of GPx substantially enhanced MeHg toxicity |
(Franco, 2009) |
Decreased GPx1, activity in cerebral cortex and hippocampus GPx1 – 0.5-fold |
Induction of oxidative stress (oxidative damage product from the reaction of ROS and deoxy-thymidine in DNA) |
Male C57BL/6NJcl mice |
MeHg |
1.5 mg kg−1 day−1 6-weeks |
(Fujimura, 2017) |
|
Depletion of GSH levels GSH-activity: 10µM – 0.75-fold 30µM – 0.6-fold 100µM – 0,5-fold |
Increased glutathione oxidation, hydroperoxide formation (xylenol orange assay) and lipid peroxidation end-products (thiobarbituric acid reactive substances, TBARS). Mitochondrial viability: 10µM – 0.75-fold 30µM – 0.6-fold 100µM – 0,5-fold Total hydroperoxidases: 10µM – 1.0-fold 30µM – 1.2-fold 100µM – 1.75-fold |
Mouse brain mitochondrial-enriched fractions |
MeHg |
10, 30, and 100 μM 30 minutes |
The co-incubation with diphenyl diselenide (100 μM) completely prevented the disruption of mitochondrial activity as well as the increase in TBARS levels. thiol peroxidase activity of organoselenium compounds accounts for their protective actions against methylmercury-induced oxidative stress |
(Meinerz, 2011) |
Depletion of mono- and disulfide glutathione in neuronal, glial and mixed cultures GSH activity – 0.83-fold |
increased reactive oxygen species (ROS) formation measured by dichlorodihydro-fluorescein (DCF) fluorescence DCF – 1.2-1.5-fold |
Mouse primary cortical cultures |
MeHg |
5 µM 24h |
glutathione monoethyl ester (GSHME : 100 µM) protects against oxidative stress formation |
(Rush, 2012) |
Reduced glutathione (GSH) content decreased in liver, kidney and brain. |
Increased lipid peroxidation and generation of reactive oxygen species |
Adult male albino Sprague-Dawley rat |
Dimethylmercury (DMM) |
10 mg/kg bw 3-days |
Supplementation with Se (2 mmol/kg and 0.5 mg/kg partially protected against DMM-induced tissue damage. |
(Deepmala, 2013) |
Reduced glutathione (GSH) level and acetyl cholinesterase activity, as well as reduced antioxidant enzyme glutathione peroxidase (GPx) |
Increased lipid peroxidation level and DNA damage. |
Adult male Sprague-Dawley rats |
MeHg |
1 mg kg-1 orally 6 months |
(Joshi, 2014) |
|
Depleted GSH levels |
Antioxidant imbalance and lipid peroxidation. |
Adult male Wistar rats |
mercuricchloride |
30 ppm in drinking water |
(Agrawal, 2015) |
|
GPx1 significantly decreased prior to neurotoxic effects being visible GPx1 – 0.7-fold |
Increased lipid peroxidation and later neuronal cell death. Lipid peroxidation - 1.75-fold |
Primary cultured mouse cerebellar granule cells |
MeHg |
300 nM nominal 24h |
Overexpression of GPx-1 prevented MeHg-induced neuronal death |
(Farina, 2009) |
Reduction of GPx activity and increased glutathione reductase activity GPx – 0.7-fold |
Increased oxidative stress – shown by increased TBA-RS and 8-OHdG content, as well as reduction of complexes I, II, and IV activities H2O2 – 1.6-fold |
Adult male Swiss albino mice |
MeHg |
3–5 µg/g brain tissue 21-days |
Treatment with diphenyl diselenide (PhSe)2 (5 µmol/kg) reversed MeHg’s inhibitory effect on mitochondrial activities, as well as the increased oxidative stress parameters |
(Glaser, 2013) |
Decreased level of GSH in blood, liver, heart, brain, lung and testis GSH – 0.4-0.7 fold |
Lipid peroxidation (increase in malondialdehyde levels in blood, liver, heart, brain, lung and testis) Lipid peroxidation – 1.4-2.0 fold |
Rats |
Acrylamide |
15 mg kg-1 day-1 60 days gastric gavage |
All effects prevented by co-treatment with boron |
(Acaroz, 2018) |
Decreased level of GSH in liver, kidney, brain, lung and testis GSH – 0.4-0.6 fold |
Lipid peroxidation (increase in malondialdehyde levels liver, kidney, brain, lung and testis) Lipid peroxidation – 1.6-2.0 fold |
Rats |
Acrylamide |
40 mg kg-1 day-1 10 days i.p. |
All effects prevented by co-treatment with resveratrol |
(Alturfan, 2012) |
Decreased level of GSH and decreased activity of GPx and SOD in cerebellum GSH – 0.5 fold GPx – 0.6 fold SOD – 0.7 fold |
Increased lipid peroxidation (MDA) and DNA fragmentation (comet assay) in cerebellum Lipid peroxidation –1.9 fold |
Rats |
Acrylamide |
40 mg kg-1 day-1 12 days gavage |
All effects prevented by melatonin |
Pan et al., 2015 |
Decreased level of GSH/GSSG ratio GSH/GSSG ratio – 0.85 to 0.70 after 0.5-1 mM, 24h and 0.85 to 0.45 fold after 01-1 mM, 96h |
Increased ROS production, increased lipid peroxidation (4-HNE), increased oxidative DNA damage (8-OHdG) ROS – 1.5 to 3.2 fold after after 0.5-1 mM, 24h 4-HNE: 1.6 fold after 1mM, 96h 8-OHdG: 1.7 and 2.1 fold after 0.1 and 1 mM, 96h |
Primary cultured mouse astrocytes and microglia |
Acrylamide |
0-1 mM 24-96 h |
Zhao et al., 2017 |
Uncertainties and Inconsistencies
No uncertainties, since a decrease in protection against oxidative stress leads, by definition, to an increase in oxidative stress
Known modulating factors
Quantitative Understanding of the Linkage
Cf table above on Empirical Evidence
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The link between decrease in antioxidant protection and induction of oxidative stress can be found in Zebrafish, rodents (mouse and rat) and in man, but may not be restricted to these species.
References
Acaroz, U. et al. (2018) The ameliorative effects of boron against acrylamide-induced oxidative stress, inflammatory response, and metabolic changes in rats. Food Chem Toxicol 118, 745-752.
Agrawal, S. et al. (2015) Changes in tissue oxidative stress, brain biogenic amines and acetylcholinesterase following co-exposure to lead, arsenic and mercury in rats. Food Chem Toxicol 86, 208-216.
Alturfan, A.A. et al. (2012) Resveratrol ameliorates oxidative DNA damage and protects against acrylamide-induced oxidative stress in rats. Mol Biol Rep 39, 4589-4596.
Branco, V. et al. (2017) Impaired cross-talk between the thioredoxin and glutathione systems is related to ASK-1 mediated apoptosis in neuronal cells exposed to mercury. Redox Biol 13, 278-287.
Deepmala, J. et al. (2013) Protective effect of combined therapy with dithiothreitol, zinc and selenium protects acute mercury induced oxidative injury in rats. J Trace Elem Med Biol 27, 249-256.
Farina, M. et al. (2009) Probucol increases glutathione peroxidase-1 activity and displays long-lasting protection against methylmercury toxicity in cerebellar granule cells. Toxicol Sci 112, 416-426.
Franco, J.L. et al. (2009) Methylmercury neurotoxicity is associated with inhibition of the antioxidant enzyme glutathione peroxidase. Free Radic Biol Med 47, 449-457.
Fujimura, M., Usuki, F. (2017) In situ different antioxidative systems contribute to the site-specific methylmercury neurotoxicity in mice. Toxicology 392, 55-63.
Glaser, V. et al. (2013) Protective effects of diphenyl diselenide in a mouse model of brain toxicity. Chem Biol Interact 206, 18-26.
Joshi, D. et al. (2014) Reversal of methylmercury-induced oxidative stress, lipid peroxidation, and DNA damage by the treatment of N-acetyl cysteine: a protective approach. J Environ Pathol Toxicol Oncol 33, 167-182.
Kohen, R., Nyska, A. (2002) Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol 30, 620-650.
Meinerz, D.F. et al. (2011) Protective effects of organoselenium compounds against methylmercury-induced oxidative stress in mouse brain mitochondrial-enriched fractions. Braz J Med Biol Res 44, 1156-1163.
Pan, X., et al. (2015) Melatonin attenuates oxidative damage induced by acrylamide invitro and in vivo. Ox. Med. Cell Longevity Vol 2015, Article ID 703709.
Rush, T. et al. (2012) Glutathione-mediated neuroprotection against methylmercury neurotoxicity in cortical culture is dependent on MRP1. Neurotoxicology 33, 476-481.
Usuki, F. et al. (2011) Post-transcriptional defects of antioxidant selenoenzymes cause oxidative stress under methylmercury exposure. J Biol Chem 286, 6641-6649.
Zhao, M et al. (2017) Effect of acrylamide-induced neurotoxicity in a primary astrocytes/microglial co-culture model. Toxicol in Vitro 39, 119-125.