API

Relationship: 1766

Title

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Protection against oxidative stress, decreased leads to Oxidative Stress

Upstream event

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Protection against oxidative stress, decreased

Downstream event

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Oxidative Stress

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI
human Homo sapiens NCBI
zebra fish Danio rerio NCBI

Sex Applicability

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Sex Evidence
Male High
Female High

Life Stage Applicability

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Term Evidence
All life stages High

Key Event Relationship Description

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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 Supporting this KER

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Biological Plausibility

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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

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KEup

 

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

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No uncertainties, since a decrease in protection against oxidative stress leads, by definition, to an increase in oxidative stress

Quantitative Understanding of the Linkage

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Cf table above on Empirical Evidence

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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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

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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.