Relationship: 1766



Protection against oxidative stress, decreased leads to Oxidative Stress

Upstream event


Protection against oxidative stress, decreased

Downstream event


Oxidative Stress

Key Event Relationship Overview


AOPs Referencing Relationship


Taxonomic Applicability


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


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 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



Oxidative stress

species; in vivo / in vitro


Dose/ conc. +

Duration of exp.

Protective/ aggravating evidence


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,



0.4 µM


9 h

Treatment with ebselen suppressed MeHg-induced oxidative


(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)


1 µM



Se supplementation gave some extent of oxidative stress protection.

(Branco, 2017)

Decreased activity of TrxR and GPx.


TrxR – 0.5-fold

GPx – 0.5-fold

Oxidative stress.



No fold reported.

Zebra fish brain

Hg2+, MeHg

1.8 molar (measured in brain tissue),

28 days


(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


40 mg/L in drinking




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.


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)


No fold-change reported.

Male C57BL/6NJcl mice


1.5 mg kg−1 day−1




(Fujimura, 2017)

Downregulation of antioxidant selenoprotein gene expression, and reduced GPx activity.


Gpx1a – 0.2-fold

Gpx4a – 0.2-fold

TxnRd1 – 0.5-fold

GPx – 0.2-fold

Indirect effects reported – larvae hypoactivity

Zebra fish


0.05 mg/kg DM



0.7 mg/kg DM Se-supplementation partially restored GPx activity





GPx activity upregulated from 0.2-fold to 0.7-fold.

(Penglase, 2014)

Depletion of GSH levels.













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 mito-chondrial-enriched



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


5 µM



glutathione monoethyl ester (GSHME) (100 µM) supplementation protected 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



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


1 mg kg−1 orally


6 months


(Joshi, 2014)

Depleted GSH levels.

Antioxidant imbalance and lipid peroxidation.

Adult male Wistar rats


30ppm in drinking water


(Agrawal, 2015)

GSH levels decreased in astrocytes.

Severe damage

to the cell membranes, as well as to mitochondria.

Primary mouse neuron and astrocyte co-cultures


10, 25, or 50 µM nominal


24h exposure


(Morken, 2005)

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


300nM nominal



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



3–5 µg/g brain tissue





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)


Oxidative stress (increased H2O2 production)

Rat astro-glioma C6 cell line


10 and 50 µM



Cell viability protective effect of 1 µM of the organic selenium compound (PhSe)2

(Glaser, 2013)


Protein oxidation (increase of protein carbonyls)

Mouse primary cortical neurons, and cerebellar granule cells


10-600 nM

All effects were prevented by co-treatment with the antioxidant probucol.

(Caballero, 2017)

Reduced glutathione peroxidase activity was found in the fetal side of human placental samples.


Human placenta tissue samples – INMA Valencia

mother-infant cohort (Spain)


20-40 µg/mL blood plasma


(Caballero, 2017)

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



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



40 mg kg-1 day-1

10 days



All effects prevented by co-treatment with resveratrol

(Alturfan, 2012)

Uncertainties and Inconsistencies


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

Quantitative Understanding of the Linkage


Cf table above on Empirical Evidence

Response-response Relationship




Known modulating factors


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.



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.

Caballero, B. et al. (2017) Methylmercury-induced developmental toxicity is associated with oxidative stress and cofilin phosphorylation. Cellular and human studies. Neurotoxicology 59, 197-209.

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.

Morken, T.S. et al. (2005) Effects of methylmercury on primary brain cells in mono- and co-culture. Toxicol Sci 87, 169-175.

Penglase, S. et al. (2014) Selenium prevents downregulation of antioxidant selenoprotein genes by methylmercury. Free Radic Biol Med 75, 95-104.

Rush, T. et al. (2012) Glutathione-mediated neuroprotection against methylmercury neurotoxicity in cortical culture is dependent on MRP1. Neurotoxicology 33, 476-481.

Shi, L.Y. et al. (2018) Protective effects of curcumin on acrolein-induced neurotoxicity in HT22 mouse hippocampal cells. Pharmacol Rep 70, 1040-1046.

Usuki, F. et al. (2011) Post-transcriptional defects of antioxidant selenoenzymes cause oxidative stress under methylmercury exposure. J Biol Chem 286, 6641-6649.