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Relationship: 1766

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Protection against oxidative stress, decreased leads to Oxidative Stress

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Protection against oxidative stress, decreased

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Oxidative Stress

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

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

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	High
Female	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

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

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

KE_up Decreased protection against oxidative stress	KE_down 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

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Cf table above on Empirical Evidence

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

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

List of the literature that was cited for this KER description. More help

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.