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Relationship: 1730


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

Oxidative Stress in Brain leads to Unfolded Prortein Response

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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
CYP2E1 activation and formation of protein adducts leading to neurodegeneration adjacent Moderate Moderate Brendan Ferreri-Hanberry (send email) Under development: Not open for comment. Do not cite

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

Sex Applicability

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

Life Stage Applicability

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

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

With the increasing ROS concentration and the accumulation of unfolded proteins an UPR is triggered in the ER. This is a defence mechanism in a cell, which starts with ER stress when there is an overload of ROS. At low level the activation of PERK in the UPR can prevent further oxidative stress. In several neurodegenerative diseases ER stress was reported. The exact mechanism and the link between ROS and UPR is not completely understood.

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

Several studies are performed to link oxidative stress with the UPR. Hayashi et al. showed that ROS, and specifically superoxide, plays a role in inducing ER stress by the UPR. Overexpression of SOD1, an antioxidant, reduces the induction of ATF-4 and CHOP, which are proteins released during UPR. Measurement were performed during ischemic brain injury. Chen et al. looked at the effect of ethanol on ER stress in neuron cells. Ethanol induces ROS formation by CYP2E1 activation, when antioxidant N-acetyl-L-cysteine (NAC) or GSH scavenged the production of ROS there an elimination of the expression of ER markers. Another possibility of ROS generating UPR is the interference of ROS with the folding of proteins in the ER. ROS can stimulate unfolded proteins to transform into misfolding proteins, or inactivate PDI/ERO1 which are responsible for the oxidation of unfolded proteins. Research on steatosis in the liver cells by Tsedensodnom et al. showed that after only after 2 hours of ethanol exposure a UPR response already can be measured. mRNAs levels of Bip, grp94 and dnajc3 were detected, which are known ER stress chaperones. Another pathway of inducing ER stress by UPR is that ROS can cause mitochondrial dysfunction. Cigarette smoke extract in retinal pigmented epithelial leads to accumulation of H2O2 in the mitochondria, which resulted in higher expression of UPR sensors.

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

There is a link between oxidative stress and the unfolded protein response, but the mechanism is not well understood.

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

The UPR and ER stress can produce ROS by itself, so inducing a cell with a toxicant can also directly lead to ER stress. Time measurements are important to find out which event occurs first. Also the overall mechanism of this KER is not exactly known.

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


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

Yang, F. & Luo, J. Endoplasmic reticulum stress and ethanol neurotoxicity. Biomolecules 5, 2538–2553 (2015).

Oakes, S. A. & Papa, F. R. The Role of Endoplasmic Reticulum Stress in Human Pathology. Annu. Rev. Pathol. Mech. Dis. 10, 173–194 (2015).

Ramirez-Alvarado, M., Kelly, J. W. & Dobson, C. M. Protein Misfolding Diseases: Current and Emerging Principles and Therapies. Protein Misfolding Diseases: Current and Emerging Principles and Therapies (2010). doi:10.1002/9780470572702

Hayashi, T. et al. Damage to the endoplasmic reticulum and activation of apoptotic machinery by oxidative stress in ischemic neurons. J. Cereb. Blood Flow Metab. 25, 41–53 (2005).

Chen, G. et al. Ethanol promotes endoplasmic reticulum stress-induced neuronal death: Involvement of oxidative stress. J. Neurosci. Res. 86, 937–946 (2008).

Tsedensodnom, O., Vacaru, A. M., Howarth, D. L., Yin, C. & Sadler, K. C. Ethanol metabolism and oxidative stress are required for unfolded protein response activation and steatosis in zebrafish with alcoholic liver disease. Dis. Model. Mech. 6, 1213–1226 (2013).

Cano, M. et al. Oxidative stress induces mitochondrial dysfunction and a protective unfolded protein response in RPE cells. Free Radic. Biol. Med. 69, 1–14 (2014).