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Relationship: 1727


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 Lipid Peroxidation

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 High High Jelle Broeders (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 Do not cite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

Lipid peroxidation is a following event after oxidative stress. During oxidative stress the level of ROS is rising, which increases the concentration of free radical species. These highly unstable free radicals can easily react with macromolecules such as lipids. The brain has a high level of PUFAs and neuronal cells are known to be relatively unable to neutralize free radicals. Together with the knowledge that free radicals mainly attack PUFAs make neuron cells vulnerable for lipid peroxidation. The reaction between free radicals and PUFAs leads to the formation of highly reactive electrophilic aldehydes, such as MDA and HNE.  Lipid peroxidation can be described by 5 steps. The initiation of the free radical, production of peroxyl radical, self-perpetuating chain reaction (leading to several by-products), termination by which radicals form stable products and finally termination, where reaction between radicals and antioxidants (vitamin C and E) give rise to non-radical products and unreactive radicals.

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

Many recent reviews describes how ROS can react with PUFAs in cell membranes, also schematic representations of moleculaire reactions are known. Examples of earlier research done showed that inducement of antioxidants decreases the level of lipid peroxidation. Devasagayam et al. showed that increased concentration of caffeine, glutathione and ascorbic acid ihibited lipid peroxidation by reducing ROS formation. Measurements were performed in rat microsomes where TBARS (known as MDA equivalent) and LOOH (product of lipid peroxidation) were used as markers. Leuter et al. showed that there was a correleation between an increased concentration of ROS and lipid peroxidation. Leuter et al. performed the study in the brain of rats which where aging overtime. Finally, in a more recent study, resveratrol was used to measure the TBARS level at various concentration. Resveratrol is known to act as an antioxidant in vitro. Nosál et al. showed that a higher concentration of resveratrol leads to a lower level of TBARS, which indirectly showes that a lower concentration of ROS leads to less lipid peroxidation

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 link between ROS and lipid peroxidation is biological plausible.

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

Lipid peroxidation is a general description, the link with ROS is well known but literature also describes the possibility that lipid peroxidation can cause oxidative stress. The product HNE of lipid peroxidation can form protein adducts which can lead to cell damage.

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

Reed, T. T. Lipid peroxidation and neurodegenerative disease. Free Radical Biology and Medicine 51, 1302–1319 (2011).

Sultana, R., Perluigi, M. & Butterfield, D. A. Lipid peroxidation triggers neurodegeneration: A redox proteomics view into the Alzheimer disease brain. Free Radical Biology and Medicine 62, 157–169 (2013).

Hernández, J. A., López-Sánchez, R. C. & Rendón-Ramírez, A. Lipids and Oxidative Stress Associated with Ethanol-Induced Neurological Damage. Oxidative Medicine and Cellular Longevity 2016, (2016).

Devasagayam, T. P. A., Kamat, J. P., Mohan, H. & Kesavan, P. C. Caffeine as an antioxidant: Inhibition of lipid peroxidation induced by reactive oxygen species. Biochim. Biophys. Acta - Biomembr. 1282, 63–70 (1996).

Leutner, S., Eckert, A. & Müller, W. E. ROS generation, lipid peroxidation and antioxidant enzyme activities in the aging brain. J. Neural Transm. 108, 955–967 (2001).

Nosáľ, R. et al. On the molecular pharmacology of Resveratrol on oxidative burst inhibition in professional phagocytes. Oxid. Med. Cell. Longev. 2014, (2014).

Ayala, A., Muñoz, M. F. & Argüelles, S. Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxidative Medicine and Cellular Longevity 2014, (2014).

Reed, T. T. Lipid peroxidation and neurodegenerative disease. Free Radical Biology and Medicine 51, 1302–1319 (2011)