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Relationship: 1728

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

Lipid Peroxidation leads to Protein Adduct Formation

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 Do not cite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

Two main products of lipid peroxidation are MDA and HNE which are highly reactive electrophilic aldehydes. Protein adduct formation by HNE-modification of proteins is the main reaction which occurs in cells after lipid peroxidation. HNE-adducts are also used as markers for lipid peroxidation. There are two main principles of HNE-modification of proteins, the Schiff’s Base Formation and the Michael Addition. Schiff’s Base Formation is the reaction of the aldehydic group of HNE with an amino group of a protein. Where the Michael Addition is a reaction of the HNE double bond to a protein side chain. HNE has the preference for amino acid modification Cys à His à Lys which results in a covalent adduct with the protein nucleophilic side chain.

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

In the 80s it was already found that HNE can react with proteins and form adducts. Since HNE is a highly reactive electrophilic aldehyde it can easily react with proteins in a timeframe of seconds to minutes. Because of the high reactivity only 1-8% of the HNE formed will interact with proteins, but the number of proteins which are altered lies in the hundreds. Several detection techniques are known to find HNE-adducts, but since some are at low abundance it is hard to find them all. One example is proteomic analysis performed by Andringa et al. After ethanol exposure in rats HNE modified proteins were detected in mitochondria. In a more recent study a direct link was made between lipid peroxidation and protein modifications. With the use of rapid SERS monitoring detection of lipid peroxidation as well as protein modification was performed.

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

It is known that protein adducts are formed by HNE after lipid peroxidation, so it 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

Other aldehyde products of lipid peroxidation can also form protein adducts with proteins. Since HNE is specific for lipid peroxidation it is widely used as marker.

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
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

References

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

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).

Andringa, K. K., Udoh, U. S., Landar, A. & Bailey, S. M. Proteomic analysis of 4-hydroxynonenal (4-HNE) modified proteins in liver mitochondria from chronic ethanol-fed rats. Redox Biol. 2, 1038–1047 (2014).

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).

Castro, J. P., Jung, T., Grune, T. & Siems, W. 4-Hydroxynonenal (HNE) modified proteins in metabolic diseases. Free Radical Biology and Medicine 111, 309–315 (2017).

Poli, G. et al. Enzymatic impairment induced by biological aldehydes in intact rat liver cells. Res. Commun. Chem. Pathol. Pharmacol. 38, (1982).

Siems, W. & Grune, T. Intracellular metabolism of 4-hydroxynonenal. in Molecular Aspects of Medicine 24, 167–175 (2003).

Codreanu, S. G., Zhang, B., Sobecki, S. M., Billheimer, D. D. & Liebler, D. C. Global analysis of protein damage by the lipid electrophile 4-hydroxy-2-nonenal. Mol. Cell. Proteomics 8, 670–80 (2009).

Gong, T. et al. Rapid SERS monitoring of lipid-peroxidation-derived protein modifications in cells using photonic crystal fiber sensor. Journal of Biophotonics 9, 32–37 (2016).