This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 3116


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 leads to Increased, LPO

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
Essential element imbalance leads to reproductive failure via oxidative stress adjacent Agnes Aggy (send email) Under development: Not open for comment. Do not cite
CYP450 upregulation leads to Chronic kidney disease adjacent High High Arthur Author (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 Do not cite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
Term Scientific Term Evidence Link
human Homo sapiens High NCBI

Sex Applicability

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

The imbalance of reactive oxygen species to antioxidants, also known as oxidative stress, can result in lipid peroxidation. It has been well studied and established that radicals such as superoxide’s can interact with nucleophilic centers in the body like lipids in membrane bylayers. These lipids are composed of polyunsaturated fasts (PUFAs) like arachidonic acid which can become oxidized and lead to a chain reaction of oxidized lipids. More specifically, oxidation of PUFAS leads to the formation of another radical, a lipoperoxyl (LOO•), which, in turn, reacts with other lipids to yield not only another lipid radical but also a lipid hydroperoxide (LOOH). Although lipid hydroperoxides are unstable they offer some local adverse effects and can also create new radicals that decompose to secondary products with longer half-lives. These breakdown products include aldehydes such as acrolein and hexanal which can diffuse and react outside of its site of formation (Barrera et al., 2012).  Antioxidants, such as vitamins or antioxidant enzymes, can react with lipid peroxy radicals to prevent further damage in the cell (Cooley et al., 2000). In addition to this, antioxidants and antioxidant enzymes can also interact with reactive oxygen species to prevent ROS damage.  

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 biological plausibility for this key event relationship is strong: The relationship and mechanism between oxidative stress leading to lipid peroxidation is very well established and studied.

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 mechanism for this KER is very well understood and there is a high degree of concordance between many species, so far no large uncertainties or inconsistencies have been found. 

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
Modulating Factor (MF) MF Specification Effect(s) on the KER Reference(s)
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
  • Taxonomic applicability:  Most data was generated from human studies, bacteria, rat, or mice studies however ROS can affect all organisms containing lipid membranes and thus may be affected by lipid peroxidation due to oxidative stress.
  • Life stages: The domain of applicability for life stages is all life stages. 
  •  Sex applicability: The domain of applicability for sex is both males and females.
  • The biological plausibility for this key event relationship is strong.
  • The empirical evidence for this key event relationship is Strong.  


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

Abrashev R, Krumova E, Dishliska V, Eneva V, Engibarov S, Abrashev I & Angelova M, (2011) Differential Effect of Paraquat and Hydrogen Peroxide on the Oxidative Stress Response in Vibrio Cholerae Non O1 26/06, Biotechnology & Biotechnological Equipment, 25:sup1, 72-76,

Barrera G. (2012). Oxidative stress and lipid peroxidation products in cancer progression and therapy. ISRN oncology2012, 137289.

Bus J, Aust S, Gibson J. (1976). Paraquat Toxicity: Proposed Mechanism of Action Involving Lipid Peroxidation. Environmental health perspectives. 16. 139-46.

Cooley HM, Evans RE, Klaverkamp JF. (2000). Toxicology of dietary uranium in lake whitefish (Coregonus clupeaformis). Aquatic Toxicology. 48(4):495–515. 

Ito F, Sono Y, Ito T. (2019) Measurement and Clinical Significance of Lipid Peroxidation as a Biomarker of Oxidative Stress: Oxidative Stress in Diabetes, Atherosclerosis, and Chronic Inflammation. Antioxidants (Basel).  Mar 25;8(3):72. doi: 10.3390/antiox8030072.

Liao S, Wei C, Wei G, Liang H, Peng F, Zhao L, Li Z, Liu C, Zhou Q, (2024) Cyclophosphamide activates ferroptosis-induced dysfunction of Leydig cells via SMAD2 pathway, Biology of Reproduction, (110) 5,1012-1024,

Ma D, Liu J, Wang L, Zhi X, Luo L, Zhao J, Qin Y., (2023) GSK-3β-dependent Nrf2 antioxidant response modulates ferroptosis of lens epithelial cells in age-related cataract, Free Radical Biology and Medicine, 204,161-176,

Peter B, Wartena M, Kampinga HH, Konings AW. (1991) Role of lipid peroxidation and DNA damage in paraquat toxicity and the interaction of paraquat with ionizing radiation. Biochem Pharmacol.  Feb 18;43(4):705-15.

Rodríguez-García A, García-Vicente R, Morales ML, Ortiz-Ruiz A, Martínez-López J, Linares M. (2020) Protein Carbonylation and Lipid Peroxidation in Hematological Malignancies. Antioxidants (Basel). Dec 1;9(12):1212

Yang H, Zhang X, Ding Y, Xiong H, Xiang S, Wang Y, Li H, Liu Z, He J, Tao Y, et al (2023). Elabela: Negative Regulation of Ferroptosis in Trophoblasts via the Ferritinophagy Pathway Implicated in the Pathogenesis of Preeclampsia. Cells.; 12(1):99. 

Zhou Y, Xu H, Cheng K, Chen F, Zhou Q, Wang M. (2022) Acrolein evokes inflammation and autophagy-dependent apoptosis through oxidative stress in vascular endothelial cells and its protection by 6-C-(E-2-fluorostyryl)naringenin, Journal of Functional Foods, 98, 1756-4646,