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Relationship: 2879


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

Increased, LPO leads to impaired, Fertility

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
Glutathione conjugation leading to reproductive dysfunction via oxidative stress adjacent High High Leonardo Vieira (send email) Under Development: Contributions and Comments Welcome

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
fish fish High NCBI
mammals mammals High NCBI

Sex Applicability

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

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Juvenile High
Adults High
Adult, reproductively mature 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

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

Biological plausibility of this KER lies in the fact that lipid peroxidation in gonad membranes induces morphological changes in seminiferous tubules, and degeneration of ovarian follicles and Sertoli and Leydig cells in testicles, damage to gametic cells, and, consequently, reduction of their viability. This directly affects animal reproductive capability, for it reduces quality and production of oocytes and spermatocytes, as well as decreases egg and sperm release (spawn), leading to a drop-in fertilization rate (Tillitt et al. 2010; Papoulias et al. 2014; Song et al. 2014; Dasmahapatra et al. 2020; Biswas et al. 2020; Mu et al. 2022). 

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

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

According to (Gomez, Irvine, and Aitken 1998), there is a negative relationship between malondialdehyde and 4-hydroxyalkenal production (MDA + 4-HA) and loss of motility in human spermatozoa. The higher the amount of these peroxidation products, the lower the cell motility. A negative correlation between sperm numbers and testicular and epididymal MDA levels (-0.85 and -0.68 correlation coefficient r, respectively) was also found by (Abarikwu et al. 2010) in rats exposed to ATZ for 7 and 16 days. Conversely, the authors observed a positive correlation between abnormal sperm rate and testicular and epididymal MDA levels (+0.78 and +0.89).  Hsieh et al. (2006), assessing MDA levels and sperm quality of 51 subfertile men, were able to establish two formulas to associate lipid peroxidation with sperm concentration and motility, which are represented, respectively, by: 

MDA = - 0.0045 x sperm cell concentration + 2.23;


MDA = - 0.014 x sperm motility + 2.62. 

On the other hand, (Mihalas et al. 2017) brought important quantitative data about the direct relation between lipid peroxidation and reduction of quality in oocytes. Experimental evidences showed that the lipid peroxidation product 4-HNE, at 0, 5, 10, 20, 30 and 50 µM, induces a dose-dependent decrease in meiotic competence during in vitro oocyte maturation, as well as aneuploidies in germinal vesicle (GV) oocytes from 20 µM of 4-HNE. They still reported this happens because tubulins, component proteins of microtubules of the mitotic spindle, generate adducts with 4-HNE. 

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

Considering the empirical domain of the evidence, the  increased lipid peroxidation leading to impaired fertility is known to occur in fish and mammals, but, based on scientific reasoning, the biologically plausible domain of applicability may also have relevance for  amphibians, reptiles, birds and and invertebrates with sexual reproduction. It can be measured in juveniles and adults and in both male and female species.


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

Tillitt, Donald E., Diana M. Papoulias, Jeffrey J. Whyte, and Catherine A. Richter. 2010. “Atrazine Reduces Reproduction in Fathead Minnow (Pimephales Promelas).” Aquatic Toxicology  99 (2): 149–59.

Papoulias, Diana M., Donald E. Tillitt, Melaniya G. Talykina, Jeffrey J. Whyte, and Catherine A. Richter. 2014. “Atrazine Reduces Reproduction in Japanese Medaka (Oryzias Latipes).” Aquatic Toxicology  154 (September): 230–39.

Song, Yang, Zhen Chao Jia, Jin Yao Chen, Jun Xiang Hu, and Li Shi Zhang. 2014. “Toxic Effects of Atrazine on Reproductive System of Male Rats.” Biomedical and Environmental Sciences: BES 27 (4): 281–88.

Dasmahapatra, Asok K., Doris K. Powe, Thabitha P. S. Dasari, and Paul B. Tchounwou. 2020. “Assessment of Reproductive and Developmental Effects of Graphene Oxide on Japanese Medaka (Oryzias Latipes).” Chemosphere 259 (November): 127221.

Biswas, Subhasri, Soumyajyoti Ghosh, Anwesha Samanta, Sriparna Das, Urmi Mukherjee, and Sudipta Maitra. 2020. “Bisphenol A Impairs Reproductive Fitness in Zebrafish Ovary: Potential Involvement of Oxidative/nitrosative Stress, Inflammatory and Apoptotic Mediators.” Environmental Pollution  267 (December): 115692.

Mu, Xiyan, Suzhen Qi, Jia Liu, Hui Wang, Lilai Yuan, Le Qian, Tiejun Li, et al. 2022. “Environmental Level of Bisphenol F Induced Reproductive Toxicity toward Zebrafish.” The Science of the Total Environment 806 (Pt 1): 149992.

Zhao, Fan, Kun Li, Lijing Zhao, Jian Liu, Qi Suo, Jing Zhao, Hebin Wang, and Shuhua Zhao. 2014. “Effect of Nrf2 on Rat Ovarian Tissues against Atrazine-Induced Anti-Oxidative Response.” International Journal of Clinical and Experimental Pathology 7 (6): 2780–89.

Farombi, E. O., S. O. Abarikwu, A. C. Adesiyan, and T. O. Oyejola. 2013. “Quercetin Exacerbates the Effects of Subacute Treatment of Atrazine on Reproductive Tissue Antioxidant Defence System, Lipid Peroxidation and Sperm Quality in Rats.” Andrologia 45 (4): 256–65.

Abdel Aziz, Rabie L., Ahmed Abdel-Wahab, Fatma I. Abo El-Ela, Nour El-Houda Y. Hassan, El-Shaymaa El-Nahass, Marwa A. Ibrahim, and Abdel-Tawab A. Y. Khalil. 2018. “Dose- Dependent Ameliorative Effects of Quercetin and L-Carnitine against Atrazine- Induced Reproductive Toxicity in Adult Male Albino Rats.” Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 102 (June): 855–64.

Adesiyan, Adebukola C., Titilola O. Oyejola, Sunny O. Abarikwu, Matthew O. Oyeyemi, and Ebenezer O. Farombi. 2011. “Selenium Provides Protection to the Liver but Not the Reproductive Organs in an Atrazine-Model of Experimental Toxicity.” Experimental and Toxicologic Pathology: Official Journal of the Gesellschaft Fur Toxikologische Pathologie 63 (3): 201–7.

Kalia, Sumiti, and M. P. Bansal. 2008. “Diethyl Maleate-Induced Oxidative Stress Leads to Testicular Germ Cell Apoptosis Involving Bax and Bcl-2.” Journal of Biochemical and Molecular Toxicology 22 (6): 371–81.

Kaur, Parminder, Sumiti Kalia, and Mohinder P. Bansal. 2006. “Effect of Diethyl Maleate Induced Oxidative Stress on Male Reproductive Activity in Mice: Redox Active Enzymes and Transcription Factors Expression.” Molecular and Cellular Biochemistry 291 (1-2): 55–61.

Boujbiha, Mohamed Ali, Khaled Hamden, Fadhel Guermazi, Ali Bouslama, Asma Omezzine, Abdelaziz Kammoun, and Abdelfattah El Feki. 2009. “Testicular Toxicity in Mercuric Chloride Treated Rats: Association with Oxidative Stress.” Reproductive Toxicology  28 (1): 81–89.

Rizzetti, Danize Aparecida, Caroline Silveira Martinez, Alyne Goulart Escobar, Taiz Martins da Silva, José Antonio Uranga-Ocio, Franck Maciel Peçanha, Dalton Valentim Vassallo, Marta Miguel Castro, and Giulia Alessandra Wiggers. 2017. “Egg White-Derived Peptides Prevent Male Reproductive Dysfunction Induced by Mercury in Rats.” Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association 100 (February): 253–64.

Ibrahim, Ahmed Th A., Mahdi Banaee, and Antoni Sureda. 2019. “Selenium Protection against Mercury Toxicity on the Male Reproductive System of Clarias Gariepinus.” Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP 225 (November): 108583.

Gomez, E., D. S. Irvine, and R. J. Aitken. 1998. “Evaluation of a Spectrophotometric Assay for the Measurement of Malondialdehyde and 4-Hydroxyalkenals in Human Spermatozoa: Relationships with Semen Quality and Sperm Function.” International Journal of Andrology 21 (2): 81–94.

Hsieh, Yao-Yuan, Chi-Chen Chang, and Chich-Sheng Lin. 2006. “Seminal Malondialdehyde Concentration but Not Glutathione Peroxidase Activity Is Negatively Correlated with Seminal Concentration and Motility.” International Journal of Biological Sciences 2 (1): 23–29.

Aitken, R. John, Jordana K. Wingate, Geoffry N. De Iuliis, and Eileen A. McLaughlin. 2007. “Analysis of Lipid Peroxidation in Human Spermatozoa Using BODIPY C11.” Molecular Human Reproduction 13 (4): 203–11.

Mihalas, Bettina P., Geoffry N. De Iuliis, Kate A. Redgrove, Eileen A. McLaughlin, and Brett Nixon. 2017. “The Lipid Peroxidation Product 4-Hydroxynonenal Contributes to Oxidative Stress-Mediated Deterioration of the Ageing Oocyte.” Scientific Reports 7 (1): 6247.

Abarikwu, S. O., E. O. Farombi, and A. B. Pant. 2011. “Biflavanone-Kolaviron Protects Human Dopaminergic SH-SY5Y Cells against Atrazine Induced Toxic Insult.” Toxicology in Vitro: An International Journal Published in Association with BIBRA 25 (4): 848–58.