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Relationship: 2976

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

Increase, Inflammation leads to General Apoptosis

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increase, Inflammation

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

General Apoptosis

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
Reactive Oxygen Species (ROS) formation leads to cancer via inflammation pathway	adjacent	High	Not Specified	John Frisch (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 Do not cite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
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	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
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

Pathways leading to apoptosis, or single cell death, have traditionally been studied as both independent and simultaneous from pathways leading to necrosis, or tissue-wide cell death, with both overlap and distinct mechanisms (Elmore 2007). For the purposes of this key event relationship, we are characterizing widespread cell-death due to inflammation (Bock and Riley 2022), while acknowledging that cell death can be caused by multiple stressors, and need not include inflammation.

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

This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. Support for this KER is referenced in publications cited in the originating work of Jeong and Choi (2020).

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 linking apoptosis to inflammation is strong. Inflammation is an indicator for damage, and cell surface markers activate apoptosis pathways for cells that have lost functional capabilities.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Apoptosis is one of the most common responses to inflammation as a controlled pathway for cell-death due to detected cell damage (for review see Balkwill (2003); Elmore (2007); for empirical studies see Gamo et al. (2008); Lu et al. (2016); Jin et al. (2018)). Generally cell-surface markers indicate damage for T-cell mediated cytotoxic response and phagocytosis; activation of tumor necrosis factor genes enhance cellular response (Elmore 2007).

Species	Duration	Dose	Increased inflammation?	Increased apoptosis?	Summary	Citation
Lab mice (Mus musculus)	56 days	NA	yes	yes	Seven-week old male mice with surgical brain nerve injury showed changes in inflammatory gene expression (increased interleukin-1beta and interleukin 6) and corresponding increase in apoptosis gene expression (tumor necrosis factor alpha).	Gamo et al. (2018)
Zebrafish (Danio rerio)	7 days	Aquatic exposure of 20, 200, 2000 μg/L of 70 nm and 5 um polystyrene microplastics.	yes	Cell death	Adult 5-month old fish had increased liver inflammation and liver necrosis.	Lu et al. (2016)
Zebrafish (Danio rerio)	14 days	Aquatic exposure of 100, 1000 ug/L of 0.5 and 50 um diameter polystyrene microplastic.	yes	yes	Adult 6-month old male fish increased changes to inflammatory gene expression, with statistically significant increases of interleukin-1alpha, interleukin-1beta, interferon, interleukin-6 and corresponding non-significant increase in apoptosis gene expression (tumor necrosis factor alpha).	Jin et al. (2018)

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. 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

Life Stage: The life stage applicable to this key event relationship is all life stages.

Sex: This key event relationship applies to both males and females.

Taxonomic: This key event relationship appears to be present broadly, with representative studies including mammals (humans, lab mice, lab rats) and teleost fish.

References

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

Balkwill, F. 2003. Chemokine biology in cancer. Seminars in Immunology 15: 49-55.

Bock, F.J. and Riley, J.S. 2023. When cell death goes wrong: inflammatory outcomes of failed apoptosis and mitotic cell death. Cell Death and Differentiation 30: 293-303.

Elmore, S. 2007. Apoptosis: A Review of Programmed Cell Death. Toxicologic pathology 35 (4): 495-516.

Gamo, K., Kiryu-Seo, S., Konishi, H., Aoki, S., Matushima, K., Wada, K., and Kiyama, H. 2008. G-protein-coupled receptor screen reveals a role for chemokine recepteor CCR5 in suppressing microglial neurotoxicity. Journal of Neuroscience 28: 11980-11988.

Jin, Y., Xia, J., Pan, Z., Yang, J., Wang, W., and Fu, Z. 2018. Polystyrene microplastics induce microbiota dysbiosis and inflammation in the gut of adult zebrafish. Environmental Pollution 235: 322-329.

Lu, Y., Zhang, Y., Dengy, Y., Jiang, W., Zhao, Y., Geng, J., Ding, L., Ren, H. 2016. Uptake and accumulation of polystyrene microplastics in zebrafish (Danio rerio) and toxic effects in liver. Environmental Science and Technology 50: 4054-4060.