Aop: 278

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

IKK complex inhibition leading to liver injury

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
IKK complex inhibition leading to liver injury

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Vrijenhoek, N.G. 1

1Leiden Academic Center for Drug Research, Leiden Univeristy, Leiden, The Netherlands

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Nanette Vrijenhoek   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Nanette Vrijenhoek

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on June 04, 2021 15:16

Revision dates for related pages

Page Revision Date/Time
Inhibition, IKK complex January 07, 2019 10:54
Inhibition, Nuclear factor kappa B (NF-kB) May 03, 2021 02:57
Activation, Caspase 8 pathway March 07, 2019 04:16
Cell injury/death July 15, 2022 09:46
Activation, Tissue resident cells (Kuppfer cells) January 07, 2019 09:04
Necrotic Tissue March 07, 2019 04:19
Liver Injury March 07, 2019 04:23
Increase, proinflammatory mediators (TNFalpha) January 07, 2019 10:44
Inhibition, IKK complex leads to Inhibition, Nuclear factor kappa B (NF-kB) March 07, 2019 05:52
Cell injury/death leads to Activation, Tissue resident cells (Kuppfer cells) January 07, 2019 09:14
Inhibition, Nuclear factor kappa B (NF-kB) leads to Activation, Caspase 8 pathway March 07, 2019 05:56
Activation, Caspase 8 pathway leads to Cell injury/death March 07, 2019 06:03
Cell injury/death leads to Necrotic Tissue March 07, 2019 06:05
Necrotic Tissue leads to Liver Injury March 07, 2019 06:07
Activation, Tissue resident cells (Kuppfer cells) leads to Increase, proinflammatory mediators (TNFalpha) January 07, 2019 10:48

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Inflammation has a critical role in liver and other types of injury. Activation of inflammatory events leads to the release of several cytokines, including TNFalpha. When this proinflammatory cytokine is released it can stimulate the TNF-receptor (TNFR), leading to a cascade of pathway activations. However, chemicals can alter these pathways in several ways and influence the TNFR related cascades.

This AOP describes the key events of chemically induced IKK complex inhibition which leads to liver injury during TNF signaling. This AOP starts with the molecular initiating event  “inhibition of the IKK complex”. When the IKK complex is inhibited, the NFkB pathway activation is disturbed, leading to less transcription of anti-apoptotic genes. Then, without apoptosis protection, the activation of Caspase 8, is not inhibited anymore. Caspase 8 activates caspase 3, leading to apoptosis, or cell death. Finally, too much cell death will lead to necrotic tissue and eventually liver failure.

This AOP will collect information about NFkB signaling and will contribute to the mechanistic insights of the inflammatory pathways during hepatotoxicity. Furthermore, since inflammation is a reoccurring KE in several AOPs, this AOP will expand the knowledge of current AOPs of the influence of TNF signaling and compound induced toxicity.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1574 Inhibition, IKK complex Inhibition, IKK complex
KE 202 Inhibition, Nuclear factor kappa B (NF-kB) Inhibition, Nuclear factor kappa B (NF-kB)
KE 1575 Activation, Caspase 8 pathway Activation, Caspase 8 pathway
KE 55 Cell injury/death Cell injury/death
KE 1576 Activation, Tissue resident cells (Kuppfer cells) Activation, Tissue resident cells (Kuppfer cells)
KE 1579 Increase, proinflammatory mediators (TNFalpha) Increase, proinflammatory mediators (TNFalpha)
AO 1548 Necrotic Tissue Necrotic Tissue
AO 1549 Liver Injury Liver Injury

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

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