This AOP is licensed under the 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.

AOP: 494

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

AhR activation leading to liver fibrosis

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

AhR and chronic liver diseases

The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help

Handbook Version v2.5

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

Authors

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

Xavier Coumoul^*, Min Ji Kim^$, Karine Audouze*, Etienne Blanc^*, Jean-Pascal de Bandt^*

Institutions : Université Paris Cité^*, Université Sorbonne Nord^$ / Inserm HealthFex Umr-S 1124

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

Xavier COUMOUL (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

Xavier COUMOUL
Min Ji Kim
Karine Audouze
Etienne Blanc

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

Tanja Burgdorf

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication. More help

OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version

This AOP was last modified on January 26, 2025 12:11

Revision dates for related pages

Page	Revision Date/Time
Activation, AhR	February 28, 2024 05:12
Increase, Cell injury/death	May 27, 2024 07:23
Activation, Stellate cells	November 10, 2019 05:25
Increased, extracellular matrix deposition	January 30, 2025 12:28
N/A, Liver fibrosis	December 05, 2018 08:29
Increased, Liver Steatosis	January 30, 2025 12:24
Activation, AhR leads to Increased, Liver Steatosis	January 30, 2025 12:29
Increased, Liver Steatosis leads to Cell injury/death	January 30, 2025 12:34
Cell injury/death leads to Activation, Stellate cells	November 29, 2016 19:54
Activation, Stellate cells leads to Increased extracellular matrix deposition	January 30, 2025 16:37
Increased extracellular matrix deposition leads to N/A, Liver fibrosis	February 01, 2025 03:32
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)	February 09, 2017 14:32

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

“Liver fibrosis, characterized by excessive accumulation of extracellular matrix proteins, represents a significant health burden worldwide. It is a hallmark of chronic hepatotoxicity, which is characterized by excessive deposition of extracellular matrix (ECM) proteins, primarily collagen, leading to disrupted liver architecture and function. It is a precursor to cirrhosis and affects millions globally, with over 1.5 million deaths annually attributed to advanced liver diseases such as cirrhosis or liver cancer. At the cellular level, hepatic fibrosis involves the activation of hepatic stellate cells (HSCs) into myofibroblasts, driven by pro-fibrotic cytokines like TGF-β1. Molecularly, it is defined by increased expression of fibrotic markers such as α-SMA and COL1A1, and dysregulation of pathways like Wnt/β-catenin and NF-κB. These processes often result from chronic exposure to hepatotoxic agents, including alcohol, drugs, or viral infections, underscoring the critical link between hepatotoxicity and fibrosis. The chemical exposome is therefore suspected to influence the occurence of liver fibrosis. The Ah receptor (AhR), a ligand-activated transcription factor primarily known for its involvement in xenobiotic metabolism, has emerged as a key player in various physiological processes, including liver homeostasis and inflammation. The AhR is now considered as an exposome receptor. Recent studies have implicated the AhR signaling pathway in the development and progression of liver fibrosis. Importantly, predictive assays are missing and a single predictive in vitro assay appears difficult to be setup with current technical knowledge. AOPs can be used to define a framework linking cellular and molecular events up to an AO, starting with AhR activation (MIE). We therefore propose anAOP providing a comprehensive overview of the molecular mechanisms underlying the association between AhR activation and liver fibrogenesis. AhR activation by endogenous ligands, such as tryptophan metabolites and environmental toxins, triggers a cascade of events leading to hepatic stellate cell activation, inflammation, and fibrogenesis. The 5 key events presented here can serve as a knowledge repository for identifying and developing new in vitro methodological approaches, integrated into the AOP in the form of IATA (Integrated Approaches to Testing and Assessment). These 5 KEs link hepatic steatosis induced by AhR activation to cell death, which leads to the recruitment and activation of stellate cells that are responsible for the production of extracellular matrix components, and hence to hepatic fibrosis. If tests are lacking, the AOP can help guide their development to assess the hazard associated with new substances or substances under development. Understanding the intricate interplay between AhR and liver fibrosis offers novel insights into the pathogenesis of chronic liver diseases and highlights AhR as a potential therapeutic target for the management of liver fibrosis. “

Pierre S, Chevallier A, Aryl hydrocarbon receptor-dependent induction of liver fibrosis by dioxin. Toxicol Sci. 2014 Jan;137(1):114-24. doi: 10.1093/toxsci/kft236. Epub 2013 Oct 23. PMID: 24154488.

Larigot L, Benoit L, et al. Aryl Hydrocarbon Receptor and Its Diverse Ligands and Functions: An Exposome Receptor. Annu Rev Pharmacol Toxicol. 2022 Jan 6;62:383-404. doi: 10.1146/annurev-pharmtox-052220-115707. Epub 2021 Sep 9. PMID: 34499523.

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

Understanding the biological link between Ah receptor (AhR) activation and liver fibrosis holds significant relevance due to its implications in the pathogenesis of various liver diseases. Liver fibrosis represents a common pathological process underlying the progression of chronic liver disorders, including hepatitis, alcoholic liver disease, and non-alcoholic fatty liver disease (NAFLD). Notably, NAFLD, characterized by hepatic steatosis, inflammation, and fibrosis, has become a global health concern, closely associated with obesity, metabolic syndrome, and insulin resistance. Given that AhR activation has been implicated in the regulation of lipid metabolism and inflammation, elucidating its role in liver fibrosis provides valuable insights into the molecular mechanisms driving NAFLD progression. Moreover, the interconnected nature of liver diseases underscores the importance of investigating AhR-mediated pathways as potential therapeutic targets for the management of liver fibrosis and its comorbidities, including hepatic steatosis. Therefore, establishing a biological link between AhR activation and liver fibrosis not only enhances our understanding of disease pathogenesis but also offers promising avenues for the development of targeted therapies for liver-related disorders.

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

We have been working for many years on chronic liver diseases and AhR. We had written a review on the subject and, following on from experimental work showing the links between AhR and fibrosis (two publications), we decided as part of the EU PARC project to take advantage of this expertise to propose this AOP.

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

Activation, AhR

KE	459	Increased, Liver Steatosis	Increased, Liver Steatosis
KE	55	Increase, Cell injury/death	Cell injury/death
KE	265	Activation, Stellate cells	Activation, Stellate cells
KE	1501	Increased, extracellular matrix deposition	Increased extracellular matrix deposition

344

N/A, Liver fibrosis

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

Title	Adjacency	Evidence	Quantitative Understanding

Activation, AhR leads to Increased, Liver Steatosis	adjacent	High	Moderate
Increased, Liver Steatosis leads to Cell injury/death	adjacent	Moderate	Moderate
Cell injury/death leads to Activation, Stellate cells	adjacent	Moderate	Moderate
Activation, Stellate cells leads to Increased extracellular matrix deposition	adjacent	High	High
Increased extracellular matrix deposition leads to N/A, Liver fibrosis	adjacent	High	High

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

Name
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Life Stage Applicability

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

Life stage	Evidence
Adults	Moderate

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

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	Moderate	NCBI
Mus musculus	Mus musculus	High	NCBI

Sex Applicability

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

Sex	Evidence
Mixed	Moderate

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

The biological plausibility of KERs is defined by the OECD as the « understanding of the fundamental biological processes involved and whether they are consistent with the causal relationship being proposed in the AOP ». The biological plausibility is strong due to the presence of overwhelming evidence present in different studies. A minor setback would be the difficulty to dismiss alternative mechanisms caused by the ligands used for AhR activation.

The essentiality of KEs refers to « experimental data for whether or not downstream KEs or the AO are prevented or modified if an upstream event is blocked ». The essentiality of KEs is strong: most works converge to imply the AhR in fibrotic processes. One setback would be that AhR knockout mice also develop a specific liver fibrosis. We propose that exogenous ligands alter the activity of endogenous ligands and therefore contribute just like the knockout to the occurence of liver fibrosis. The AhR activation needs to be considered then as the binding of exogenous ligands (xenobiotics) counteracting on the physiological processes which regulate the physiological functions.

Finally, the empirical support of KERs, is often « based on toxicological data derived by one or more reference chemicals where dose–response and temporal concordance for the KE pair can be assessed ». The overall assessment of the empirical support of our KERs is also strong. There is evidence in human cell lines and mice showing a dose–response and temporal concordance for severity of our KEs and the adverse outcomes (for example, a dose-dependant effect of TCDD on the development of liver fibrosis in mice).

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

The AOP described is valid for both sexes. Epidemiological studies carried out on chronic hepatitis patients living around the Da Nang air base in Vietnam have shown that increased levels of TCDD in the blood were associated, among other things, with elevated stages of liver fibrosis (classified using the METAVIR fibrosis staging system); this is also true for PCDF. Dioxins and furans are specific ligands of the AhR (whose activation represents MIE and hepatic fibrosis AO) (doi: 10.3390/toxics10060315). These results suggest that exposure to TCDD can influence an evolution of the hepatic environment towards fibrosis, which also increases the risk of liver cancer. They suggest that all subjects living in dioxin-contaminated areas in Vietnam should undergo regular check-ups, in particular liver function tests and imaging examinations. These results are consistent with experimental studies, which are consistent with the conservation of the AhR pathway in vertebrates. Thus, animal models (mainly rodents) have been used to study this fibrogenesis, demonstrating that the co-occurrence of external factors (high-fat diet, for example) contributes to this fibrosis at low doses of AhR ligands.

Pham PQ, Nguyen VB, Pham TT, Duong NX, Nguyen HT, Ha QV, Nguyen TD, Hoang TM, Dinh DT, Tran QTN, Bui LK, Vu TT, Phan MV, Luong TM, Nguyen K, Vu DA, Pham TN. Histopathological Alterations in the Livers of Chronic Hepatitis Patients Exposed to Agent Orange/Dioxin in Vietnam. Toxics. 2022 Jun 10;10(6):315. doi: 10.3390/toxics10060315. PMID: 35736923; PMCID: PMC9229980.

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

KEY EVENT	LEVEL OF ESSENTIALITY	EVIDENCE
KE 459: Increased, Liver Steatosis	STRONG	Liver steatosis or fatty liver, is essential in promoting liver fibrosis because it sets off a cascade of pathological mechanisms that drive liver damage and the fibrotic response (and all other key events) and subsequently It is considered as a risk factor for fibrosis, according to the two-strikes hypothesis (Day and James, 1998): this hypothesis is a conceptual framework describing how liver damage progresses, often culminating in fibrosis, cirrhosis, or even liver failure. This hypothesis highlights the sequential and synergistic nature of liver injury and involves two key stages: the first strike involves an initial liver insult, such as accumulation of fat in liver cells (KE 459); this stage is often asymptomatic and involves increased liver vulnerability due to mild oxidative stress, fat accumulation, or mild inflammation. The second strike involves additional insults that exacerbate the damage, leading to inflammation and fibrogenesis (see other KEs below). Liver steatosis is characterized by the accumulation of lipids in hepatocytes. This can result from metabolic disturbances, such as excess free fatty acids, insulin resistance, or oxidative stress (Pafili K et al, 2021). Subsequently, steatosis sensitizes the liver to further injury by increasing oxidative stress, ultimately leading to activation of Hepatic Stellate Cells (HSCs), apoptosis or necrosis of hepatocytes. While liver steatosis is reversible in early stages, chronic steatosis exacerbates damage as it perpetuates a feedback loop of inflammation and fibrosis. This sequence makes steatosis an essential precursor and contributor to liver fibrosis. *Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998 Apr;114(4):842-5. Doi: 10.1016/s0016-5085(98)70599-2. PMID: 9547102.* Pafili K, Roden M. Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans. Mol Metab. 2021 Aug;50:101122. doi: 10.1016/j.molmet.2020.101122. Epub 2020 Nov 19. PMID: 33220492; PMCID: PMC8324683.
KE 55: Increase, Cell injury/death	STRONG	Cell injury and death are crucial initiating events in this AOP leading to liver fibrosis. Indeed, damaged hepatocytes release damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS), which stimulate inflammation and HSC activation, a key event in liver fibrosis (see below). Hepatocyte cell death in the liver also leads to Kupffer cell activation (liver-resident macrophages), which secrete pro-inflammatory cytokines like TNF-α and IL-1β. The essentiality of this KE regarding liver fibrosis is demonstrated by inhibition of hepatocyte apoptosis or necrosis which reduces fibrosis in animal models (Guo R et al, 2022; Jiang M et al, 2023). Moreover, chronic liver diseases associated with fibrosis, such as non-alcoholic steatohepatitis (NASH), viral hepatitis, or alcoholic liver disease, show marked hepatocyte injury/death (Gaul S et al, 2021). Such observations make increased cell injury/death, an essential precursor and contributor to liver fibrosis. Guo R, Jia X, Ding Z, Wang G, Jiang M, Li B, Chen S, Xia B, Zhang Q, Liu J, Zheng R, Gao Z, Xie X. Loss of MLKL ameliorates liver fibrosis by inhibiting hepatocyte necroptosis and hepatic stellate cell activation. *Theranostics. 2022 Jul 4;12(11):5220-5236. doi: 10.7150/thno.71400. PMID: 35836819; PMCID: PMC9274737.* *Jiang M, Huang C, Wu Q, Su Y, Wang X, Xuan Z, Wang Y, Xu F, Ge C. Sini San ameliorates CCl4-induced liver fibrosis in mice by inhibiting AKT-mediated hepatocyte apoptosis.* *J Ethnopharmacol. 2023 Mar 1;303:115965. doi: 10.1016/j.jep.2022.115965. Epub 2022 Nov 29. PMID: 36460296.* Gaul S, Leszczynska A, Alegre F, Kaufmann B, Johnson CD, Adams LA, Wree A, Damm G, Seehofer D, Calvente CJ, Povero D, Kisseleva T, Eguchi A, McGeough MD, Hoffman HM, Pelegrin P, Laufs U, Feldstein AE. Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis. J Hepatol. 2021 Jan;74(1):156-167. doi: 10.1016/j.jhep.2020.07.041. Epub 2020 Aug 4. PMID: 32763266; PMCID: PMC7749849.
KE 265: Activation, Stellate cells	STRONG	Activation of hepatic stellate cells (HSCs) in liver fibrosis is considered as a critical and central event in the pathogenesis of fibrosis. Indeed, activation of HSCs leads to HSCs transition from a quiescent, vitamin A-storing phenotype to a myofibroblast-like phenotype that actively produces extracellular matrix (ECM) components such as collagen type I (Kamm DR et al, 2022), but also to the secretion of pro-fibrotic mediators (e.g., transforming growth factor-beta, TGF-β) and cytokines, amplifying the fibrotic response and creating a feed-forward loop of chronic liver damage (Dewidar B et al, 2019). A link of causality can be drawn as inhibition of HSC activation (e.g., through targeting TGF-β signaling, oxidative stress, or specific HSC markers like Hexokinase 2) significantly reduces fibrosis in animal models (Rho H et al, 2023). As a conclusion, the activation of HSC is essential for liver fibrosis, with strong experimental and mechanistic evidence supporting its central role. It serves as a critical target in developing anti-fibrotic therapies. *Kamm DR, McCommis KS. Hepatic stellate cells in physiology and pathology. J Physiol. 2022 Apr;600(8):1825-1837. doi: 10.1113/JP281061. Epub 2022 Mar 30. PMID: 35307840; PMCID: PMC9012702.* *Dewidar B, Meyer C, Dooley S, Meindl-Beinker AN. TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019.* *Cells. 2019 Nov 11;8(11):1419. doi: 10.3390/cells8111419. PMID: 31718044; PMCID: PMC6912224.* Rho H, Terry AR, Chronis C, Hay N. Hexokinase 2-mediated gene expression via histone lactylation is required for hepatic stellate cell activation and liver fibrosis. Cell Metab. 2023 Aug 8;35(8):1406-1423.e8. doi: 10.1016/j.cmet.2023.06.013. Epub 2023 Jul 17. PMID: 37463576; PMCID: PMC11748916.
KE 1501: Increased, extracellular matrix deposition	HIGH	Extracellular matrix (ECM) deposition is a critical hallmark of liver fibrosis. It represents the accumulation of fibrotic scar tissue due to excessive synthesis and reduced degradation of ECM components (e.g., collagen types I and III) (Caligiuri A et al, 2021). This deposition disrupts liver architecture and impairs function. ECM deposition is considered a highly essential event for liver fibrosis progression because it marks the transition from reversible inflammation to irreversible fibrosis, it correlates with disease severity and progression to cirrhosis (Caligiuri A et al, 2021). Experimental evidence often supports the essentiality, such as fibrosis models showing reduced ECM deposition when specific pathways (e.g., TGF-β or integrin signaling) are inhibited (Fan W et al, 2019). ECM deposition is a measurable KE using histological, biochemical, and imaging methods (e.g., Masson’s trichrome staining, hydroxyproline content, or MRI elastography, Red sirius). *Caligiuri A, Gentilini A, Pastore M, Gitto S, Marra F. Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression.* *Cells. 2021 Oct 15;10(10):2759. doi: 10.3390/cells10102759. PMID: 34685739; PMCID: PMC8534788.* Fan W, Liu T, Chen W, Hammad S, Longerich T, Hausser I, Fu Y, Li N, He Y, Liu C, Zhang Y, Lian Q, Zhao X, Yan C, Li L, Yi C, Ling Z, Ma L, Zhao X, Xu H, Wang P, Cong M, You H, Liu Z, Wang Y, Chen J, Li D, Hui L, Dooley S, Hou J, Jia J, Sun B. ECM1 Prevents Activation of Transforming Growth Factor β*, Hepatic Stellate Cells, and Fibrogenesis in Mice.* *Gastroenterology. 2019 Nov;157(5):1352-1367.e13. doi: 10.1053/j.gastro.2019.07.036. Epub 2019 Jul 27. PMID: 31362006.*

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

Modulating Factor (MF)	Influence or Outcome	KER(s) involved

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