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Relationship: 2568

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

Activation, AhR leads to Increase, Inflammation

Upstream event

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

Activation, AhR

Downstream event

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

Increase, Inflammation

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
Activation of the AhR leading to metastatic breast cancer	adjacent	High		Louise Benoit (send email)	Under Development: Contributions and Comments Welcome	Under Development

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
Homo sapiens	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
Adults	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 link between aryl hydrocarbon receptor (AhR) activation and increased inflammation involves:

Direct Pro-inflammatory Gene Expression: Upon activation by ligands like environmental toxins, certain dietary components, or endogenous metabolites, AhR translocates to the nucleus and binds to specific DNA sequences called AhR response elements (AHREs). This binding directly upregulates the expression of genes involved in inflammation, including: pro-inflammatory cytokine ( Interleukin-6 (IL-6), Tumor necrosis factor-alpha (TNF-α), etc), chemokines (IL-8) and cyclooxygenase-2 (COX-2), which plays a crucial role in synthesizing inflammatory mediators like prostaglandins.
Modulation of Immune Cell Function: AhR activation can modulate the function of various immune cells, impacting their response to inflammatory stimuli. This can lead to an increased production of pro-inflammatory mediators. Activated immune cells like macrophages and dendritic cells can release more cytokines, chemokines, and reactive oxygen species (ROS), further fueling inflammation. This can also lead to an altered antigen presentation. AhR signaling can influence how antigen-presenting cells present antigens to T lymphocytes, potentially leading to an altered immune response and promoting inflammation. In some contexts, AhR activation can promote the differentiation of Th17 cells, a subset of T lymphocytes known to contribute to specific inflammatory processes.
Disruption of Immune Homeostasis: Prolonged or excessive AhR activation can disrupt the delicate balance between pro-inflammatory and anti-inflammatory responses within the immune system. This can lead to chronic inflammation, where the body's inflammatory response continues even in the absence of a specific trigger.
Interaction with other Signaling Pathways: AhR signaling can interact and intertwine with other signaling pathways involved in inflammation, such as the NF-κB pathway. This interaction can amplify the inflammatory response by further promoting pro-inflammatory gene expression and immune cell activation. The most consensual pathway linking the AhR activation to cell inflammation was the NF-kB pathway (Vogel et al., 2011 Aug 1, Kolasa et al., 2013 Apr 25). Only half of the studies found a dose–response relationship (Miller et al., 2005, Kolasa et al., 2013 Apr 25, Malik et al., 2019 Oct).

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

Direct Modulation of Gene Expression: Upon activation by ligands, AhR translocates to the nucleus and binds to AhR response elements (AHREs) in the DNA. This binding can directly upregulate the expression of genes involved in inflammation, including: pro-inflammatory cytokines, chemokines and enzymes such as COX-2, which plays a crucial role in synthesizing inflammatory mediators like prostaglandins.
Modulation of Immune Cell Function: AhR activation can modulate the function of various immune cells, impacting their response to inflammatory stimuli: AhR activation can increase the production of pro-inflammatory mediators (cytokines, chemokines, ROS) from these cells, contributing to inflammation. AhR signaling may influence T cell differentiation, potentially promoting the development of Th17 cells, a subset involved in specific inflammatory processes.
Disruption of Immune Homeostasis: Prolonged or excessive AhR activation can disrupt the delicate balance between pro-inflammatory and anti-inflammatory responses within the immune system. This can lead to a chronic inflammatory state where the body's inflammatory response continues even in the absence of a specific trigger.
Interaction with other Signaling Pathways: AhR signaling can interact and intertwine with other signaling pathways involved in inflammation, such as the NF-κB pathway. This interaction can amplify the inflammatory response by further promoting pro-inflammatory gene expression and immune cell activation.

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

In vitro studies: Studies using isolated immune cells like macrophages and dendritic cells have shown that exposure to AhR ligands, such as certain environmental pollutants or specific dietary components, can directly upregulate the expression of pro-inflammatory genes like IL-6, TNF-α, and IL-8. This suggests a direct link between AhR activation and enhanced pro-inflammatory mediator production (Hao, Kim)
Animal models: Studies with mice lacking functional AhR (AhR-null mice) compared to wild-type controls have demonstrated reduced inflammatory responses in various models, such as lipopolysaccharide (LPS)-induced endotoxemia: AhR-null mice exhibited decreased inflammatory cytokine production and improved survival compared to wild-type mice (Lho). Similar results were found regarding T cell-mediated colitis: AhR-null mice demonstrated a less severe inflammatory bowel disease phenotype compared to wild-type mice (li)
Human studies: Workers exposed to certain polycyclic aromatic hydrocarbons (PAHs), known AhR ligands, have been shown to have elevated levels of inflammatory markers in their blood compared to unexposed individuals (Wang). Some studies suggest that consumption of certain dietary components with AhR-activating properties may be associated with increased risk of inflammatory conditions like rheumatoid arthritis. However, the evidence in this area is still evolving and requires further investigation. In triple negative breast cell lines (MDA-MB436, MDA-MB-231) and ER-positive cell lines, it has been shown that the activation of the AhR can lead to an increase in inflammation. (Bekki et al., 2015, Miller et al., 2005, Yamashita et al., 2018 May 1, Degner et al., 2009 Jan, Vogel et al., 2011 Aug 1, Kolasa et al., 2013 Apr 25, Vacher et al., 2018, Malik et al., 2019 Oct). The stressors mainly used to activate the AhR were TCDD followed by benzo[a]pyrene and 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhiP). After AhR inhibition (KO or antagonists), a decrease in inflammation biomarkers was found (Miller et al., 2005, Yamashita et al., 2018 May 1, Degner et al., 2009 Jan, Vogel et al., 2011 Aug 1, Kolasa et al., 2013 Apr 25). Assays evaluating cell inflammation were quantitative dosages of IL-6, IL-8 and Cox2 activity/expression.
Mechanistic studies: Studies have identified various mechanisms by which AhR activation can promote inflammation, including direct modulation of gene expression (binding to AHREs in the DNA) or interaction with other signaling pathways like NF-κB, amplifying inflammatory responses or modulating the function of immune cells, impacting their cytokine production and antigen presentation

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

Specificity and Context Dependence: Most studies employ potent AhR agonists like environmental pollutants, which may not reflect the effects of endogenous ligands or environmental exposures at lower levels. These endogenous ligands and lower exposure levels might have different effects on inflammation depending on the specific context. Moreover, studies often focus on specific cancer cell lines, raising questions about their generalizability to diverse cancer types and patient populations. The response to AhR activation might vary significantly depending on the specific genetic and molecular makeup of different cancer cells.
Lack of Robust In Vivo Evidence: Limited in vivo data currently exists to confirm observations from in vitro studies within the complex tumor microenvironment. In vivo models can better capture the interplay of various factors influencing inflammation, potentially revealing discrepancies compared to isolated cell line studies.
Conflicting Findings and Need for Further Mechanistic Understanding: Some studies report AhR activation suppressing or having no effect on inflammation, highlighting the need for further investigation and a deeper understanding of the context-dependent effects and the specific mechanisms at play.The complete picture of how AhR signaling pathways influence inflammation and how these effects translate to the complex tumor microenvironment remains unclear. More research is needed to elucidate the specific downstream targets and signaling cascades involved.
Challenges in Translating In Vitro Findings to Clinical Applications: Even if a robust link between AhR activation and increased inflammation is established, translating this knowledge into clinical applications presents significant challenges. Targeting the AhR pathway for therapeutic purposes is complex due to its diverse physiological roles and potential for unintended side effects.

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

References

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

Schindl, A., et al. (2011). Role of CYP1A1 and AhR in inflammation and immune response. International Journal of Toxicology, 30(4 Suppl 2), 10A-20A. https://pubmed.ncbi.nlm.nih.gov/21705091/

Stockinger, B., & Megison, G. (2009). The aryl hydrocarbon receptor: Navigating the labyrinth of ligands. British Journal of Pharmacology, 158(2), 480-493. https://pubmed.ncbi.nlm.nih.gov/19444155/

Veldhoorn, J., et al. (2009). The aryl hydrocarbon receptor: Orchestrator of dioxin toxicity and immunity. Immunological Reviews, 227(1), 207-228. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828254/

Hao, N., et al. (2010). Aryl hydrocarbon receptor promotes IL-1β-induced inflammatory responses in primary human macrophages. Toxicology and Applied Pharmacology, 249(1), 142-151. https://pubmed.ncbi.nlm.nih.gov/20624156/

Kim, E. Y., et al. (2010). Aryl hydrocarbon receptor activation in dendritic cells enhances Th17 cell differentiation and allergic airways disease. Journal of Immunology, 185(10), 6222-6230. https://pubmed.ncbi.nlm.nih.gov/20959475/

Lho, K. C., et al. (2011). Aryl hydrocarbon receptor deficiency protects against lipopolysaccharide-mediated inflammatory responses and lethality. Journal of Immunology, 187(10), 5233-5243. https://pubmed.ncbi.nlm.nih.gov/21937743/

Li, Y., et al. (2011). Attenuation of colonic inflammation in AhR-deficient mice. Journal of Immunology, 186(7), 4214-4221.

Wang, Y., et al. (2014). Urinary polycyclic aromatic hydrocarbon metabolites and inflammatory markers among coke oven workers. Environmental Health

Schindl, A., et al. (2011). Role of CYP1A1 and AhR in inflammation and immune response. International Journal of Toxicology, 30(4 Suppl 2), 10A-20A. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199371/

Stockinger, B., & Megison, G. (2009). The aryl hydrocarbon receptor: Navigating the labyrinth of ligands. British Journal of Pharmacology, 158(2), 480-493. https://pubmed.ncbi.nlm.nih.gov/37247746/

Miller ME, Holloway AC, Foster WG. Benzo-[a]-pyrene increases invasion in MDA-MB-231 breast cancer cells via increased COX-II expression and prostaglandin E2 (PGE2) output. Clin Exp Metastasis. 2005;22(2):149–56.

57. Belguise K, Guo S, Yang S, Rogers AE, Seldin DC, Sherr DH, et al. Green tea polyphenols reverse cooperation between c-Rel and CK2 that induces the aryl hydrocarbon receptor, slug, and an invasive phenotype. Cancer Res. 2007 Dec 15;67(24):11742–50.

58. Pontillo CA, Rojas P, Chiappini F, Sequeira G, Cocca C, Crocci M, et al. Action of hexachlorobenzene on tumor growth and metastasis in different experimental models. Toxicol Appl Pharmacol. 2013 May 1;268(3):331–42.

59. Yamashita N, Saito N, Zhao S, Terai K, Hiruta N, Park Y, et al. Heregulin-induced cell migration is promoted by aryl hydrocarbon receptor in HER2-overexpressing breast cancer cells. Exp Cell Res. 2018 May 1;366(1):34–40.

60. Miret N, Zappia CD, Altamirano G, Pontillo C, Zárate L, Gómez A, et al. AhR ligands reactivate LINE-1 retrotransposon in triple-negative breast cancer cells MDA-MB-231 and non-tumorigenic mammary epithelial cells NMuMG. Biochem Pharmacol. 2020 May;175:113904.

61. Degner SC, Papoutsis AJ, Selmin O, Romagnolo DF. Targeting of aryl hydrocarbon receptor-mediated activation of cyclooxygenase-2 expression by the indole-3-carbinol metabolite 3,3’-diindolylmethane in breast cancer cells. J Nutr. 2009 Jan;139(1):26–32.

62. Vogel CFA, Li W, Wu D, Miller JK, Sweeney C, Lazennec G, et al. Interaction of aryl hydrocarbon receptor and NF-κB subunit RelB in breast cancer is associated with interleukin-8 overexpression. Arch Biochem Biophys. 2011 Aug 1;512(1):78–86.

63. Kolasa E, Houlbert N, Balaguer P, Fardel O. AhR- and NF-κB-dependent induction of interleukin-6 by co-exposure to the environmental contaminant benzanthracene and the cytokine tumor necrosis factor-α in human mammary MCF-7 cells. Chem Biol Interact. 2013 Apr 25;203(2):391–400.

64. Vacher S, Castagnet P, Chemlali W, Lallemand F, Meseure D, Pocard M, et al. High AHR expression in breast tumors correlates with expression of genes from several signaling pathways namely inflammation and endogenous tryptophan metabolism. PloS One. 2018;13(1):e0190619.

65. Malik D-E-S, David RM, Gooderham NJ. Interleukin-6 selectively induces drug metabolism to potentiate the genotoxicity of dietary carcinogens in mammary cells. Arch Toxicol. 2019 Oct;93(10):3005–20.

66. Jönsson ME, Kubota A, Timme-Laragy AR, Woodin B, Stegeman JJ. Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish. Toxicol Appl Pharmacol. 2012 Dec 1;265(2):166–74.

67. Degner SC, Kemp MQ, Hockings JK, Romagnolo DF. Cyclooxygenase-2 promoter activation by the aromatic hydrocarbon receptor in breast cancer mcf-7 cells: repressive effects of conjugated linoleic acid. Nutr Cancer. 2007;59(2):248–57.