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Relationship: 3466

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

dimerization, AHR/ARNT leads to increased, Bax

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
Aryl hydrocarbon Receptor (AhR) activation causes Premature Ovarian Insufficiency leading to Reproductive Failure adjacent Moderate Sapana Kushwaha (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 Do not cite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
mouse Mus musculus High NCBI
rat Rattus norvegicus Moderate NCBI
human Homo sapiens Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Female Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages Moderate

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 AHR exist in the cytoplasm as a core tetrameric complex, composed of the ligand-binding subunit, a dimer of hsp90, the X-associated protein 2 (also referred to as ARA9 or AIP), and p23 (reviewed in Petrulis and Perdew, 2002). The hsp90 and XAP2 are considered a chaperone complex that stabilizes the AHR in the cytoplasm, protecting it from proteolysis and helping the receptor maintain its ligand-binding conformation. Upon binding an agonist, a conformational change in the AHR occurs that allows access to its nuclear localization sequence, and the receptor rapidly translocates into the nucleus. Aryl hydrocarbon nuclear translocator (ARNT), is the dimerization partner for the AHR. In the nucleus, ARNT appears to cause displacement of hsp90, leading to the formation of the AHR/ ARNT complex, which can then bind to dioxin-responsive elements (DRE) and regulate many of the receptor’s target genes, including those involved in xenobiotic metabolism (CYP1A1, CYP1B1) and apoptosis (such as Bax). Studies highlights the importance of sequence-specific DNA interactions in determining whether AHR-ARNT can upregulate Bax expression. Bax, a pro-apoptotic member of the Bcl-2 family, promotes mitochondrial outer membrane permeabilization (MOMP) and apoptosis. This relationship between AHR/ARNT activation and Bax upregulation is particularly relevant in toxicological contexts, where exposure to xenobiotics that activate AHR contributes to oxidative stress, mitochondrial dysfunction, and cell death.

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

The mechanistic linkage between AhR/ARNT dimerization and Bax upregulation is supported by molecular biology and toxicology studies. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that, upon binding to xenobiotics such as polycyclic aromatic hydrocarbons, translocates into the nucleus and forms a heterodimeric complex with AhR nuclear translocator (ARNT). This dimerization is an essential step for AhR’s transcriptional activity, as it enables binding to xenobiotic response elements (XREs) within the promoter regions of target genes. Activation of the AhR/ARNT complex has been shown to directly regulate Bax transcription, leading to increased expression of Bax protein. This aligns with the well-established role of AhR in modulating gene expression through XRE-dependent transcriptional activation. The structural and functional interplay between AhR/ARNT and the transcriptional machinery further supports the plausibility of this Key Event Relationship.

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

While the AhR/ARNT complex is known to bind XREs and regulate gene transcription, it remains unclear whether Bax expression is solely driven by XRE binding or if additional co-regulatory elements contribute to its upregulation. Studies suggest that AhR can modulate gene expression through non-DRE mechanisms, including protein-protein interactions, which may influence Bax levels. Species differences in AhR ligand affinity and downstream signaling responses introduce variability in observed Bax expression levels.

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
Modulating Factor (MF) MF Specification Effect(s) on the KER Reference(s)

Ligand Type and Concentration

Different AhR ligands (e.g., TCDD, PAHs, DMBA) exhibit varying potency in inducing Bax expression, with PAHs demonstrating strong activation. Strong ligands will lead to higher bax expression and increased apoptosis.

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Species-Specific Differences, i.e. variations in AhR and ARNT sequences between species affect ligand sensitivity and downstream transcriptional responses. Rodents with higher sensitivity, shows higher bax expression (8). Bax upregulation in ovarian cells suggests tissue-specific regulation, but its expression may differ in other tissues. Wherein ovarian cells strong Bax upregulation leads to higher follicular apoptosis, moderate effects in other tissues as influenced by other anti-apoptotic mechanisms (2).

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

Observed in mammals, including rodents and humans. Most prominently studied in reproductive and developmental contexts (e.g., ovarian failure in female mice), across multiple life stages due to Bax’s role in apoptosis. Strong evidence in female reproductive systems (ovarian cells).Likely relevant in males due to the universal role of Bax in apoptosis.

References

List of the literature that was cited for this KER description. More help
  1. Hankinson O. The aryl hydrocarbon receptor complex. Annu Rev Pharmacol Toxicol. 1995;35:307-40.
  2. Matikainen T, Perez GI, Jurisicova A, Pru JK, Schlezinger JJ, Ryu HY, et al. Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat Genet. 2001;28(4):355-60.
  3. Puga A, Ma C, Marlowe JL. The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways. Biochem Pharmacol. 2009;77(4):713-22.
  4. Nebert DW, Roe AL, Dieter MZ, Solis WA, Yang Y, Dalton TP. Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem Pharmacol. 2000;59(1):65-85.
  5. Swanson HI. DNA binding and protein interactions of the AHR/ARNT heterodimer that facilitate gene activation. Chem Biol Interact. 2002;141(1-2):63-76.
  6. Perdew GH. Ah receptor binding to its cognate response element is required for dioxin-mediated toxicity. Toxicol Sci. 2008;106(2):301-3.
  7. Denison MS, Soshilov AA, He G, DeGroot DE, Zhao B. Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol Sci. 2011;124(1):1-22.
  8. Xu X, Zhang X, Yuan Y, Zhao Y, Fares HM, Yang M, et al. Species-Specific Differences in Aryl Hydrocarbon Receptor Responses: How and Why? Int J Mol Sci. 2021;22(24).
  9. Matikainen TM, Moriyama T, Morita Y, Perez GI, Korsmeyer SJ, Sherr DH, Tilly JL. Ligand activation of the aromatic hydrocarbon receptor transcription factor drives Bax-dependent apoptosis in developing fetal ovarian germ cells. Endocrinology. 2002;143(2):615-20.
  10. Kugu K, Ratts VS, Piquette GN, Tilly KI, Tao XJ, Martimbeau S, et al. Analysis of apoptosis and expression of bcl-2 gene family members in the human and baboon ovary. Cell Death Differ. 1998;5(1):67-76.