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Relationship: 3466
Title
dimerization, AHR/ARNT leads to increased, Bax
Upstream event
Downstream event
Key Event Relationship Overview
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 Do not cite |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
Sex Applicability
Sex | Evidence |
---|---|
Female | Moderate |
Life Stage Applicability
Term | Evidence |
---|---|
All life stages | Moderate |
Key Event Relationship Description
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
Evidence Supporting this KER
Biological Plausibility
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.
Empirical Evidence
The AhR/ARNT heterodimer binds to xenobiotic response elements (XREs) in the promoter regions of target genes, regulating their transcription, including apoptosis-related genes. It highlights how AhR, upon binding to environmental toxins, forms a complex with ARNT, allowing it to bind to DNA and activate detoxification genes. The pathway is conserved in vertebrates and some invertebrates, with species-specific variations in function and ligand sensitivity. It also emphasizes that ARNT is crucial, as AhR alone cannot bind DNA (1).
Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals study provides direct experimental evidence that AhR activation by toxicants induces Bax gene expression, leading to apoptosis in ovarian cells (2).
The AHR-ARNT dimer is essential for mediating both detoxification and non-detoxification pathways,including apoptosis regulation through the Bax gene (3).
The AhR "battery" genes, AHR-ARNT dimerization influences the transcription of detoxification genes and stress-response pathways,i nterplay between BAX, BCL2, and AHR-ARNT signaling suggests a key role in determining cell fate—whether to continue the cell cycle or undergo apoptosis (4).
AHR-ARNT’s ability to regulate gene expression is not just dependent on the presence of the GCGTG site but also on adjacent nucleotide sequences. Bax gene expression is selectively regulated by AHR-ARNT, with specific flanking nucleotides determining whether the complex can successfully activate transcription (5).
AHR/ARNT binds to its cognate DNA response element (DRE) to regulate gene transcription, it can interact at a promoter region, modulating its activity. DRE-dependent transcription is required for TCDD-mediated toxicity, as observed in genetically modified mice for expression of genes like bax (6).
Uncertainties and Inconsistencies
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
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. |
(7) |
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).
Quantitative Understanding of the Linkage
The quantitative relationship between AhR/ARNT dimerization and Bax induction is not fully established but follows a dose-dependent pattern. Bax expression increases following AhR dimerization and nuclear translocation, typically occurring within hours post-exposure to AhR ligands.Immunohistochemical analysis of fetal ovaries before culture or after a 24-h culture with cytokines indicated the presence of little, if any, detectable Bax protein. However, inclusion of DMBA in cytokine-supported cultures caused a marked increase in Bax immunoreactivity in many germ cells. High levels of AhR activation may be required to induce significant Bax upregulation, suggesting a non-linear dose-response relationship (9, 10).
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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
- Hankinson O. The aryl hydrocarbon receptor complex. Annu Rev Pharmacol Toxicol. 1995;35:307-40.
- 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.
- Puga A, Ma C, Marlowe JL. The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways. Biochem Pharmacol. 2009;77(4):713-22.
- 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.
- 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.
- Perdew GH. Ah receptor binding to its cognate response element is required for dioxin-mediated toxicity. Toxicol Sci. 2008;106(2):301-3.
- 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.
- 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).
- 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.
- 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.