Abnormal Liver Development and Resistance to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Toxicity in Mice Carrying a Mutation in the DNA-Binding Domain of the Aryl Hydrocarbon Receptor
Open accessAbstract
The aryl hydrocarbon receptor (AHR) is known for its role in the adaptive and toxic responses to a large number of environmental contaminants, as well as its role in hepatovascular development. The classical AHR pathway involves ligand binding, nuclear translocation, heterodimerization with the AHR nuclear translocator (ARNT), and binding of the heterodimer to dioxin response elements (DREs), thereby modulating the transcription of an array of genes. The AHR has also been implicated in signaling events independent of nuclear localization and DNA binding, and it has been suggested that such pathways may play important roles in the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here, we report the generation of a mouse model that expresses an AHR protein capable of ligand binding, interactions with chaperone proteins, functional heterodimerization with ARNT, and nuclear translocation, but is unable to bind DREs. Using this model, we provide evidence that DNA binding is required AHR-mediated liver development, as Ahr(dbd/dbd) mice exhibit a patent ductus venosus, similar to what is seen in Ahr(-/-) mice. Furthermore, Ahr(dbd/dbd) mice are resistant to TCDD-induced toxicity for all endpoints tested. These data suggest that DNA binding is necessary for AHR-mediated developmental and toxic signaling.
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After ligand binding, the Ahrdbd construct retains the ability to translocate to the nucleus and dimerize with ARNT in vitro.
“Examination of the Ahrdbd construct in vitro revealed that after ligand binding, it retained the ability to translocate to the nucleus and dimerize with ARNT (Bunger et al., 2008).”
From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Bunger et al., 2008
The Results report a ligand-inducible interaction between AHRdbd and ARNT, supporting the dimerization part of the claim. But the subcellular-localization results say AHRdbd was already nuclear without ligand and that TCDD did not alter its localization; they do not support ligand-induced translocation. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPreliminary evidence from the authors' laboratory suggests that the NeoPGK transgene reduces RNA expression from multiple loci independent of its direction or position.
“While extensive studies to explain how the presence of the NeoPGK cassette leads to hypomorphism are lacking, preliminary evidence from multiple alleles in our own laboratory suggest that the presence of the NeoPGK transgene reduces RNA expression from multiple loci, independent of direction or position (Bunger et al., 2008; Bunger et al., 2003; Lin et al., 2008; Walisser, Bunger, Glover, & Brad”
From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Bunger et al., 2008
The Results (page not provided) show lower AHR protein expression when the neomycin cassette was present at the Ahr locus and wild-type-equivalent expression after its removal. This supports a cassette-associated hypomorphic effect at one locus, but the paper does not show reduced RNA expression at multiple loci or establish that the effect is independent of cassette direction or position. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe Ahrdbd mutation unexpectedly affects the neighboring NLS and makes the construct constitutively nuclear.
“Interestingly, this mutation had an unexpected influence on the neighboring NLS and the construct became constitutively nuclear.”
From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Bunger et al., 2008
In two-hybrid assays, Ahrdbd maintains ligand responsiveness and capacity to dimerize with ARNT.
“Yet, in two-hybrid assays, it was shown to maintain its ligand responsiveness and its capacity to dimerize with ARNT (Bunger et al., 2008).”
From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Bunger et al., 2008
The Ahrdbd mutant cannot activate Cyp1 gene expression or interact with AHREs.
“In keeping with its predicted activity, the Ahrdbd mutant could not activate Cyp1 gene expression or interact with AHREs.”
From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Bunger et al., 2008
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“Examination of the Ahrdbd construct in vitro revealed that after ligand binding, it retained the ability to translocate to the nucleus and dimerize with ARNT (Bunger et al. 2008).”
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- Authors
- Bunger, M. K., Glover, E., Moran, S. M., Walisser, J. A., Lahvis, G. P., Hsu, E. L., & Bradfield, C. A.
- Affiliations
- University of Wisconsin–Madison (US)
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-07-27
- Volume
- 106
- Issue
- 1
- Pages
- 83-92
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- PMC
- PMC2563146
- OpenAlex
- W2148529156
- Cited by
- 139
- References
- 40
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 1 · 2023: 5 · 2022: 4 · 2021: 9 · 2020: 3 · 2019: 7 · 2018: 4 · 2017: 9 · 2016: 6 · 2015: 4 · 2014: 12 · 2013: 12 · 2012: 7
- FWCI
- 11.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA014520)
- National Cancer Institute (T32CA009135, P01CA022484, P30CA014520)
- National Institute of Environmental Health Sciences (R01ES013566, F32ES005877, R01-ES-013566-01)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- aryl hydrocarbon receptor, 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD toxicity, liver development, patent ductus venosus, dioxin response element, mouse model
- MeSH terms
- Polychlorinated Dibenzodioxins, Animals, Carcinogens, Environmental, Carrier Proteins, Cleft Palate, DNA, Fetal Proteins, Hydronephrosis, Liver, Male, Mice, Mutant Strains, Microtubule-Associated Proteins, Portal Vein, Thymus Gland, Transfection, Signal Transduction, 3T3 Cells, Receptors, Aryl Hydrocarbon, Gene Expression Regulation, Developmental, Cytochrome P-450 CYP1A1, Response Elements, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors
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