Liver Tumor Promotion by 2,3,7,8-Tetrachlorodibenzo-p-dioxin Is Dependent on the Aryl Hydrocarbon Receptor and TNF/IL-1 Receptors
Open accessAbstract
We set out to better understand the signal transduction pathways that mediate liver tumor promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxn ("dioxin"). To this end, we first employed congenic mice homozygous for either the Ahr(b1) or Ahr(d) alleles (encoding an aryl hydrocarbon receptor (AHR) with high or low binding affinity for dioxin, respectively) and demonstrated that hepatocellular tumor promotion in response to dioxin segregated with the Ahr locus. Once we had genetic evidence for the importance of AHR signaling, we then asked if tumor promotion by dioxin was influenced by "interleukin-1 (IL-1)-like" inflammatory cytokines. The importance of this question arose from our earlier observation that aspects of the acute hepatocellular toxicity of dioxin are dependent upon IL1-like cytokine signaling. To address this issue, we employed a triple knock-out (TKO) mouse model with null alleles at the loci encoding the three relevant receptors for tumor necrosis factors α and β and IL-1α and IL-1β (i.e., null alleles at the Tnfrsf1a, Tnfrsf1b, and Il-1r1 loci). The observation that TKO mice were resistant to the tumor promoting effects of dioxin in liver suggests that inflammatory cytokines play an important step in dioxin mediated liver tumor promotion in the mouse. Collectively, these data support the idea that the mechanism of dioxin acute hepatotoxicity and its activity as a promoter in a mouse two stage liver cancer model may be similar, i.e., tumor promotion by dioxin, like acute hepatotoxicity, are mediated by the linked action of two receptor systems, the AHR and the receptors for the "IL-1-like" cytokines.
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This mouse continues to be widely used as a nonresponsive control for studies examining the AHR-mediated effects of ligands like TCDD and BaP on common end points such as carcinogenesis and inflammation.
“This mouse continues to be widely used as a nonresponsive control for studies examining the AHR-mediated effects of ligands like TCDD and BaP on common end points such as carcinogenesis and inflammation (Kennedy et al., 2014; Wong et al., 2018).”
From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Kennedy et al., 2014
The Animals section identifies the congenic Ahr d/d mouse as having a lower-affinity AHR, and the Discussion reports that it still showed dioxin-promoted tumors after 40 weeks. That contradicts describing it as a nonresponsive control without qualification. This paper studies TCDD-related liver tumor promotion, not BaP or the mouse’s widespread use. (LLM, conf=0.84)
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Experimental — accuracy not yet measuredUsing the Ahrfx model can require high concentrations of ligands such as beta-naphthoflavone or highly potent ligands such as TCDD to elicit a response.
“Thus, use of Ahrfx model can require high concentrations of certain ligands like beta-naphthoflavone (BNF) or the use of highly potent ligands like TCDD in order to illicit a response (Kennedy et al., 2014).”
From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Kennedy et al., 2014
The Animals section describes Ahr b1/b1 and Ahr d/d congenic mice, not an Ahrfx model. The Discussion reports a delayed tumor-promotion response to dioxin in Ahr d/d mice, but does not address whether Ahrfx requires high concentrations of beta-naphthoflavone or a potent ligand such as TCDD. Searches for Ahrfx, floxed Ahr, and beta-naphthoflavone found no passage addressing that claim; page numbers were unavailable in our copy. (LLM, conf=0.76)
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Cites
The Aryl Hydrocarbon Receptor Complex
Hankinson, O. (1995) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pa.35.040195.001515 · Cited by 1,649 · cited 2× · see citing works
“…as cancer, we do know that much of dioxin-induced acute toxicity is mediated by the direct interaction of this ligand with the aryl hydrocarbon receptor (AHR), a member of the basic helix-loop-helix/Per-Arnt-Sim (PAS) family of transcription factors (Hankinson, 1995; Schmidt and Bradfield, 1996).”
BackgroundAH RECEPTOR SIGNALING PATHWAYS
Schmidt, J. V., & Bradfield, C. A. (1996) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.12.1.55 · Cited by 899 · see citing works
Self-citationAnalysis of the four alleles of the murine aryl hydrocarbon receptor
Poland, A., Palen, D., & Glover, E. (1994) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)09833-5 · Cited by 303 · see citing works
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Research works printed but not linked: 4
- Drinkwater, N. R., and Denniston, C. (2011) Statistical Problems in Genet- ics and Molecular Biology, pp. 89-163. CreatSpace Independent Publishing Platform
- Giri, A. K. (1986). Mutagenic and genotoxic effects of 2,3,7,8- tetrachlorodibenzo-p-dioxin, a review. Mutat. Res. 168, 241-248.
- Nukaya, M., Moran, S., and Bradfield, C. A. (2009). The role of the dioxin- responsive element cluster between the Cyp1a1 and Cyp1a2 loci in aryl hy- drocarbon receptor biology. Proc. Natl. Acad. Sci. U.S.A. 106, 4923-4928.
- Walisser, J. A., Glover, E., Pande, K., Liss, A. L., and Bradfield, C. A. (2005). Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types. Proc. Natl. Acad. Sci. U.S.A. 102, 17858- 17863.
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Rodent Genetic Models of Ah Receptor Signaling
Wilson, R. H., & Bradfield, C. A. (2021) · Drug Metabolism Reviews · doi:10.1080/03602532.2021.1955916 · Cited by 16 · see citing works
“Thus, use of Ahrfx model can require high concentrations of certain ligands like beta-naphthoflavone (BNF) or the use of highly potent ligands like TCDD in order to elicit a response (Kennedy et al. 2014).”
BackgroundMethodSelf-citation
- Authors
- Kennedy, G. D., Nukaya, M., Moran, S. M., Glover, E., Weinberg, S., Balbo, S., Hecht, S. S., Pitot, H. C., Drinkwater, N. R., & Bradfield, C. A.
- Affiliations
- University of Wisconsin–Madison (US)
- University of Minnesota (US)
- ORCID
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-04-09
- Volume
- 140
- Issue
- 1
- Pages
- 135-143
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- PMC
- PMC4133587
- OpenAlex
- W2169354960
- Cited by
- 42
- References
- 3
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 10 · 2017: 4 · 2016: 4 · 2015: 5 · 2014: 2
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Toxicological Sciences (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (T32HL076139)
- National Cancer Institute (P01CA022484, P30CA014520)
- National Institute of Environmental Health Sciences (R01ES020668, K08ES017283)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- 2,3,7,8-tetrachlorodibenzo-p-dioxin, dioxins, liver tumor promotion, hepatocellular carcinoma, aryl hydrocarbon receptor, TNF receptor, IL-1 receptor, inflammatory cytokines, AhR knockout mice, triple knockout mice, hepatotoxicity, signal transduction
- MeSH terms
- Animals, Caprylates, Cocarcinogenesis, Diethylnitrosamine, Dioxins, Liver Neoplasms, Experimental, Male, Mice, Inbred C57BL, Triglycerides, Receptors, Interleukin-1, Receptors, Tumor Necrosis Factor, Receptors, Aryl Hydrocarbon, Mice, Knockout
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