Upstream eventdimerization, AHR/ARNT
reduced dimerization, ARNT/HIF1-alpha
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Aryl hydrocarbon receptor activation leading to early life stage mortality, via reduced VEGF||adjacent||Moderate||Low|
|Atlantic killifish||Fundulus heteroclitus||High||NCBI|
|Fundulus heteroclitus||Fundulus heteroclitus||High||NCBI|
Life Stage Applicability
|During development and at adulthood||High|
Key Event Relationship Description
The aryl hydrocarbon receptor nuclear translocator (ARNT) is common dimerization partner for both the aryl hydrocarbon receptor (AHR) and hypoxia inducible factor alpha (HIF-1α). There is considerable cross talk between the two nuclear receptors, leading to the hypothesis that AHR activation leads to sustained AHR/ARNT dimerization and reduced HIF-1α/ARNT dimerization, assuming ARNT is not available in excess (Chan et al. 1999; Vorrink et al 2014b).
Evidence Supporting this KER
The ARNT serves as a dimerization partner for multiple transcription factors including the xenobiotic sensing AHR and HIF1α; therefore, it is plausible that sequestration of ARNT by one receptor would reduce the responsiveness of the other, assuming that ARNT is available in limited quantity (Vorrink et al. 2014b). Gel-shift and coimmunoprecipitation experiments have shown that the AHR and HIF1α compete for ARNT in vitro, with approximately equal dimerization efficiencies (Schmidt and Bradfield 1996).
Include consideration of temporal concordance here
- Activation of either AHR (by 2,3,7,8-tetrachlorodibenzo-p-dioxin) or HIF1 (by hypoxia) inhibits the activity of the other, in Hep3B cells (Chan et al. 1999)
- TCDD and hypoxia together reduced the stabilization of HIF1α and HRE-mediated promoter activity when compared to hypoxia alone, in MCF-7 and HepG2 cells (Seifert et al. 2008).
- Hypoxia increased EF5 binding (hypoxic tissue marker) in chicken embryos, whereas it was decreased by TCDD relative to controls (D10 of incubation) (Ivnitski-Steele et al. 2004)
- TCDD reduces the expression of cardiac HIF1α mRNA in chicken embryos (Ivnitski-Steele et al. 2004)
- ARNT overexpression rescued human HepG2 and HaCaT cells from inhibitory effect of hypoxia on XRE-luciferase reporter activity. This indicates that the mechanism of interference between the AHR and HIF1α pathways at least partially dependent on ARNT availability (Vorrink et al. 2014)
- Ischemia-induced upregulation of the expression of HIF1α and ARNT and DNA binding activity of the HIF1α-ARNT complex were enhanced in AHR-null mice (Ichihara et al. 2007).
- Vorrink et al (2014b) provides a thorough summary of supporting evidence as well as contradictions and uncertainties in the literature.
Uncertainties and Inconsistencies
Although crosstalk between AHR and HIF1α clearly exists, the nature of the relationship is still not clearly defined (Vorrink et al 2014). It has been suggested that HIF1α and AHR do not competitively regulate each other for hetero-dimerization with ARNT, as ARNT is constitutively and abundantly expressed in cells and does not deplete due to hypoxia or AHR activation (Chan et al. 1999; Pollenz et al. 1999). Nie et al. (2001) hypothesized that the degree of interaction among ARNT-dependent pathways depends on the abundance of ARNT in the cells. They observed crosstalk in Hepa 1 cells but not H4IIE cells, and attributed this to the ratio of AhR to ARNT of 0.3 (i.e. excess ARNT), compared to a ratio of 10 in Hepa 1 cells (Holmes and Pollenz, 1997)
Some studies have shown that the effect of hypoxia on AHR mediated pathways is stronger than effects of a AHR-mediated xenobiotic response on the HIF1α pathway (Gassmann et al. 1997; Gradin et al. 1996; Nie et al. 2001; Prasch et al. 2004); this has been attributed to the stronger binding affinity of HIF1α to ARNT relative to AHR (Gradin et al. 1996).
Quantitative Understanding of the Linkage
The quantitative nature of this relationship is not well understood.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The cross-talk between AHR and HIF1α has been demonstrated in chicken embryos (Ivnitski-Steele et al. 2004) mice (Ichihara et al. 2007) Atlantic killifish and zebrafish (McElroy et al. 2012), Mummichog (Kraemer et al. 2004) and a number of human cell lines (Chan et al. 1999; Seifert et al. 2008; Vorrink et al. 2014a, Vorrink et al. 2014b).
1. Chan, W. K., Yao, G., Gu, Y. Z., and Bradfield, C. A. (1999). Cross-talk between the aryl hydrocarbon receptor and hypoxia inducible factor signaling pathways. Demonstration of competition and compensation. J Biol. Chem. 274(17), 12115-12123.
2. Ichihara, S., Yamada, Y., Ichihara, G., Nakajima, T., Li, P., Kondo, T., Gonzalez, F. J., and Murohara, T. (2007). A role for the aryl hydrocarbon receptor in regulation of ischemia-induced angiogenesis. Arterioscler. Thromb. Vasc. Biol. 27(6), 1297-1304.
3. Ivnitski-Steele, I. D., Sanchez, A., and Walker, M. K. (2004). 2,3,7,8-tetrachlorodibenzo-p-dioxin reduces myocardial hypoxia and vascular endothelial growth factor expression during chick embryo development. Birth Defects Res. A Clin. Mol. Teratol. 70(2), 51-58.
4. Nie, M., Blankenship, A. L., and Giesy, J. P. (2001). Interactions between aryl hydrocarbon receptor (AhR) and hypoxia signaling pathways. Environ. Toxicol. Pharmacol. 10(1-2), 17-27.
5. Pollenz, R. S., Davarinos, N. A., and Shearer, T. P. (1999). Analysis of aryl hydrocarbon receptor-mediated signaling during physiological hypoxia reveals lack of competition for the aryl hydrocarbon nuclear translocator transcription factor. Mol. Pharmacol. 56(6), 1127-1137.
6. Schmidt, J. V., and Bradfield, C. A. (1996). Ah receptor signaling pathways. Annu. Rev. Cell Dev. Biol. 12, 55-89.
7. Seifert, A., Katschinski, D. M., Tonack, S., Fischer, B., and Navarrete, S. A. (2008). Significance of prolyl hydroxylase 2 in the interference of aryl hydrocarbon receptor and hypoxia-inducible factor-1 alpha signaling. Chem Res. Toxicol. 21(2), 341-348.
8. Vorrink, S. U., Severson, P. L., Kulak, M. V., Futscher, B. W., and Domann, F. E. (2014a). Hypoxia perturbs aryl hydrocarbon receptor signaling and CYP1A1 expression induced by PCB 126 in human skin and liver-derived cell lines. Toxicol. Appl. Pharmacol. 274(3), 408-416.
9. McElroy, A., Clark, C., Duffy, T., Cheng, B., Gondek, J., Fast, M., Cooper, K., and White, L. (2012). Interactions between hypoxia and sewage-derived contaminants on gene expression in fish embryos. Aquat. Toxicol. 108, 60-69.
10. L.D. Kraemer and P.M. Schulte, (2004) Prior PCB exposure suppresses hypoxia-induced up-regulation of glycolytic enzymes in Fundulus heteroclitus, Comp. Biochem. Physiol. C Toxicol. Pharmacol. 139: 23–29.
11. Vorrink, S.A. and Domann, F.E. (2014b) Regulatory crosstalk and interference between the xenobiotic and hypoxia sensing pathways at the AhR-ARNT-HIF1a signaling node. Chemico-Biological Interactions 218: 82–88