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Relationship: 973

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 reduced dimerization, ARNT/HIF1-alpha

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

dimerization, AHR/ARNT

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

reduced dimerization, ARNT/HIF1-alpha

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 activation leading to early life stage mortality, via reduced VEGF	adjacent	Moderate	Low	Amani Farhat (send email)	Open for citation & comment	WPHA/WNT Endorsed
AhR activation leading to preeclampsia	adjacent			Sabrina Tait (send email)	Under development: Not open for comment. Do not cite	Under Development

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
chicken	Gallus gallus	High	NCBI
mouse	Mus musculus	High	NCBI
Atlantic killifish	Fundulus heteroclitus	High	NCBI
zebrafish	Danio rerio	High	NCBI
Fundulus heteroclitus	Fundulus heteroclitus	High	NCBI
human	Homo sapiens	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Embryo	High
During development and at adulthood	High

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 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 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 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).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

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

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

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).

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

The quantitative nature of this relationship is not well understood.

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

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).

References

List of the literature that was cited for this KER description. More help

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