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Relationship: 972

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

Activation, AhR leads to dimerization, AHR/ARNT

Upstream event

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

Activation, AhR

Downstream event

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

dimerization, AHR/ARNT

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	High	Moderate	Arthur Author (send email)	Open for citation & comment	WPHA/WNT Endorsed
Aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2	adjacent	High	Moderate	Allie Always (send email)	Open for citation & comment	WPHA/WNT Endorsed
Embryonic Activation of the AHR leading to Reproductive failure, via epigenetic down-regulation of GnRHR	adjacent	High	Moderate	Arthur Author (send email)	Under development: Not open for comment. Do not cite
AhR activation leading to preeclampsia	adjacent			Agnes Aggy (send email)	Under development: Not open for comment. Do not cite	Under Development
Aryl hydrocarbon receptor activation leading to early life stage mortality via sox9 repression induced impeded craniofacial development	adjacent	High	Moderate	Agnes Aggy (send email)	Under development: Not open for comment. Do not cite	EAGMST Under Review
Aryl hydrocarbon receptor activation leading to early life stage mortality via sox9 repression induced cardiovascular toxicity	adjacent	High	Moderate	Allie Always (send email)	Under development: Not open for comment. Do not cite	EAGMST Under Review

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
Mus musculus	Mus musculus	High	NCBI
Danio rerio	Danio rerio	High	NCBI
rainbow trout	Oncorhynchus mykiss	High	NCBI
Pagrus major	Pagrus major	High	NCBI
Acipenser fulvescens	Acipenser fulvescens	High	NCBI
Salmo salar	Salmo salar	High	NCBI
Acipenser transmontanus	Acipenser transmontanus	High	NCBI
Xenopus laevis	Xenopus laevis	High	NCBI
Ambystoma mexicanum	Ambystoma mexicanum	High	NCBI
Microgadus tomcod	Microgadus tomcod	High	NCBI
human	Homo sapiens	High	NCBI
Gallus gallus	Gallus gallus	High	NCBI
Phasianus colchicus	Phasianus colchicus	High	NCBI
Coturnix japonica	Coturnix japonica	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
All life stages	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

In its unliganded form, the AHR is part of a cytosolic complex containing heat shock protein 90 (HSP90), the HSP90 co-chaperone p23 and AHR-interacting protein (AIP) (Fujii-Kuriyama et al. 2010). Upon ligand binding, the aryl hydrocarbon receptor (AHR) migrates to the nucleus where it dissociates from the cytosolic complex and forms a heterodimer with AHR nuclear translocator (ARNT) (Mimura and Fujii-Kuriyama 2003).

AhRs can heterodimerize with ARNT1 and ARNT2 isoforms in order to activate reporter constructs in transfected cells and recognize response elements in gel shift assays in all investigated vertebrates, including birds, fishes, and reptiles (Abnet et al 1999; Andreasen et al 2002a; 2002b; Bak et al 2013; Doering et al 2014; Doering et al 2015; Farmahin et al 2012; 2013; Hansson & Hahn 2008; Karchner et al 1999; 2006; Lavine et al 2005; Shoots et al 2015; Tanguay et al 1999; 2000; Wirgin et al 2011).

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 Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

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

There are uncertainties in the precise physiological and toxicological roles of different AhR clades (AhR1, AhR2, AhR3) and isoforms (α, β, δ, γ).
There are uncertainties in the precise physiological and toxicological roles of different ARNT clades (ARNT1, ARNT2, ARNT3) and isoforms (a, b, c).
Nothing is known about differences in binding affinity of AhR for ARNT and of the AhR/ARNT heterodimer for DNA among species and taxa.
There is uncertainty in whether anthropogenic contaminants that act as ligands of the AhR and lead to dimerization of AhR with ARNT in vertebrates also act as ligands in invertebrates.

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

Strong quantitative relationships are known for exposure to ligands and interaction with DREs on the DNA by use of transfected COS-7 cells and gel shift assays (Abnet et al 1999; Andreasen et al 2002a; 2002b; Bak et al 2013; Doering et al 2014; Doering et al 2015; Farmahin et al 2012; 2013; Hansson & Hahn 2008; Karchner et al 1999; 2006; Lavine et al 2005; Manning et al 2012; Oka et al 2016; Shoots et al 2015; Tanguay et al 1999; 2000; Wirgin et al 2011).
Specifically, greater concentrations of ligands or greater potency ligands cause greater interaction with DREs on the DNA.
Numerous ligands of the AhR are rapidly metabolized and only cause transient activation of the AhR. These ligands do not result in sustained interaction with DREs and do not cause downstream effects (Farmhin et al 2016).
However, no studies specifically investigate AHR/ARNT dimerization quantitatively despite considerable indirect quantitative information.

Because ARNT is a necessary dimerization partner for the transcriptional activation of AHR, it can be assumed that AHR interaction with DREs correlates with AHR/ARNT dimerization, which provides some insight into the quantitative understanding of this key event relationship. However, it is not clear as to whether AHR interaction with DREs is directly proportional to AHR/ARNT dimerization. Therefore, the quantitative understanding of this link is based solely on indirect evidence.

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 aryl hydrocarbon receptor (AhR) and aryl hydrocarbon receptor nuclear translocator (ARNT) are highly conserved and ancient proteins with homologs having been identified in most major animal groups, apart from the most ancient lineages, such as sponges (Porifera) (Hahn et al 2002).
In vitro dimerization of AhRs and ARNTs have been demonstrated in mammals, birds, reptiles, amphibians, teleost and non-teleost fishes, and some invertebrates (Butler et al 2001; Emmons et al 1999; Hahn et al 2002; Powell-Coffman et al 1998).