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Relationship: 869

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 Induction, CYP1A2/CYP1A5

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

Induction, CYP1A2/CYP1A5

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 uroporphyria	adjacent	High	High	Allie Always (send email)	Open for citation & comment	WPHA/WNT Endorsed
AhR activation in the thyroid leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals	adjacent	High	Moderate	Brendan Ferreri-Hanberry (send email)	Under development: Not open for comment. Do not cite

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
mammals	mammals	High	NCBI
chicken	Gallus gallus	High	NCBI
fish	fish	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

Figure 1. The molecular mechanism of activation of gene expression by Aryl hydrocarbon receptor 1 (AHR1).

The molecular mechanism for AHR-mediated activation of gene expression is presented in Figure 1. 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)^[1]. Upon ligand binding, the AHR migrates to the nucleus where it dissociates from the cytosolic complex and forms a heterodimer with Ahr nuclear translocator (ARNT)^[2]. The AHR-ARNT complex then binds to a xenobiotic response element (XRE) found in the promoter of an AHR-regulated gene and recruits co-regulators such as CREB binding protein/p300, steroid receptor co-activator (SRC) 1, SRC-2, SRC-3 and nuclear receptor interacting protein 1, leading to induction of gene expression^[1].

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 no knowledge gaps or inconsistencies/conflicting lines of evidence for this KER.

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

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

The relationship between chemical structure and response potencies of AHR ligands has been well studied. With additional knowledge of intrinsic efficacy, it is possible to build a computational model of receptor action to predict transactivation potential, as demonstrated by Hestermann et al.^[12]. This model was able to explain the less-than additive effect of some DLC mixtures on AHR activation. Quantitative structure-activity relationships (QSARs) have also been developed^[13]^[14].

As mentioned above, the identity of two amino acids within the LBD of the AHR can also be used to predict transactivation sensitivity. This quality has been studied extensively in birds, resulting in the categorization of bird species into 3 groups: type 1, high sensitivity (e.g. chicken); type 2, moderate sensitivity (e.g. ring-necked pheasant); and type 3, low sensitivity (e.g. Japanese quail)^[5]^[4]^[15]. Furthermore, a non-invasive method for RNA extraction using plucked feathers has been determined^[16], making it possible to predict the sensitivity of any bird species to AHR agonists, and mediating the selection of priority species for risk assessment purposes.

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

Multiple AHR isoforms have been isolated and characterized in mammals, fish and birds^[17]. Mammals possess a single AHR that controls the expression of CYP1A2, while birds and fish possess 2 AHR isoforms (AHR-1 and AHR-2), with AHR-1 being homologous to the mammalian AHR. The avian orthologue to CYP1A2 is CYP1A5^[18]. Most fish species only express a single CYP1A gene^[19].