API

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Relationship: 1023

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

Binding of antagonist, PPAR alpha leads to stabilization, PPAR alpha co-repressor

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Binding of antagonist, PPAR alpha
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
stabilization, PPAR alpha co-repressor

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
Antagonist binding to PPARα leading to body-weight loss adjacent High Moderate Agnes Aggy (send email) Open for citation & comment WPHA/WNT Endorsed

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
human Homo sapiens High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male High
Female High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Not Otherwise Specified Not Specified

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

Binding of molecules to peroxisome proliferator-activated receptor α (PPARα) can cause either agonistic or antagonistic signaling depending on molecular structure (Xu et al 2001, Xu et al 2002).  Certain molecules that can bind to the PPARα ligand binding domain have been observed to cause conformational changes that induce increased affinity to co-repressors which decrease PPARα nuclear signaling (Xu et al 2002). The transcription co-repressors, silencing mediator for retinoid and thyroid hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR) have been observed to compete with transcriptional co-activators for binding to nuclear receptors (including PPARα) thus suppressing nuclear signaling activity (Nagy et al 1999, Xu et al 2002). Regarding the present MIE, PPARα antagonists such as GW6471 which leads to the KE where increased binding and stabilization of the co-repressors to the PPARα signaling complex suppressing nuclear signaling.

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

Regarding the present MIE, GW6471 has highly specific binding to the SMRT and N-CoR binding domains (Nagy et al 1999, Xu et al 2002).  The degree to which other chemicals cause PPARα antagonism by this specific MIE needs to be explored.  For example, Wilbanks et al. (2014) and Gust et al (2015) demonstrated inhibition of human PPARα nuclear signaling in in vitro nuclear signaling bioassays in response to 2,4-dinitrotoluene(2,4-DNT) and 2-amino-4,6-dinitrotoluene (2A-DNT), respectively.  However, it is unknown if this response was manifested through the co-repressor binding stabilization that was identified in (Xu et al 2002).

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

Unknown.

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 majority of the studies cited herein provide evidence for human and rat, however much of the signaling architecture is also present in yeast (Krogsdam et al 2002).