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Relationship: 2077

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, Glucocorticoid Receptor leads to Increase, Cripto-1 expression

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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
Glucocorticoid Receptor Agonism Leading to Impaired Fin Regeneration adjacent Moderate Brendan Ferreri-Hanberry (send email) Open for citation & comment

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
zebrafish Danio rerio Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed Moderate

Life Stage Applicability

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

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 glucocorticoid receptor (GR) is a steroid receptor belonging to the nuclear receptor (NR) family of ligand-dependent transcription factors. In the absence of a ligand, the GR is transcriptionally inactive in the cytoplasm. 
  • Cripto-1 is responsible for growth factor activity, as well as activin binding on the cell membrane.  Cripto-1  may also be referred to as teratocarcinoma-derived growth factor 1, tdgf1, or one-eyed pinhead protein, depending on the species (Uniprot).
  • It is believed that GR is a transcription factor that helps to regulate Cripto-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 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

It is believed that GR is a transcription factor that helps to regulate Cripto-1

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
  • Increases in cripto-1 expression are dependent on the structure or potency of the GR-Agonist used during exposure. Well-known GR-agonists such as Dexamethasone, hydrocortisone, and beclomethasone have no effect on cripto-1 expression at 1µM while beclomethasone dipropionate does. (Sengupta et al., 2012).
  • Due to a lack of evidence for different life stages, increases in cripto-1 expression can only be assumed in larval fish.

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

Not yet evaluated.

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Not yet evaluated.

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

Not yet evaluated.

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

Not yet evaluated.

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

Due to limited evidence, the relationship between GR and Cripto-1 is only known in Zebrafish (Garland et al., 2019). However, GR is fairly conserved across species (Stolte et al., 2006) as is cripto-1 (Ravisankar et al., 2011). The activation of GR may have a similar outcome dependant on the sensitivity of the receptor (Stolte et al., 2006). It can be presumed that the relationship between GR and cripto-1 is conserved across teleost with the exception of receptor sensitivity. 

References

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

Garland MA, Sengupta S, Mathew LK, Truong L, Jong ED, Piersma AH, Du JL, Tanguay RL. 2019. Glucocorticoid receptor-dependent induction of cripto-1 (one-eyed pinhead) inhibits zebrafish caudal fin regeneration. Toxicology Reports 6:529-537. https://doi.org/10.1016/j.toxrep.2019.05.013

Ravisankar V, Signh TP, Manoj N. 2011. Molecular evolution of the EGF-CFC protein family. Gene, 428:43-50. doi:10.1016/j.gene.2011.05.007

Sengupta S, Bisson WH, Mathew LK, Kolluri SK, Tanguay RL. 2012. Alternative glucocorticoid receptor ligand binding structures influence outcomes in an in vivo tissue regeneration model. Comparative Biochemistry and Physiology, Part C 156:121-129. doi:10.1016/j.cbpc.2012.05.003

Solte EH, Lidy Verberg van Kemenade BM, Savelkoul FJ, Flik G. 2006. Evolution of glucocorticoid receptors with different glucocorticoid sensitivity. Journal of Endocrinology 190:17-28. DOI: 10.1677/joe.1.06703