API

This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 2561

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

Decreased, atRA concentration leads to Disruption, Progenitor cells of second heart field

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Decreased, atRA concentration
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Disruption, Progenitor cells of second heart field

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
Inhibition of RALDH2 causes reduced all-trans retinoic acid levels, leading to transposition of the great arteries adjacent High Low Arthur Author (send email) 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 Do not cite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
mouse Mus musculus NCBI
chicken Gallus gallus NCBI
zebrafish Danio rerio NCBI

Sex Applicability

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

Life Stage Applicability

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

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 biological plausibility between the ATRA gradient stimulating the patterning of the SHF is high, because vertebrate embryo-fetal cardiovascular development involves multiple steps and great knowledge is available including the importance of all-trans retinoic acid (ATRA) which has been reviewed in multiple papers (Brade et al., 2018; Duong & Waxman, 2021; Nakajima, 2019; Perl & Waxman, 2019; Stefanovic & Zaffran, 2017; S. Wang & Moise, 2019). As different processes in embryodevelopment benefit from varying levels of ATRA, an ATRA gradient exists which is generated by multiple enzymes that synthesize and degrade ATRA to maintain the preferred balance (Kedishvili, 2013; Menegola et al., 2021; Tonk & Pennings, 2015). In case cells sense high ATRA levels, proteins involved in ATRA degradation or storage are stimulated (STRA6, DHRS3, CRBP1, CRABP2, LRAT, CYP26A1) and proteins involved in ATRA generation are decreased in expression (RBP4, RDH10, ALDH1A2). In case cells sense low ATRA levels, proteins involved in ATRA generation are stimulated (RBP4, RDH10, ALDH1A2) and proteins involved in ATRA degradation or storage are decreased in expression (STRA6, DHRS3, CRBP1, CRABP2, LRAT, CYP26A1) (Duong & Waxman, 2021).

This ATRA gradient during cardiovascular development induces correct patterning of progenitor cells and later correct looping of the heart tube to form a four-chambered heart including formation of the great vessels. In case this gradient is disturbed, cardiovascular developmental defects can occur (Nakajima, 2019; Perl & Waxman, 2019; Sirbu et al., 2020; Stefanovic & Zaffran, 2017).

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

ATRA levels can also be diminished through a feedback loop by for instance Cyp26. For creating an ATRA gradient, the Cyp26a1 negative feedback loop is critical as was confirmed when coupling in vivo zebrafish studies with mathematical modeling (A. Q. Cai et al., 2012; Duong & Waxman, 2021; Schilling et al., 2012; White et al., 2007).

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

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