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Relationship: 2401

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

ALDH1A (RALDH), inhibition leads to Decreased, atRA concentration

Upstream event

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

ALDH1A (RALDH), inhibition

Downstream event

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

Decreased, atRA concentration

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 ALDH1A (RALDH) leading to impaired fertility via disrupted meiotic initiation of fetal oogonia of the ovary	adjacent	High	Moderate	Cataia Ives (send email)	Under development: Not open for comment. Do not cite	Under Development
Inhibition of RALDH2 causes reduced all-trans retinoic acid levels, leading to transposition of the great arteries	adjacent	High	Moderate	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 Do not cite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
human	Homo sapiens	High	NCBI
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	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
All life stages

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

All-trans retinoic acid (atRA) is the active metabolite of vitamin A in developing mammals and its physiological levels is tightly regulated by enzymatic pathways. This KER is particularly relevant for mammalian embryogenesis/fetal development stages.

atRA is synthesized from dietary vitamin A (retinol) by a two-step oxidation pathway (Chatzi et al, 2013; Kedishvili, 2016): 1) retinol dehydrogenase (RDH10) metabolizes retinol to retinaldehyde (reversible step), 2) retinaldehyde dehydrogenase ALDH1A (ALDH1A1, ALDH1A2, ALDH1A3) metabolizes retinaldehyde to RA (irreversible step). All three isoenzymes can carry out the second (irreversible step) to produce atRA, but ALDH1A2 is the most active form during development (Kedishvili, 2016). Thus, inhibition of ALDH1A2 during development will decrease atRA concentrations.

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

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

The distribution of retinoic acid in cells and tissues are highly variable, as has been shown across species including chicken (Maden et al, 1998), frogs (Chen et al, 1994), mice (Kane et al, 2005; Obrochta et al, 2014) and rats (Bhat, 1997), as well as serum/plasma from humans (Kane et al, 2008; Miyagi et al, 2001; Napoli et al, 1985).

The exact relationship between ALDH1A2 inhibition and resulting atRA concentrations in mammalian ovaries is unclear. The ALDH1A2 inhibitor WIN18,446 inhibits enzyme activity in vitro with an IC(50) of 0.3 μM (Amory et al, 2011), and a dose of only 0.01 µM is sufficient to significantly reduce expression of Stra8 in cultured mouse fetal ovaries and with actual loss of oocytes from 2 µM (Rosario et al, 2020).

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

Since atRA must be enzymatically synthesized by ALDH1A enzymes (in this case ALDH1A2), the temporal and linear relationship between the two KEs are essential.

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

Retinoic acid status is regulated by complex feedback loops. For instance, atRA induces expression of retinoid enzymes to promote synthesis of retinyl esters, but simultaneously atRA induces expression of its own catabolizing CYP26 enzymes (Kedishvili, 2013; Kedishvili, 2016; Teletin et al, 2017).

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