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Event: 1888

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increased (ectopic) all-trans retinoic acid concentration

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

increased atRA concentration

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Ectopic ATRA in fetal testis leads to reduced sperm count	MolecularInitiatingEvent	Terje Svingen (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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Vertebrates	Vertebrates		NCBI
mammals	mammals	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Fetal	Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Male	High
Female	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Retinoic acid (RA) function and metabolism

RA and retinoid signaling is central for numerous physiological processes, and has important roles within reproduction, vision, development and the immune system (O'Byrne & Blaner, 2013). As an important morphogen, the levels of RA is tightly controlled within tissues both spatially and temporally. Both insufficient and excess RA has proven to cause severe adverse effects (Kedishvili, 2013).

RA homeostasis is maintained by tissue-specific enzymes controlling a 2-step biosynthesis pathway: the precursor retinol is converted into retinaldehyde via retinol dehydrogenases (RDHs). Retinaldehyde dehydrogenases (RALDHs) then irreversibly oxidize retinaldehyde into biologically active RA (reviewed by (Shannon et al, 2017)). RA is removed via degradation to polar inactive metabolites by cytochrome P450 (CYP) family hydroxylases; chiefly CYP26A1, B1 and C1 (Topletz et al, 2015).

RA signals through the nuclear Retinoic Acid Receptors (RARs) and Retinoid X Receptors (RXRs) thereby regulating transcription of target genes (Cunningham & Duester, 2015).

Ectopic RA as Key Event

Inhibition or disruption of any of the enzymes in the RA degradation pathway, including the Cyp26 family, lead to increased concentrations of biologically active RA in target cells.

Equally, application of RA for medical treatments, including for acute promyelocytic leukemia and cystic acne, lead to increased concentrations of biologically active RA in target cells.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

In vitro

Indirect measurement of activity and potency of RXRs and RARs is possible via luciferase assays in cell lines, for example (Chassot et al, 2020; Jurutka & Wagner, 2019).

In vivo

Direct measurements of atRA in serum (humans, animals) can be performed by various chromatographic methods (Gundersen et al, 2007), for instance by high performance liquid chromatography (HPLC) (De Leenheer et al, 1982) or liquid chromatography-tandem mass spectrometry (LC-MS) (Morgenstern et al, 2021).

Indirect measurements in animal models can be performed with various reporter assays with RAR-RXR-RARE or RXR-RXR-RARE promoter elements driving expression of reporter proteins. These reporter assays can detect the presence of ATRA in tissues in a semi-quantitative manner. Examples include reporter mouse lines (Carlsen et al, 2021; Rossant et al, 1991; Solomin et al, 1998).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

The retinoid signaling pathway is highly evolutionary conserved between vertebrates. This KE is applicable for both mammalian sexes, across developmental stages into adulthood, in numerous cells and tissues and across taxa.