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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

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; 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 spem 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.


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

Bowles J, Knight D, Smith C, Wilhelm D, Richman J, Mamiya S, Yashiro K, Chawengsaksophak K, Wilson MJ, Rossant J, Hamada H, Koopman P (2006) Retinoid signaling determines germ cell fate in mice. Science 312: 596-600

Carlsen H, Ebihara K, Kuwata NH, Kuwata K, Aydemir G, Rühl R, Blomhoff R (2021) A transgenic reporter mouse model for in vivo assessment of retinoic acid receptor transcriptional activation International Journal for Vitamin and Nutrition Research In Press

Chassot AA, Le Rolle M, Jolivet G, Stevant I, Guigonis JM, Da Silva F, Nef S, Pailhoux E, Schedl A, Ghyselinck NB, Chaboissier MC (2020) Retinoic acid synthesis by ALDH1A proteins is dispensable for meiosis initiation in the mouse fetal ovary. Sci Adv 6: eaaz1261

Cunningham TJ, Duester G (2015) Mechanisms of retinoic acid signalling and its roles in organ and limb development Nat Rev Mol Cell Biol 16: 110-123

De Leenheer AP, Lambert WE, Claeys I (1982) All-trans-retinoic acid: measurement of reference values in human serum by high performance liquid chromatography. J Lipid Res 23: 1362-1367

Esteban J, Serrano-Maciá M, Sánchez-Pérez i, Alonso-Magdalena P, Pellín MC, García-Arévalo M, Nadal A, Barril J (2019) In utero exposure to bisphenol-A disrupts key elements of retinoid system in male mice offspring. Food Chem Toxicol 126: 142-151

Gundersen TE, Bastani NE, Blomhoff R (2007) Quantitative high-throughput determination of endogenous retinoids in human plasma using triple-stage liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 21: 1176-1186

Jurutka PW, Wagner CE (2019) Methods to Assess Activity and Potency of Rexinoids Using Rapid Luciferase-Based Assays: A Case Study with NEt-TMN. Methods Mol Biol 2019

Kedishvili NY (2013) Enzymology of retinoic acid biosynthesis and degradation. J Lipid Res 54: 1744-1760

Morgenstern J, Fleming T, Kliemank E, Brune M, Nawroth P, Fischer A (2021) Quantification of All-Trans Retinoic Acid by Liquid Chromatography-Tandem Mass Spectrometry and Association with Lipid Profile in Patients with Type 2 Diabetes. Metabolites 11: 60

O'Byrne S, Blaner WS (2013) Retinol and retinyl esters: biochemistry and physiology. J Lipid Res 54: 1731-1743

Rossant J, Zirngibl R, Cado D, Shago M, Giguère V (1991) Expression of a retinoic acid response element-hsplacZ transgene defines specific domains of transcriptional activity during mouse embryogenesis. Genes Dev 5: 1333-1344

Shannon SR, Moise AR, Trainor PA (2017) New insights and changing paradigms in the regulation of vitamin A metabolism in development. Wiley Interdiscip Rev Dev Biol 6: 10.1002/wdev.1264

Solomin L, Johansson CB, Zetterström RH, Bissonnette RP, Heyman RA, Olson L, Lendahl U, Frisén J, Perlmann T (1998) Retinoid-X receptor signalling in the developing spinal cord. Nature 395: 398-402

Stevison F, Hogarth CA, Tripathy S, Kent T, Isoherranen N (2017) Inhibition of the all-trans Retinoic Acid ( at RA) Hydroxylases CYP26A1 and CYP26B1 Results in Dynamic, Tissue-Specific Changes in Endogenous at RA Signaling. Drug Metab Dispos 45

Stoppie P, Borgers M, Borghgraef P, Dillen L, Goossens J, Sanz G, Szel G, Van Hove C, Van Nyen G, Nobels G, Vanden Bossche H, Venet M, Willemsens G, Van Wauwe J (2000) R115866 inhibits all-trans-retinoic acid metabolism and exerts retinoidal effects in rodents. J Pharmacol Exp Ther 293: 304-312

Topletz AR, Tripathy S, Foti RS, Shimshoni JA, Nelson WL, Isoherranen N (2015) Induction of CYP26A1 by metabolites of retinoic acid: evidence that CYP26A1 is an important enzyme in the elimination of active retinoids. Mol Pharmacol 87: 430-441