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Key Event: 2419

Key Event Title

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

Decreased, Retinoic Acid Receptor Activation

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
Decreased, RAR activation
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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

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
Decreased ALDH1A activity leading to decreased fertility KeyEvent Terje Svingen (send email) Under development: Not open for comment. Do not cite Under Development

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

Life Stages

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

Sex Applicability

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

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

This KE refers to decreased activation of the retinoic acid receptor (RAR) occurring in complex biological systems in vivo, such as tissues and organs. Thus, decreased activation of RAR is here distinguished from direct antagonism of the RAR and from reduced availability or synthesis of its endogenous ligand, all‑trans retinoic acid (atRA). Instead, it is downstream of these events. This KE occurs in tissues and organs in vivo, and it is not a tissue‑specific event.

RARs are ligand-activated receptors regulated by retinoid ligands, particularly atRA. They mediate several crucial biological processes (e.g., morphogenesis, cell growth regulation, apoptosis, homeostasis etc.). Perturbations of RAR signaling are associated with adverse developmental and physiological outcomes. RARs are members of the nuclear hormone receptor superfamily. There are three major subtypes: RARα, RARβ, and RARγ. RARα may be broadly expressed, while RARβ is related to neurogenesis and development of epithelial tissues, and RARγ in bone and cartilage development. There are different isoforms for each subtypes arising from alternative splicing (RARα1-2, RARβ1–4, and RARγ1-2) (Germain et al, 2006, Petkovich et al, 2022).

The canonical signaling mechanism of RARs involves heterodimerization with retinoid X receptors (RXRs), DNA binding to retinoic acid response elements (RAREs), and ligand‑dependent regulation of transcription. RARs heterodimerize with RXRs, with the RAR-RXR complex binding to RAREs in promoters of target genes. In the absence of ligand, RAR–RXR complexes are often associated with co‑repressor proteins (e.g., NCoR and SMRT), maintaining transcriptional repression. Upon ligand binding with atRA or other retinoids, the RAR–RXR heterodimers undergo conformational changes that promote dissociation of co‑repressors and recruitment of co‑activator proteins (e.g., SRC1-3), leading to chromatin remodeling and transcriptional activation of several target genes (Germain et al, 2006, Petkovich et al, 2022, Rhinn et al, 2012, Gutierrez et al, 2014).

Decreased RAR activation can result from direct antagonism of RAR or from reduced availability of atRA, its main endogenous ligand. RAR antagonists act through the impairment of ligand‑dependent receptor activation, while decreased atRA levels (e.g., due to altered synthesis) acts through the reduction of the available ligand that can bind the receptor and lead to transcriptional activation. Both mechanisms reduce RAR‑dependent gene expression and disrupt retinoid‑regulated biological processes (Germain et al, 2006, Altucci et al, 2007, Stevison et al, 2017, Kedishvili et al, 2013).

Non‑canonical RAR signaling mechanisms, independent of direct transcriptional regulation, have been described in some experimental systems. However, their conservation and quantitative contribution to adverse outcomes in vivo remain unclear (Al Tanoury et al 2013). Accordingly, this KE addresses decreased RAR activation via the canonical, transcription‑dependent pathway.

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

This KE describes decreased RAR activation in vivo. However, currently there are no methods available for direct measurement of this KE. Hence, only indirect measurements are available by in vitro RAR and RAR-RXR transactivation assays (OECD Detailed review paper on the Retinoid System, 2021, OECD Validation report on a RAR transactivation method, 2025), as measured in upstream KEs. AOP developers are encouraged to add new methods to measure RAR activation levels in vivo whenever they become available.

Domain of Applicability

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

RARs are well-conserved throughout vertebrate evolution; therefore, this KE should be considered broadly applicable across vertebrate species. Regarding invertebrates, evidence for the presence of RARs has been reported within chordate phyla, including non-vertebrate chordates. However, multiple invertebrate lineages appear to have lost RAR genes. Although components of RA signaling have been described in some invertebrate species, it remains debated whether they possess a functional RA signaling pathway (Stevison et al, 2017). AOP developers are encouraged to add additional relevant knowledge to expand on the applicability to also include other vertebrates.

References

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

Al Tanoury Z, Piskunov A, Rochette-Egly C. Vitamin A and retinoid signaling: genomic and nongenomic effects. J Lipid Res. 2013;54(7):1761-1775. doi:10.1194/jlr.R030833

Altucci L, Leibowitz MD, Ogilvie KM, de Lera AR, Gronemeyer H. RAR and RXR modulation in cancer and metabolic disease. Nat Rev Drug Discov. 2007;6(10):793-810. doi:10.1038/nrd2397

Kedishvili NY. Enzymology of retinoic acid biosynthesis and degradation. J Lipid Res. 2013;54(7):1744-1760. doi:10.1194/jlr.R037028

Germain P, Chambon P, Eichele G, et al. International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol Rev. 2006;58(4):712-725. doi:10.1124/pr.58.4.4

Gutierrez-Mazariegos J, Schubert M, Laudet V. Evolution of retinoic acid receptors and retinoic acid signaling. Subcell Biochem. 2014;70:55-73. doi:10.1007/978-94-017-9050-5_4

Organisation for Economic Co-operation and Development (OECD). Detailed Review Paper on the Retinoid System. OECD Environment Directorate, Chemicals and Biotechnology Committee; 2021. Accessed April 23, 2026. https://www.oecd.org/en/publications/detailed-review-paper-on-the-retinoid-system_4fbb70a9-en.html

Organisation for Economic Co‑operation and Development (OECD). Peer Review of the Retinoic Acid Receptor Transactivation Method Validation: Validation Report. OECD; 2025. Accessed April 23, 2026. https://www.oecd.org/content/dam/oecd/en/events/2025/09/peer-review-of-the-retinoic-acid-receptor-transactivation-method-validation/validation-report-retinoic-acid-receptor-transactivation-method.pdf

Petkovich M, Chambon P. Retinoic acid receptors at 35 years. J Mol Endocrinol. 2022;69(4):T13-T24. Published 2022 Oct 11. doi:10.1530/JME-22-0097

Rhinn M, Dollé P. Retinoic acid signalling during development. Development. 2012;139(5):843-858. doi:10.1242/dev.065938

Stevison F, Hogarth C, Tripathy S, Kent T, Isoherranen N. Inhibition of the all-trans Retinoic Acid (atRA) Hydroxylases CYP26A1 and CYP26B1 Results in Dynamic, Tissue-Specific Changes in Endogenous atRA Signaling. Drug Metab Dispos. 2017;45(7):846-854. doi:10.1124/dmd.117.075341