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Event: 1881

Key Event Title

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

Decreased all-trans retinoic acid (atRA) 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
decreased, atRA concentration
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Biological Context

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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
Inhibition of ALDH1A leading to reduced fertility, female KeyEvent Terje Svingen (send email) Under development: Not open for comment. Do not cite Under Development
RALDH2 and cardiovascular developmental defects KeyEvent Gina Mennen (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 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
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI
human Homo sapiens High NCBI
Vertebrates Vertebrates Moderate NCBI

Life Stages

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

All-trans retinoic acid (atRA) is the active form of vitamin A/all-trans retinol and is involved in regulating a large number of developmental processes (Bushue & Wan, 2010a; Ghyselinck & Duester, 2019). Although 9-cis RA and 13-cis RA are other metabolic derivatives of vitamin A, atRA is generally considered the primary active metabolite during development, mainly acting as a short-range paracrine signaling molecule (Cunningham & Duester, 2015). atRA exerts dose-dependent effects on morphogenesis, so disruption to atRA concentrations during development can lead to malformations in numerous tissues and organs. During development the spatiotemporal regulation of atRA concentrations in target tissues is tightly controlled by a balance of synthesis and degradation enzymes (Kedishvili, 2013).

Cellular atRA synthesis starts by oxidation of vitamin A to retinaldehyde (RAL) by retinol dehydrogenase-10 (RDH10). RAL is then irreversibly converted to atRA by RAL dehydrogenases (ALDH1A1, ALD1A2, or ALDH1A3). To maintain appropriate retinoid levels in tissues, RAL can be converted back to retinol by enzymatic reactions; further retinoid levels can be controlled by enzymatic degradation of atRA by the cytochrome P450 enzymes CYP26A1, CYP26B1, or CYP26C1, which are differentially expressed throughout the mammalian body (Isoherranen & Zhong, 2019; Shimozono et al, 2013). Inhibition/disruption of any of the enzymes of the atRA synthesis pathway, or increased expression of the atRA degradation enzymes can lead to decreased concentrations of atRA in target cells (Kedishvili, 2013).

The atRA functions as a ligand for the nuclear retinoic acid receptors (RARs), which form heterodimers with the retinoid X receptors (RXRs); the atRA:RAR:RXR complex then binds to retinoic acid response elements (RAREs) upstream of target genes, leading to activation or repression of gene expression in target cells (Chambon, 1996; le Maire et al, 2019). The type and number of RAR/RXRs differ between evolutionary distant animals, but functionally they are all involved in the regulation of development (Gutierrez-Mazariegos et al, 2014).

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

Direct measurements of atRA in serum (humans, animals) can be performed by various chromatographic methods (Gundersen, 2006), including high performance liquid chromatography (HPLC) or liquid chromatography-tandem mass spectrometry (LC-MS) (Morgenstern et al, 2021).

Indirect measurements in cells and animal models can be performed with reporter assays utilizing RAR-RXR-RARE or RXR-RXR-RARE promoter elements, which are activated by atRA, 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), reporter cell lines (Wagner et al, 1992) and transient transfection of constructs for in vitro cell-based assays (Chassot et al, 2020).

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 system is highly conserved across animal species (Bushue & Wan, 2010b; Rhinn & Dollé, 2012). atRA acts as a ligand for the nuclear retinoic acid (RAR) receptors, which upon activation regulate gene transcription in target cells. The type and number of RARs differ between evolutionary distant animals, but functionally they are all involved in the regulation of development.   

References

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

Arnold SLM, Kent T, Hogarth CA, Griswold MD, Amory JK, Isoherranen N (2015) Pharmacological inhibition of ALDH1A in mice decreases all-trans retinoic acid concentrations in a tissue specific manner. Biochem Pharmacol 95: 177-192

Bushue N, Wan YJ (2010a) Retinoid pathway and cancer therapeutics. Adv Drug Deliv Rev 62: 1285-1298

Bushue N, Wan YJY (2010b) Retinoid pathway and cancer therapeutics. Adv Drug Deliv Rev 62: 1285-1298

Carlsen H, Ebihara K, Kuwata NH, Kuwata K, Aydemir G, Ruhl R, Blomhoff R (2021) A transgenic reporter mouse model for in vivo assessment of retinoic acid receptor transcriptional activation. Int J Vitam Nutr Res: 1-13

Chambon P (1996) A decade of molecular biology of retinoic acid receptors. FASEB J 10: 940-954

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

Deltour L, Ang HL, Duester G (1996) Ethanol inhibition of retinoic acid synthesis as a potential mechanism for fetal alcohol syndrome. FASEB J 10: 1050-1057

Ghyselinck NB, Duester G (2019) Retinoic acid signaling pathways. Development 146

Gundersen TE (2006) Methods for detecting and identifying retinoids in tissue. J Neurobiol 66: 631-644

Gutierrez-Mazariegos J, Schubert M, Laudet V (2014) Evolution of retinoic acid receptors and retinoic acid signaling. Subcell Biochem 70: 55-73

Isoherranen N, Zhong G (2019) Biochemical and physiological importance of the CYP26 retinoic acid hydroxylases. Pharmacol Ther 204: 107400

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

Le HGT, Dowling JE, Cameron DJ (2012) Early retinoic acid deprivation in developing zebrafish results in microphthalmia. Vis Neurosci 29: 219-228

le Maire A, Teyssier C, Balaguer P, Bourguet W, Germain P (2019) Regulation of RXR-RAR Heterodimers by RXR- and RAR-Specific Ligands and Their Combinations. Cells 8

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

Rhinn M, Dollé P (2012) Retinoic acid signalling during development. Development 139: 843-858

Rossant J, Zirngibl R, Cado D, Shago M, Giguere 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

Shimozono S, Iimura T, Kitaguchi T, Higashijima S, Miyawaki A (2013) Visualization of an endogenous retinoic acid gradient across embryonic development. Nature 496: 363-366

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

Wagner M, Han B, Jessell TM (1992) Regional differences in retinoid release from embryonic neural tissue detected by an in vitro reporter assay. Development 116: 55-66