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Key Event Title
Increased (ectopic) all-trans retinoic acid concentration
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|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 Do not cite|
Key Event Description
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
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).
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
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.
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