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Event: 1880

Key Event Title

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

Inhibition of ALDH1A (RALDH)

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
ALDH1A (RALDH), inhibition
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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
Molecular

Cell 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
Cell term
eukaryotic cell

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 MolecularInitiatingEvent Terje Svingen (send email) Under development: Not open for comment. Do not cite Under Development
RALDH2 and cardiovascular developmental defects MolecularInitiatingEvent 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
human Homo sapiens Moderate NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus Moderate NCBI

Life Stages

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

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

The oxidation of retinal to all-trans retinoic acid (atRA) is an irreversible reaction carried out by retinaldehyde dehydrogenases ALDH1A1, ALDH1A2, ALDH1A3 (RALDH1, RALDH2, RALDH3). ALDH1A2 is responsible for the second step of the metabolism of vitamin A into atRA (Chatzi et al, 2013; Shannon et al, 2017).The role of that reaction is to maintain atRA concentrations, with ALDH1A2 being most active during early development (Koppaka et al, 2012; Shannon et al, 2017). Raldh2-deficient mice exhibit severe developmental defects due to loss of atRA, but the phenotype is rescued by administration of exogenous RA (Niederreither et al, 1999). Thus, ALDH1A2 activity is essential for atRA-dependent developmental processes.

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

There are no OECD validated assays for measuring ALDH1A2 inhibition.

ALDH1A2 mRNA and protein levels can be measured using various probes, antibodies as well as ELISA kits that are commercially available.

Enzyme activity can be assessed in assays including measurement of atRA formation (Arnold et al, 2015) or NADH formation (Harper et al, 2018; Schindler et al, 1998) and several ALDH activity assay kits using different approaches are commercially available; e.g. AldeflourTM kit (Flahaut et al, 2016).

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 distant animal species (Bushue & Wan, 2010; Rhinn & Dollé, 2012).

References

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

Allen EMG, Anderson DGR, Florang VR, Khanna M, Hurley TD, Doorn JA (2010) Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase 2: implications for the mechanism of enzyme inhibition. Chem Res Toxicol 23: 1843-1850

Arnold SL, Kent T, Hogarth CA, Schlatt S, Prasad B, Haenisch M, T. W, Muller CH, Griswold MD, Amory JK, Isoherranen N (2015) Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations. J Lipid Res 56: 342-357

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

Chatzi C, Cunningham TJ, Duester G (2013) Investigation of retinoic acid function during embryonic brain development using retinaldehyde-rescued Rdh10 knockout mice. Dev Dyn 242: 1056-1065

Chen Y, Zhu JY, Hong KH, Mikles DC, Georg GI, Goldstein AS, Amory JK, Schönbrunn E (2018) Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors. ACS Chem Biol 13: 582-590

Flahaut M, Jauquier N, Nardou K, Bourloud KB, Joseph JM, Barras D, Widmann C, Gross N, Renella R, Mühlethaler-Mottet A (2016) Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma. BMC Cancer 16: 781

Harper AR, Le AT, Mather T, Burgett A, Berry W, Summers JA (2018) Design, synthesis, and ex vivo evaluation of a selective inhibitor for retinaldehyde dehydrogenase enzymes. Bioorg Med Chem 26: 5766-5779

Koppaka V, Thompson DC, Chen Y, Ellermann M, Nicolaou KC, Juvonen RO, Petersen D, Deitrich RA, Hurley TD, Vasilio V (2012) Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. Pharmacol Rev 64: 520-539

Lowe ED, Gao GY, Johnson LN, Keung WM (2008) Structure of daidzin, a naturally occurring anti-alcohol-addiction agent, in complex with human mitochondrial aldehyde dehydrogenase. J Med Chem 51: 4482-4487

Nagasawa HT, DeMaster EG, Redfern B, Shirota FN, Goon DJ (1990) Evidence for nitroxyl in the catalase-mediated bioactivation of the alcohol deterrent agent cyanamide. J Med Chem 33: 3120-3122

Niederreither K, Subbarayan V, Dollé P, Chambon P (1999) Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet 21: 444-448

Paik J, Haenisch M, Muller CH, Goldstein AS, Arnold S, Isoherranen N, Brabb T, Treuting PM, Amory JK (2014) Inhibition of retinoic acid biosynthesis by the bisdichloroacetyldiamine WIN 18,446 markedly suppresses spermatogenesis and alters retinoid metabolism in mice. J Biol Chem 289: 15104-15117

Quistad GB, Sparks SE, Casida JE (1994) Aldehyde dehydrogenase of mice inhibited by thiocarbamate herbicides. Life Sci 55: 1537-1544

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

Schindler JF, Berst KB, Plapp BV (1998) Inhibition of human alcohol dehydrogenases by formamides. J Med Chem 41: 1696-1701

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

Shirota FN, DeMaster EG, Nagasawa HT (1987) Cyanide is a product of the catalase-mediated oxidation of the alcohol deterrent agent, cyanamide. Toxicol Lett 37: 7-12

Staub RE, Quistad GB, Casida JE (1998) Mechanism for benomyl action as a mitochondrial aldehyde dehydrogenase inhibitor in mice. Chem Res Toxicol 11: 535-543