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Event: 1880

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. 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. The short name should be less than 80 characters in length. More help
ALDH1A (RALDH), inhibition

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization
Molecular

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help
Cell term
eukaryotic cell

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. 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 Cataia Ives (send email) Under development: Not open for comment. Do not cite Under Development
RALDH2 and cardiovascular developmental defects MolecularInitiatingEvent Arthur Author (send email) Open for comment. Do not cite

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
All life stages High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. 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. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. 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

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. 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).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

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

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

The retinoid signaling system is highly conserved across distant animal species (Bushue & Wan, 2010; Rhinn & Dollé, 2012).

Evidence for Perturbation by Stressor

Overview for Molecular Initiating Event

When a specific MIE can be defined (i.e., the molecular target and nature of interaction is known), in addition to describing the biological state associated with the MIE, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to list stressors known to trigger the MIE and provide evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). Depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). Known stressors should be included in the MIE description, but it is not expected to include a comprehensive list. Rather initially, stressors identified will be exemplary and the stressor list will be expanded over time. For more information on MIE, please see pages 32-33 in the User Handbook.

Benomyl

Benomyl (methyl-[1-[(butylamino)carbonyl]-1H-benzimidazol-2-yl]carbamate, an azole fungicide, inhibits RALDH2 in vivo (IC50 = 24 µmol/kg) (Staub et al, 1998). Same inhibitory effect is not observed in vitro, suggesting that there is a metabolite (e.g. MBT) of benomyl that is most active in vivo (Koppaka et al, 2012; Staub et al, 1998).

WIN18,466

WIN18,446 inhibits ALDH1A2 enzyme activity in vitro (Chen et al, 2018; Paik et al, 2014)

(~13~C,~15~N_2_)Cyanamide

Cyanamide is a prodrug used as an alcohol-aversion agent  (Nagasawa et al, 1990; Shirota et al, 1987) that can inhibit RALDH2 activity.

Daidzein

Daidzin, an antoxidant isoflavone, is a potent RALDH2 inhibitor with IC50 = 80 nM (Lowe et al, 2008), as are several structural analogs (Koppaka et al, 2012).

Molinate

Molinate, a thiocarbamate derivative, is a pesticide previously used on rice. Both molinate and its metabolites can inhibit RALDH2 in vitro (Allen et al, 2010).

Pebulate

Pebulate, a thiocarbamate herbicides, can inhibit RALDH (Quistad et al, 1994).

Vernolate

Vernolate, a thiocarbamate herbicides, can inhibit RALDH (Quistad et al, 1994).

Butylate

Butylate, a thiocarbamate herbicides, can inhibit RALDH (Quistad et al, 1994).

Tri-allate

Tri-allate, a thiocarbamate herbicides, can inhibit RALDH (Quistad et al, 1994).

Cycloate

Cycloate a thiocarbamate herbicides, can inhibit RALDH (Quistad et al, 1994).

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). 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