Aop: 434


A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

CYP26 inhibition leading to disturbed dorsal lateral hinge point bending which causes neural tube closure defects

Short name
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CYP26 inhibition leads to neural tube closure defects

Graphical Representation

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Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Cataia Ives   (email point of contact)


Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Job Berkhout
  • Cataia Ives


Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
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Under development: Not open for comment. Do not cite
This AOP was last modified on July 16, 2022 18:37

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A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

ATRA gradients play critical roles in early embryonic cell differentiation, and are regulated in time and space throughout embryo development. In the neural tube ATRA as a differentiation inducer counteracts the activity of fibroblast growth factor (FGF) which stimulates cell proliferation. Opposite gradients of ATRA and FGF direct development along the rostro-caudal axis of the vertebrate embryo. It is the local balance between ATRA-producing retinol dehydrogenase families and ATRA-metabolizing cytochrome P450 family 26 (CYP26) enzyme families that determines local ATRA concentrations. This interaction is controlled in the somites through direct transcriptional repression of FGF by ATRA and FGF-induced expression of zinc finger proteins 1 and 3 (ZIC1 and ZIC3 respectively), which induce the expression of CYP26 enzymes (Heusinkveld et al. 2021).

Inhibition of CYP26 causes the local ATRA concentrations to rise, which reduces local FGF levels due to an increase in transcriptional repression of FGF by ATRA and causes a reduced expression of ZIC1 and ZIC3. The reduced amount of ZIC proteins result in a lower amount of noggin (NOG) in the neuroectoderm. Noggin (NOG) inhibits BMP binding to its receptor, which crucial for proper hinge formation In the DLHP (Heusinkveld et al. 2021).

In chick embryos was demonstrated that intermediate amounts of BMP signaling in the neural plate is required for proper hinge point size and location. Complete loss of BMP caused ectopic and exaggerated DLHPs to form. In contrast, an increase in BMP signaling results in protein recruitment that serve to stabilize junctional proteins, which represses apical constriction and prevents bending of the DLHPs (Eom et al. 2011, 2012, 2013). Absence of DLHPs caused by loss of NOG results in severe failure in closure of the neural tube, which was demonstrated in mice (Stottman et al. 2006).

AOP Development Strategy


Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Neural tube closure is a fundamental process in vertebrate brain and spinal cord development, in which the neural plate folds up along most of its length to form a tube. Folding of the neural plate occurs at specific locations through asymmetric changes in the shapes of cells such that their apical sides contract, generating hinge points of tissue bending. The initial bending of the neural plate is mediated by the medial hinge point cells (MHP), which are anchored to the notochord beneath them and form a hinge that establishes the neural groove at the dorsal midline. Shortly thereafter, the cells at the dorsolateral hinge points (DLHPs) undergo apical constriction, causing wedge-shaped cells that bend the neural folds, bringing them in contact with each other. The neural and surface ectoderm cells from one side fuse with their counterparts from the other side, which closes the neural tube.


Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

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Molecular Initiating Events (MIE)
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Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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Prototypical Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Known Modulating Factors

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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

Harm Heusinkveld et al. “An ontology for developmental processes and toxicities of neural tube closure”. In: Reproductive Toxicology 99 (Jan. 2021), pp. 160–167. doi: 10.1016/j.reprotox.2020.09.002.