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AOP: 434

Title

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
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
CYP26 inhibition leads to neural tube closure defects
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Handbook Version v2.0

Graphical Representation

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Authors

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Point of Contact

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Job Berkhout   (email point of contact)

Contributors

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  • Job Berkhout

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on April 29, 2023 16:03

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Abstract

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

Context

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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.

Strategy

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Summary of the AOP

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Events:

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)
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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

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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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References

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.