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

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
W1siziisijiwmjivmdevmdcvnwc2bjuzbjjwdf9dexaynmluagliaxrfqu9qx290agvyzm9ybwf0lnbuzyjdlfsiccisinrodw1iiiwintaweduwmcjdxq?sha=362300cb7bb5bea8

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

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
Job Berkhout   (email point of contact)

Contributors

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

Status

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
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on January 17, 2022 07:50

Revision dates for related pages

Page Revision Date/Time

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

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.

Strategy

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

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
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)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

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

Sex Applicability

The sex for which the AOP is known to be applicable. More help

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

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

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.