Aop: 449

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

Ceramide synthase inhibition leading to neural tube defects

Short name
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CerS leads to NTDs

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
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Authors

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

Lola Bajard1, Annick D. van den Brand2, Jochem Louisse3, Marcel J.B. Mengelers2, Alberto Mantovani4

1RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic

2Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands

3Wageningen Food Safety Research (WFSR), Wageningen, The Netherlands

4Istituto Superiore di Sanità (ISS), Rome, Italy

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
Lola Bajard   (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
  • Lola Bajard

Status

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Author status OECD status OECD project SAAOP status
Open for citation & comment
This AOP was last modified on July 21, 2022 04:37

Revision dates for related pages

Page Revision Date/Time
Inhibition of Ceramide Synthase July 19, 2022 06:16
Reduced complex sphingolipids July 19, 2022 06:29
Affected folate transporter July 14, 2022 09:23
decreased folate uptake July 14, 2022 09:23
Increased sphingolipid-1-phosphate July 19, 2022 05:43
Histone deacetylase inhibition July 14, 2022 16:18
Neural tube defects December 20, 2018 08:40
Inhibition CerS leads to Reduced complex sphingolipids July 20, 2022 04:14
Histone deacetylase inhibition leads to Neural tube defects July 19, 2022 05:47
Reduced complex sphingolipids leads to Affected folate transporter July 20, 2022 05:12
decrease folate leads to Neural tube defects July 19, 2022 05:50
Affected folate transporter leads to decrease folate July 19, 2022 05:46
Inhibition CerS leads to Increased S1-P July 19, 2022 05:46
Increased S1-P leads to Histone deacetylase inhibition July 19, 2022 05:47
Fumonisin B1 July 14, 2022 09:19

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

Defects in neural tube formation during early embryogenesis are congenital malformations that may lead to morbidity or lethality (Finnell et al., 2021; Isaković et al., 2022). The etiology of  neural tube defects (NTDs) is not fully understood, but many studies highlight the role of environmental factors, in addition to genetic risks (Finnell et al., 2021; Isaković et al., 2022). Higher incidence of NTDs was observed in regions where higher frequency of fumonisin FB1 in maize was also reported (Hendricks, 1999; Marasas et al., 2004; Moore et al., 1997). This circumstantial evidence suggests possible associations between FB1 exposure and NTDs, that are further supported by a case-control study in human and several animal studies (Gelineau-Van Waes et al., 2005; Marasas et al., 2004; Missmer et al., 2006; Voss et al., 2014). FB1 is a well established inhibitor of the ceramide synthase (CerS) (Wang et al., 1991), a central enzyme in sphingolipid metabolism. This AOP has therefore been developped to depict the key events leading from CerS inhibition and perturbations in sphingolipid metabolism to NTDs (van den Brand et al., 2022). It is largely based on the mode of action description in the EFSA Scientific opinion on fumonisins (EFSA et al., 2018) and proposes two routes. The first route involves effects on folate uptake - the role of folate in preventing NTDs is known and very well supported by many studies (Wahbeh and Manyama, 2021). The other route involves the inhibition of histone deacethylase (HDAC) - the key events leading from HDAC inhibition to NTDs are described in the AOP 275.

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

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

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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
Type Event ID Title Short name
MIE 2023 Inhibition of Ceramide Synthase Inhibition CerS
KE 2024 Reduced complex sphingolipids Reduced complex sphingolipids
KE 2025 Affected folate transporter Affected folate transporter
KE 2026 decreased folate uptake decrease folate
KE 2033 Increased sphingolipid-1-phosphate Increased S1-P
KE 1502 Histone deacetylase inhibition Histone deacetylase inhibition
AO 1561 Neural tube defects Neural tube defects

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

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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

Type

Title

Essentiality

Evidence

MIE

Inhibition of ceramide synthases (Cers)

KE

Reduced complex sphingolipids

Moderate

Ganglioside supplementation rescues FB1-induced decrease in folate concentrations and increased incidence of exencephaly, in one mouse strain (LM/Bc).

KE

Increase sphingolipid-1-phosphatase

KE

Affected folate transporter Folbp1

KE

Inhibition of histone deacetylase (HDAC)

KE

Decreased folate uptake

Moderate

Folate supplementation partially rescues FB1-induced NTDs in mice (Gelineau-van Waes, 2005) and mouse embryo culture, but not at the lowest FB1 dose (2uM) (Sadler, 2002)

Evidence Assessment

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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

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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