
This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Aop: 449
Title
Ceramide synthase inhibition leading to neural tube defects
Short name
Graphical Representation
Point of Contact
Contributors
- Lola Bajard
- Agnes Aggy
Status
Author status | OECD status | OECD project | SAAOP status |
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Under development: Not open for comment. Do not cite |
This AOP was last modified on July 16, 2022 18:37
Revision dates for related pages
Page | Revision Date/Time |
---|---|
Inhibition of Ceramide Synthase | July 14, 2022 09:20 |
Reduced complex sphingolipids | July 14, 2022 09:22 |
Affected folate transporter | July 14, 2022 09:23 |
decreased folate uptake | July 14, 2022 09:23 |
Fumonisin B1 | July 14, 2022 09:19 |
Abstract
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. 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), and the key events leading from HDAC inhibition to NTDs are described in the AOP 275.
AOP Development Strategy
Context
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
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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 |
Relationships Between Two Key Events (Including MIEs and AOs)
Network View
Prototypical Stressors
Name |
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Fumonisin B1 |
Life Stage Applicability
Taxonomic Applicability
Sex Applicability
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
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) |
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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) |