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AOP: 449
Title
Ceramide synthase inhibition leading to neural tube defects
Short name
Graphical Representation
Point of Contact
Contributors
- Lola Bajard
Coaches
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
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This AOP was last modified on April 29, 2023 16:03
Revision dates for related pages
Page | Revision Date/Time |
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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
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
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 |
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)
Title | Adjacency | Evidence | Quantitative Understanding |
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Histone deacetylase inhibition leads to Neural tube defects | non-adjacent | ||
decrease folate leads to Neural tube defects | non-adjacent | High |
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) |
||
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) |