
This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Aop: 275
Title
Histone deacetylase inhibition leads to neural tube defects
Short name
Graphical Representation
Contributors
- Marvin Martens
Status
Author status | OECD status | OECD project | SAAOP status |
---|---|---|---|
Under development: Not open for comment. Do not cite |
This AOP was last modified on December 20, 2018 08:33
Revision dates for related pages
Page | Revision Date/Time |
---|---|
Histone deacetylase inhibition | February 10, 2020 03:09 |
Histone acetylation, increase | February 10, 2020 03:15 |
Altered, Gene Expression | March 06, 2019 10:03 |
Altered differentiation | December 20, 2018 08:39 |
Neural tube defects | December 20, 2018 08:40 |
Histone deacetylase inhibition leads to Histone acetylation, increase | February 10, 2020 03:50 |
Histone acetylation, increase leads to Altered, Gene Expression | December 20, 2018 08:48 |
Altered, Gene Expression leads to Altered differentiation | December 20, 2018 08:53 |
Altered differentiation leads to Neural tube defects | December 20, 2018 09:00 |
Abstract
The expression and function of histone deacetylases (HDAC) are well known during embryonic development and especially plays a pivotal role in the development of the nervous system. HDAC inhibition during embryonic development has been correlated to several congenital malformations mainly affecting neurodevelopment. However, the kind of malformation strongly depends on the timing of disturbance, i.e. when during embryonic development the exposure occurred. This AOP concentrates on disturbances by HDAC inhibition during the first weeks of neurodevelopment, before or around the time point of neural tube closure. Therefore, this AOP suggests a mechanism how HDAC inhibitors could lead to the observed neural tube defects. It assumes that HDAC inhibition leads to an imbalance of histone modifications and eventually to altered gene expression. In the next KE altered gene expression may lead to a wrong differentiation of neuroectodermal cells that cannot close the neural tube anymore and therefore leads to neural tube closure defects. This AOP is linked to case study 2 that investigates the effects of VPA and its structural analogs the EU-ToxRisk DART (development and reproductive toxicology) test methods.
Background (optional)
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Sequence | Type | Event ID | Title | Short name |
---|
1 | MIE | 1502 | Histone deacetylase inhibition | Histone deacetylase inhibition |
2 | KE | 1503 | Histone acetylation, increase | Histone acetylation, increase |
3 | KE | 1239 | Altered, Gene Expression | Altered, Gene Expression |
4 | KE | 1560 | Altered differentiation | Altered differentiation |
5 | 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 Histone acetylation, increase | adjacent | Not Specified | Not Specified |
Histone acetylation, increase leads to Altered, Gene Expression | adjacent | Not Specified | Not Specified |
Altered, Gene Expression leads to Altered differentiation | adjacent | Not Specified | Not Specified |
Altered differentiation leads to Neural tube defects | adjacent | Not Specified | Not Specified |