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Aop: 275

AOP Title

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Histone deacetylase inhibition leads to neural tube defects

Short name:

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HDAC inhibition leads to neural tube defects

Graphical Representation

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Click to download graphical representation template

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Authors

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Tanja Waldmann

Point of Contact

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Marvin Martens   (email point of contact)

Contributors

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  • Marvin Martens

Status

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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 Do not cite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

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Revision dates for related pages

Page Revision Date/Time
Histone deacetylase inhibition November 20, 2019 03:51
Histone acetylation, increase November 18, 2019 23:12
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 November 18, 2019 23:50
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

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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)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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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)

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Title Adjacency Evidence Quantitative Understanding
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

Network View

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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