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Aop: 274

AOP Title

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Histone deacetylase inhibition leads to impeded craniofacial development

Short name:

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HDAC inhibition leads to impeded craniofacial development

Graphical Representation

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Click to download graphical representation template

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Authors

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Bjorn Koch, Annemarie Meijer, Herman Spaink, Thomas Braunbeck

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 Do not cite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 04:39

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Revision dates for related pages

Page Revision Date/Time
Histone deacetylase inhibition July 25, 2018 22:27
Neural crest cell migration, reduced December 20, 2018 04:10
Collagen production, reduced December 20, 2018 04:15
Facial cartilage structures are reduced in size and morphologically distorted December 20, 2018 04:16
Histone deacetylase inhibition leads to Reduced neural crest cell migration December 20, 2018 04:22
Histone deacetylase inhibition leads to Reduced collagen production December 20, 2018 04:33
Reduced neural crest cell migration leads to Reduced collagen production December 20, 2018 04:27
Reduced collagen production leads to Smaller and morphologically distorted facial cartilage structures December 20, 2018 04:30
Valproic acid December 20, 2018 04:35
Butyrate January 21, 2018 20:39
Trichostatin A January 21, 2018 20:39
Suberoylanilide hydroxamic acid December 20, 2018 04:36
MS-275 December 20, 2018 04:37
Apicidin December 20, 2018 04:37

Abstract

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Histone deacetylases (HDACs) regulate gene expression through modulating chromatin structure and are known to impact many aspects of development in animals. Several compounds have been found to inhibit the action of HDACs leading to various adverse outcomes. This AOP aims to describe the sequence of events by which HDAC inhibition leads to impeded craniofacial development.
The MIE is the inhibition, at early embryonic stages, of histone deacetylases. This leads to inhibition of cranial neural crest cell migration and inhibition of chondrocyte differentiation. The attenuation of chondrocyte differentiation reduces the production of collagen, a key structural component of cartilage, resulting in the reduced size and morphologically distorted facial cartilage features.
This AOP concerns very specific developmental effects of an MIE which has very broad gene regulatory implications. This means that the progression through KEs and AO are mainly applicable at early developmental stages prior to neural crest migration and chondrocyte differentiation.
The AOP is linked to case study 2, concerning the developmental and reproductive toxicity of valproic acid (VPA) and several structural homologs. One of the well-described developmental toxicity effects of fetal VPA exposure is craniofacial deformities.


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 1557 Neural crest cell migration, reduced Reduced neural crest cell migration
3 KE 1558 Collagen production, reduced Reduced collagen production
4 AO 1559 Facial cartilage structures are reduced in size and morphologically distorted Smaller and morphologically distorted facial cartilage structures

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Histone deacetylase inhibition leads to Reduced neural crest cell migration adjacent Not Specified Not Specified
Reduced neural crest cell migration leads to Reduced collagen production adjacent Not Specified Not Specified
Reduced collagen production leads to Smaller and morphologically distorted facial cartilage structures adjacent Not Specified Not Specified
Histone deacetylase inhibition leads to Reduced collagen production non-adjacent Not Specified Not Specified

Network View

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Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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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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