Upstream eventAltered, Gene Expression
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Histone deacetylase inhibition leads to neural tube defects||adjacent||Not Specified||Not Specified|
Life Stage Applicability
Key Event Relationship Description
During early embryonic development of the nervous system-specific developmental genes need to be activated in a highly regulated and concerted manner. Genes need to be expressed (or silenced) at the right time and space. If this concerted regulation is disturbed this may lead to severe malformations in the later fetus. The type of malformation depends strongly on the timing of disturbance, i.e. during which developmental stage the disturbance happened. For the development of neural tube defects, especially neural tube closure, the disturbance must happen before neurulation at the stage when neuroepithelial cells arise. Therefore, for this AOP the imbalance of gene expression must occur before neural tube closure. However, compare AOP23 the inhibition of neural crest migration by HDAC inhibition happens later in embryonic development.
Evidence Supporting this KER
Gene expression during embryonic development is a highly regulated process. The genes need to be expressed and silenced at the right time and place. Therefore, if cells that are determined to differentiate into e.g. NEP wrongly express neural crest marker genes this may lead to a failure of neural tube closure. One reason for this effect is that these cells lose their epithelial character and undergo an epithelial mesenchymal transition as neural crest cells do (Park and Gumbiner, 2010). In summary, imbalanced gene expression may lead to the differentiation of the wrong cell type at the wrong time and space.
It was shown that HDAC inhibition changes the gene expression pattern during the differentiation of hESC towards NEP cells. Furthermore, the changed differentiation track points to a wrong differentiation towards neural crest cells (Balmer et al., 2014).
The differentiation track of hESC towards NEP is strongly disturbed in vitro by 6 different (structurally not related) HDAC inhibitors in a comparable manner (Rempel et al., 2015).
TSA treated chicken embryos showed a disturbed gene expression pattern of the posterior neural tube, that points to a wrong differentiation track towards neural crest cells (Murko et al., 2013).
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Balmer, N. V., Klima, S., Rempel, E. et al. (2014). From transient transcriptome responses to disturbed neurodevelopment: Role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol 88, 1451-1468. doi:10.1007/s00204-014-1279-6
Murko, C., Lagger, S., Steiner, M. et al. (2013). Histone deacetylase inhibitor trichostatin a induces neural tube defects and promotes neural crest specification in the chicken neural tube. Differentiation 85, 55-66. doi:10.1016/j.diff.2012.12.001
Park, K. S. and Gumbiner, B. M. (2010). Cadherin 6b induces bmp signaling and de-epithelialization during the epithelial mesenchymal transition of the neural crest. Development 137, 2691-2701. doi:10.1242/dev.050096
Rempel, E., Hoelting, L., Waldmann, T. et al. (2015). A transcriptome-based classifier to identify developmental toxicants by stem cell testing: Design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol 89, 1599-1618. doi:10.1007/s00204-015-1573-y