Expression classifiers for developmental toxicants

In its recent edition the Archives of Toxicology have published a transcriptome-based classifier that identifies developmental toxicants acting as histone deacetylase inhib-itors. The authors, Eugen Rempel and colleagues from Dortmund Technical University , demonstrate that based on only eight genes the gene expression pattern of developmental toxicants acting as histone deacety-lase inhibitors can be identified. They used a test system that recapitulates generation of neuroectoderm from pluripotent stem cells Exposure of the test cells for six days to six histone deacetylase inhibitors (HDACi) caused alterations in expression profiles that could be clearly differentiated from other compound classes, such as a heterogeneous group of 'mercurials'. Currently, classification and grouping represents a cutting-edge topic in toxicologi-To reach this goal in the field of developmental toxicity, stem cell based test systems have been developed that recapitu-late different phases of human development Using these systems it has been shown that three concentration ranges can be differentiated, namely tolerated concentrations where no gene expression changes occur, the teratogenic range which leads to deregulation of critical developmental genes and the cytotoxic concentration range where additional genes associated with cell death and catabolic metabolism are observed (Waldmann et al., 2014). Importantly , the 'teratogenic concentration range' in vitro overlapped with concentrations known to cause teratogenic effects in humans in vivo. A next challenge in test system development is to develop expression signatures which indicate that specific toxic mechanisms are active. In this respect the present work of Rempel et al., using a set of structurally not related compounds acting by a similar mechanism, represents an important proof of concept (Rempel et al., 2015). Next open questions to be addressed are whether the test systems correctly identify further classes of developmental compounds and differentiate them from compounds acting by unspecific toxic mechanisms or substances that preferentially cause other types of tox-icities. In the past and also presently developmental toxicity has mostly been tested in Although some first important steps have been achieved in this field of in vitro research there seems to be a long