Journal
CHEMOSPHERE
Volume 304, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.chemosphere.2022.135298
Keywords
Developmental neurotoxicity; Human stem cells; Embryonic stem cells; Nervous system; In vitro; Toxicogenomics
Categories
Funding
- Dutch NGO Stichting Proefdiervrij
- Dutch Ministry of Agriculture, Nature and Food Quality
- Dutch Ministry of Health, Welfare and Sports
- European Union [874583]
Ask authors/readers for more resources
There is an increasing recognition of the limitations of using animals for compound-induced developmental neurotoxicity (DNT) testing. Human stem cell-based models, such as the human neural progenitor test (hNPT), play a pivotal role in studying DNT as they can replicate relevant processes in human brain development. This study characterized the differentiation of neural progenitor cells over time and identified neurodevelopmental processes sensitive to compound exposure using transcriptomics.
There is an increased awareness that the use of animals for compound-induced developmental neurotoxicity (DNT) testing has limitations. Animal-free innovations, especially the ones based on human stem cell-based models are pivotal in studying DNT since they can mimic processes relevant to human brain development. Here we present the human neural progenitor test (hNPT), a 10-day protocol in which neural progenitor cells differentiate into a neuron-astrocyte co-culture. The study aimed to characterise differentiation over time and to find neurodevelopmental processes sensitive to compound exposure using transcriptomics. 3992 genes regulated in unexposed control cultures (p <= 0.001, log2FC >= 1) showed Gene Ontology (GO-) term enrichment for neuronal and glial differentiation, neurite extension, synaptogenesis, and synaptic transmission. Exposure to known or suspected DNT compounds (acrylamide, chlorpyrifos, fluoxetine, methyl mercury, or valproic acid) at concentrations resulting in 95% cell viability each regulated unique combinations of GO-terms relating to neural progenitor proliferation, neuronal and glial differentiation, axon development, synaptogenesis, synaptic transmission, and apoptosis. Investigation of the GO-terms 'neuron apoptotic process' and 'axon development' revealed common genes that were responsive across compounds, and might be used as biomarkers for DNT. The GO-term 'synaptic signalling', on the contrary, whilst also responsive to all compounds tested, showed little overlap in gene expression regulation patterns between the conditions. This GO-term may articulate compound specific effects that may be relevant for revealing differences in mechanism of toxicity. Given its focus on neural progenitor cell to mature multilineage neuronal cell maturation and its detailed molecular readout based on gene expression analysis, hNPT might have added value as a tool for neurodevelopmental toxicity testing in vitro. Further assessment of DNT-specific biomarkers that represent these processes needs further studies.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available