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miRNA expression profiling in a human stem cell-based model as a tool for developmental neurotoxicity testing

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Abstract

The main aim of this study was to evaluate whether microRNA (miRNA) profiling could be a useful tool for in vitro developmental neurotoxicity (DNT) testing. Therefore, to identify the possible DNT biomarkers among miRNAs, we have studied the changes in miRNA expressions in a mixed neuronal/glial culture derived from carcinoma pluripotent stem cells (NT2 cell line) after exposure to methyl mercury chloride (MeHgCl) during the process of neuronal differentiation (2–36 days in vitro (DIV1)). The neuronal differentiation triggered by exposure to retinoic acid (RA) was characterized in the control culture by mRNA expression analysis of neuronal specific markers such as MAP2, NF-200, Tubulin βIII, MAPT-tau, synaptophysin as well as excitatory (NMDA, AMPA) and inhibitory (GABA) receptors. The results obtained from the miRNA expression analysis have identified the presence of a miRNA signature which is specific for neural differentiation in the control culture and another for the response to MeHgCl-induced toxicity. In differentiated neuronal control cultures, we observed the downregulation of the stemness phenotype-linked miR-302 cluster and the overexpression of several miRNAs specific for neuronal differentiation (e.g. let-7, miR-125b and miR-132). In the cultures exposed to MeHgCl (400 nM), we observed an overexpression of a signature composed of five miRNAs (miR-302b, miR-367, miR-372, miR-196b and miR-141) that are known to be involved in the regulation of developmental processes and cellular stress response mechanisms. Using gene ontology term and pathway enrichment analysis of the validated targets of the miRNAs deregulated by the toxic treatment, the possible effect of MeHgCl exposure on signalling pathways involved in axon guidance and learning and memory processes was revealed. The obtained data suggest that miRNA profiling could provide simplified functional evaluation of the toxicity pathways involved in developmental neurotoxicity in comparison with the transcriptomics studies.

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Abbreviations

AATK:

Apoptosis-associated tyrosine kinase

AB assay:

Alamar blue assay

CNS:

Central nervous system

DAVID:

Database for Annotation Visualization and Integrated Discovery

DIV:

Days in vitro

DNT:

Developmental neurotoxicity

EMT:

Epithelial–mesenchymal transition

ES:

Cell embryonic stem cell

GO term:

Gene ontology term

hESC:

Human embryonic stem cell

MeHgCl:

Methyl mercury chloride

miRNA:

MicroRNA

NT2 cell line:

NTERA-2 cell line

RA:

Retinoic acid

UTRs:

Untranslated regions

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Acknowledgments

M. Fabbri is a student of the PhD program in Biotechnology, School of Biological and Medical Sciences, University of Insubria (Italy).

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Authors and Affiliations

  1. Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra, Varese, Italy

    Giorgia Pallocca, Marco Fabbri, Maria Grazia Sacco, Laura Gribaldo, David Pamies, Incoronata Laurenza & Anna Bal-Price

  2. Department of Experimental and Clinical Medicine, University of Insubria, Varese, Italy

    Marco Fabbri

  3. ECVAM, IHCP, European Commission JRC, TP 580, Via Fermi 1, 21020, Ispra, Varese, Italy

    Anna Bal-Price

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  1. Giorgia Pallocca
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  2. Marco Fabbri
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  3. Maria Grazia Sacco
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  6. Incoronata Laurenza
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Correspondence to Anna Bal-Price.

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Pallocca, G., Fabbri, M., Sacco, M.G. et al. miRNA expression profiling in a human stem cell-based model as a tool for developmental neurotoxicity testing. Cell Biol Toxicol 29, 239–257 (2013). https://doi.org/10.1007/s10565-013-9250-5

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