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Neural crest related gene transcript regulation by valproic acid analogues in the cardiac embryonic stem cell test.

Authors
  • Mennen, R H Gina1
  • Pennings, J L A Jeroen2
  • Piersma, A H Aldert3
  • 1 Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. Electronic address: [email protected] , (Netherlands)
  • 2 Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. , (Netherlands)
  • 3 Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Institute for Risk Assessment Sciences (IRAS), Utrecht University, the Netherlands. , (Netherlands)
Type
Published Article
Journal
Reproductive toxicology (Elmsford, N.Y.)
Publication Date
Dec 01, 2019
Volume
90
Pages
44–52
Identifiers
DOI: 10.1016/j.reprotox.2019.08.013
PMID: 31445079
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

In vivo, neural crest (NC) cells contribute critically to heart formation. The embryonic stem cells in the cardiac Embryonic Stem cell Test (ESTc) differentiate into a heterogeneous cell population including non-cardiomyocyte cells. The use of molecular biomarkers from different mechanistic pathways can refine quantitative embryotoxicity assessment. Gene expression levels representing different signalling pathways that could relate to beating cardiomyocyte formation were analysed at different time-points. Immunocytochemistry showed NC cells were present in the ESTc and RT-qPCR showed upregulation of NC related gene expression levels in a time-dependent manner. NC related genes were sensitive to VPA and its analogues 2-ethylhexanoic acid (EHA) and 2-ethylhexanol (EHOL) and indicated VPA as the most potent one. STITCH ('search tool for interactions of chemicals') analysis showed relationships between the examined signalling pathways and suggested additional candidate marker genes. Biomarkers from dedicated mechanistic pathways, e.g. NC differentiation, provide promising tools for monitoring specific effects in ESTc. Copyright © 2019 Elsevier Inc. All rights reserved.

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