A novel human pluripotent stem cell-based assay to predict developmental toxicity

Karin Lauschke, Anna Kjerstine Rosenmai, Ina Meiser, Julia Christiane Neubauer, Katharina Schmidt, Mikkel Aabech Rasmussen, Bjørn Holst, Camilla Taxvig, Jenny Emnéus, Anne Marie Vinggaard*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

There is a great need for novel in vitro methods to predict human developmental toxicity to comply with the 3R principles and to improve human safety. Human-induced pluripotent stem cells (hiPSC) are ideal for the development of such methods, because they are easy to retrieve by conversion of adult somatic cells and can differentiate into most cell types of the body. Advanced three-dimensional (3D) cultures of these cells, so-called embryoid bodies (EBs), moreover mimic the early developing embryo. We took advantage of this to develop a novel human toxicity assay to predict chemically induced developmental toxicity, which we termed the PluriBeat assay. We employed three different hiPSC lines from male and female donors and a robust microtiter plate-based method to produce EBs. We differentiated the cells into cardiomyocytes and introduced a scoring system for a quantitative readout of the assay—cardiomyocyte contractions in the EBs observed on day 7. Finally, we tested the three compounds thalidomide (2.3–36 µM), valproic acid (25–300 µM), and epoxiconazole (1.3–20 µM) on beating and size of the EBs. We were able to detect the human-specific teratogenicity of thalidomide and found the rodent toxicant epoxiconazole as more potent than thalidomide in our assay. We conclude that the PluriBeat assay is a novel method for predicting chemicals’ adverse effects on embryonic development.

Original languageEnglish
JournalArchives of Toxicology
Volume94
Pages (from-to)3831–3846
ISSN0340-5761
DOIs
Publication statusPublished - 2020

Keywords

  • Developmental toxicity
  • Embryonic stem cell test
  • Epoxiconazole
  • Human-induced pluripotent stem cells
  • Thalidomide
  • Valproic acid

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