Dose response analysis of monophthalates in the murine embryonic stem cell test assessed by cardiomyocyte differentiation and gene expression

Sjors H.W. Schulpen*, Joshua F. Robinson, Jeroen L.A. Pennings, Dorien A.M. van Dartel, Aldert H. Piersma

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

23 Citations (Scopus)

Abstract

The embryonic stem cell test (EST) is based on compound-induced inhibition of cardiomyocyte differentiation of pluripotent stem cells. We examined the use of transcriptomics to assess concentration-effect relationships and performed potency ranking within a chemical class. Three embryotoxic phthalate monoesters, monobutyl phthalate (MBuP), monobenzyl phthalate (MBzP) and mono-(2-ethylhexyl) phthalate (MEHP) and the non-embryotoxic monomethyl phthalate (MMP) were studied for their effects on gene expression. Effects on gene expression were observed at concentrations that did not inhibit cardiomyocyte differentiation or induce cytotoxicity. The embryotoxic phthalate monoesters altered the expression of 668 commonly expressed genes in a concentration-dependent fashion. The same potency ranking was observed for morphology and gene expression (MEHP > MBzP > MBuP > MMP). These results indicate that integrating transcriptomics provides a sensitive method to measure the dose-dependent effects of phthalate monoester exposure and enables potency ranking based on a common mode of action within a class of compounds. Transcriptomic approaches may improve the applicability of the EST, in terms of sensitivity and specificity.

Original languageEnglish
Pages (from-to)81-88
Number of pages8
JournalReproductive Toxicology
Volume35
Issue number1
DOIs
Publication statusPublished - Jan 2013

Keywords

  • Cardiomyocyte differentiation
  • Developmental toxicity
  • Embryonic stem cell test
  • Mouse embryonic stem cells
  • Phthalate monoesters
  • Potency ranking
  • Transcriptomics

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