Dose response analysis of monophthalates in the murine embryonic stem cell test assessed by cardiomyocyte differentiation and gene expression.
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.
Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. sjors.schulpen@rivm.nl
Sjors H W
SH
Schulpen
Joshua F
JF
Robinson
Jeroen L A
JL
Pennings
Dorien A M
DA
van Dartel
Aldert H
AH
Piersma
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D010795:Phthalic Acids / Q000633:toxicity*; D010968:Plasticizers / Q000633:toxicity*
D010795:Phthalic Acids; D010968:Plasticizers