TY - JOUR
T1 - Dose response analysis of monophthalates in the murine embryonic stem cell test assessed by cardiomyocyte differentiation and gene expression
AU - Schulpen, Sjors H. W.
AU - Robinson, Joshua F.
AU - Pennings, Jeroen L. A.
AU - van Dartel, Dorien A. M.
AU - Piersma, Aldert H.
PY - 2013/1
Y1 - 2013/1
N2 - 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.
AB - 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.
KW - Mouse embryonic stem cells
KW - Embryonic stem cell test
KW - Developmental toxicity
KW - Cardiomyocyte differentiation
KW - Phthalate monoesters
KW - Potency ranking
KW - Transcriptomics
U2 - 10.1016/j.reprotox.2012.07.002
DO - 10.1016/j.reprotox.2012.07.002
M3 - Article
C2 - 22813628
SN - 0890-6238
VL - 35
SP - 81
EP - 88
JO - Reproductive Toxicology
JF - Reproductive Toxicology
ER -