Potency ranking of valproic acid analogues as to inhibition of cardiac differentiation of embryonic stem cells in comparison to their in vivo embryotoxicity

E. de Jong; A.M. Doedée; M.A. Reis-Fernandes; H. Nau; A.H. Piersma

doi:10.1016/j.reprotox.2010.11.012

Potency ranking of valproic acid analogues as to inhibition of cardiac differentiation of embryonic stem cells in comparison to their in vivo embryotoxicity

E. de Jong, A.M. Doedée, M.A. Reis-Fernandes, H. Nau, A.H. Piersma

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Abstract

The embryonic stem cell test (EST) is one of the more promising and extensively studied tests in the field of developmental toxicology. We evaluated the effect of a series of structurally related valproic acid analogues on cardiomyocyte differentiation in the EST. The goal of the present study was to determine the applicability of the EST by potency ranking within this chemical class. Cardiomyocyte differentiation was evaluated by morphological scoring as well as by gene expression analysis of cardiac markers using RT-PCR. All VPA analogues tested inhibited cardiomyocyte differentiation, with the exception of (±)-2-ethyl-4-methyl pentanoic acid, which correlates to their known in vivo developmental toxicity. Effects were also evident on gene expression of cardiomyocyte differentiation-regulated genes, such as MHC and Nkx2.5. Overall, the present results indicate that the assay can be a valuable screening tool in potency ranking of structurally related compounds.

Original language	Undefined/Unknown
Pages (from-to)	375-382
Number of pages	8
Journal	Reproductive Toxicology
Volume	31
Issue number	4
DOIs	https://doi.org/10.1016/j.reprotox.2010.11.012
Publication status	Published - 2011

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10.1016/j.reprotox.2010.11.012

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title = "Potency ranking of valproic acid analogues as to inhibition of cardiac differentiation of embryonic stem cells in comparison to their in vivo embryotoxicity",

abstract = "The embryonic stem cell test (EST) is one of the more promising and extensively studied tests in the field of developmental toxicology. We evaluated the effect of a series of structurally related valproic acid analogues on cardiomyocyte differentiation in the EST. The goal of the present study was to determine the applicability of the EST by potency ranking within this chemical class. Cardiomyocyte differentiation was evaluated by morphological scoring as well as by gene expression analysis of cardiac markers using RT-PCR. All VPA analogues tested inhibited cardiomyocyte differentiation, with the exception of (±)-2-ethyl-4-methyl pentanoic acid, which correlates to their known in vivo developmental toxicity. Effects were also evident on gene expression of cardiomyocyte differentiation-regulated genes, such as MHC and Nkx2.5. Overall, the present results indicate that the assay can be a valuable screening tool in potency ranking of structurally related compounds.",

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T1 - Potency ranking of valproic acid analogues as to inhibition of cardiac differentiation of embryonic stem cells in comparison to their in vivo embryotoxicity

AU - de Jong, E.

AU - Doedée, A.M.

AU - Reis-Fernandes, M.A.

AU - Nau, H.

AU - Piersma, A.H.

PY - 2011

Y1 - 2011

N2 - The embryonic stem cell test (EST) is one of the more promising and extensively studied tests in the field of developmental toxicology. We evaluated the effect of a series of structurally related valproic acid analogues on cardiomyocyte differentiation in the EST. The goal of the present study was to determine the applicability of the EST by potency ranking within this chemical class. Cardiomyocyte differentiation was evaluated by morphological scoring as well as by gene expression analysis of cardiac markers using RT-PCR. All VPA analogues tested inhibited cardiomyocyte differentiation, with the exception of (±)-2-ethyl-4-methyl pentanoic acid, which correlates to their known in vivo developmental toxicity. Effects were also evident on gene expression of cardiomyocyte differentiation-regulated genes, such as MHC and Nkx2.5. Overall, the present results indicate that the assay can be a valuable screening tool in potency ranking of structurally related compounds.

AB - The embryonic stem cell test (EST) is one of the more promising and extensively studied tests in the field of developmental toxicology. We evaluated the effect of a series of structurally related valproic acid analogues on cardiomyocyte differentiation in the EST. The goal of the present study was to determine the applicability of the EST by potency ranking within this chemical class. Cardiomyocyte differentiation was evaluated by morphological scoring as well as by gene expression analysis of cardiac markers using RT-PCR. All VPA analogues tested inhibited cardiomyocyte differentiation, with the exception of (±)-2-ethyl-4-methyl pentanoic acid, which correlates to their known in vivo developmental toxicity. Effects were also evident on gene expression of cardiomyocyte differentiation-regulated genes, such as MHC and Nkx2.5. Overall, the present results indicate that the assay can be a valuable screening tool in potency ranking of structurally related compounds.

U2 - 10.1016/j.reprotox.2010.11.012

DO - 10.1016/j.reprotox.2010.11.012

M3 - Article

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