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Relative developmental toxicity of glycol ether alkoxy acid metabolites in the embryonic stem cell test as compared with the in vivo potency of their parent compounds

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Author: Jong, E. de · Louisse, J. · Verwei, M. · Blaauboer, B.J. · Sandt, J.J.M. van de · Woutersen, R.A. · Rietjens, I.M.C.M. · Piersma, A.H.
Type:article
Date:2009
Institution: TNO Kwaliteit van Leven
Source:Toxicological Sciences, 1, 110, 117-124
Identifier: 241606
doi: doi:10.1093/toxsci/kfp083
Keywords: Chemistry · Toxicology and Applied Pharmacology · Alternatives to animal testing · Developmental toxicology · Embryonic stem cells · Glycol ethers · butoxyacetic acid · ethoxyacetic acid · glycol ether alkoxy acid metabolite · methoxyacetic acid · phenoxyacetic acid · toxin · unclassified drug · animal cell · article · cell differentiation · chemical analysis · chemical structure · concentration response · controlled study · cytotoxicity test · developmental disorder · developmental toxicity · embryonic stem cell · embryonic stem cell test · embryotoxicity · heart muscle cell · in vivo study · mouse · nonhuman · sensitivity analysis · toxicokinetics · Animal Testing Alternatives · Animals · Biotransformation · Cell Differentiation · Cell Survival · Dose-Response Relationship, Drug · Embryonic Development · Embryonic Stem Cells · Glycols · Kinetics · Mice · Models, Statistical · Myocytes, Cardiac · Predictive Value of Tests · Reference Standards · Structure-Activity Relationship · Teratogens · Animalia

Abstract

The embryonic stem cell test (EST) has been proposed as an in vitro assay that might reduce animal experimentation in regulatory developmental toxicology. So far, evaluation of the EST was not performed using compounds within distinct chemical classes. Evaluation within a distinct class of chemically related compounds can define the usefulness of the assay for the chemical class tested. The aim of the present study was to evaluate the relative sensitivity of the EST for a selected series of homologous compounds and to compare the data to the relative developmental toxicity of the compounds in vivo. To this end a series of proximate developmentally toxic glycol ether alkoxy acid metabolites was tested in the EST. All glycol ether alkoxy acid metabolites tested showed a concentration-dependent inhibition of cardiomyocyte differentiation at noncytotoxic concentrations, with methoxyacetic acid as the most potent compound followed by ethoxyacetic acid, butoxyacetic acid, and phenoxyacetic acid, respectively. The potency ranking of the compounds in the EST corresponds with the available in vivo data. The relative differences between the potencies of the compounds appeared more pronounced in the in vivo studies than in the EST. A possible explanation for this discrepancy could be the difference in the kinetics of the compounds in vivo as compared with their in vitro kinetics. This study illustrates that the EST can be used to set priorities for developmental toxicity testing within classes of related compounds. © The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.