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Decrease of intracellular pH as possible mechanism of embryotoxicity of glycol ether alkoxyacetic acid metabolites

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Author: Louisse, J. · Bai, Y. · Verwei, M. · Sandt, J.J.M. van de · Blaauboer, B.J. · Rietjens, I.M.C.M.
Institution: TNO Kwaliteit van Leven
Source:Toxicology and Applied Pharmacology, 2, 245, 236-243
Identifier: 360819
Keywords: Biology · Biomedical Research · BALB/c-3T3 cells · Embryonic stem cells · Embryotoxicity · Glycol ethers · Intracellular pH · Mechanism · acetazolamide · acetic acid derivative · alkoxyacetic acid glycol ether derivative · amiloride · butoxyacetic acid · ethoxyacetic acid · fluorouracil · methoxyacetic acid · phenoxyacetic acid · retinoic acid · unclassified drug · valproic acid · acidification · animal cell · animal cell culture · article · cell differentiation · cell pH · cell strain 3T3 · controlled study · embryonic stem cell · embryotoxicity · metabolite · mouse · nonhuman · pH measurement · Acetazolamide · Acetic Acids · Animals · BALB 3T3 Cells · Cell Differentiation · Embryo, Mammalian · Embryonic Stem Cells · Ethylene Glycols · Glycolates · Hydrogen-Ion Concentration · Intracellular Fluid · Mice · Teratogens · Valproic Acid


Embryotoxicity of glycol ethers is caused by their alkoxyacetic acid metabolites, but the mechanism underlying the embryotoxicity of these acid metabolites is so far not known. The present study investigates a possible mechanism underlying the embryotoxicity of glycol ether alkoxyacetic acid metabolites using the methoxyacetic acid (MAA) metabolite of ethylene glycol monomethyl ether as the model compound. The results obtained demonstrate an MAA-induced decrease of the intracellular pH (pH<sub>i</sub>) of embryonic BALB/c-3T3 cells as well as of embryonic stem (ES)-D3 cells, at concentrations that affect ES-D3 cell differentiation. These results suggest a mechanism for MAA-mediated embryotoxicity similar to the mechanism of embryotoxicity of the drugs valproic acid and acetazolamide (ACZ), known to decrease the pH<sub>i</sub> in vivo, and therefore used as positive controls. The embryotoxic alkoxyacetic acid metabolites ethoxyacetic acid, butoxyacetic acid and phenoxyacetic acid also caused an intracellular acidification of BALB/c-3T3 cells at concentrations that are known to inhibit ES-D3 cell differentiation. Two other embryotoxic compounds, all-trans-retinoic acid and 5-fluorouracil, did not decrease the pH<sub>i</sub> of embryonic cells at concentrations that affect ES-D3 cell differentiation, pointing at a different mechanism of embryotoxicity of these compounds. MAA and ACZ induced a concentration-dependent inhibition of ES-D3 cell differentiation, which was enhanced by amiloride, an inhibitor of the Na<sup>+</sup>/H<sup>+</sup>-antiporter, corroborating an important role of the pH<sub>i</sub> in the embryotoxic mechanism of both compounds. Together, the results presented indicate that a decrease of the pH<sub>i</sub> may be the mechanism of embryotoxicity of the alkoxyacetic acid metabolites of the glycol ethers. © 2010 Elsevier Inc.