Decrease of intracellular pH as possible mechanism of embryotoxicity of glycol ether alkoxyacetic acid metabolites
article
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.
Topics
Biomedical ResearchBALB/c-3T3 cellsEmbryonic stem cellsEmbryotoxicityGlycol ethersIntracellular pHMechanismacetazolamideacetic acid derivativealkoxyacetic acid glycol ether derivativeamiloridebutoxyacetic acidethoxyacetic acidfluorouracilmethoxyacetic acidphenoxyacetic acidretinoic acidunclassified drugvalproic acidacidificationanimal cellanimal cell culturearticlecell differentiationcell pHcell strain 3T3controlled studyembryonic stem cellembryotoxicitymetabolitemousenonhumanpH measurementAcetazolamideAcetic AcidsAnimalsBALB 3T3 CellsCell DifferentiationEmbryo, MammalianEmbryonic Stem CellsEthylene GlycolsGlycolatesHydrogen-Ion ConcentrationIntracellular FluidMiceTeratogensValproic Acid
TNO Identifier
360819
ISSN
0041008X
Source
Toxicology and Applied Pharmacology, 245(2), pp. 236-243.
Pages
236-243
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