Print Email Facebook Twitter Decrease of intracellular pH as possible mechanism of embryotoxicity of glycol ether alkoxyacetic acid metabolites Title Decrease of intracellular pH as possible mechanism of embryotoxicity of glycol ether alkoxyacetic acid metabolites Author Louisse, J. Bai, Y. Verwei, M. van de Sandt, J.J.M. Blaauboer, B.J. Rietjens, I.M.C.M. TNO Kwaliteit van Leven Publication year 2010 Abstract 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 (pHi) 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 pHi 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 pHi 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+/H+-antiporter, corroborating an important role of the pHi in the embryotoxic mechanism of both compounds. Together, the results presented indicate that a decrease of the pHi may be the mechanism of embryotoxicity of the alkoxyacetic acid metabolites of the glycol ethers. © 2010 Elsevier Inc. Subject BiologyBiomedical 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 To reference this document use: http://resolver.tudelft.nl/uuid:2a12b5b5-eb14-44c1-a686-472d34929f8e TNO identifier 360819 ISSN 0041-008X Source Toxicology and Applied Pharmacology, 245 (2), 236-243 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.