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

Autor: Louisse, J., Bai, Y., Verwei, M., van de Sandt, J.J.M., Blaauboer, B.J., Rietjens, I.M.C.M., Risk Assessment of Toxic and Immunomodulatory Agents, Dep IRAS
Přispěvatelé: TNO Kwaliteit van Leven, Risk Assessment of Toxic and Immunomodulatory Agents, Dep IRAS
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Intracellular Fluid
Biomedical Research
BALB 3T3 Cells
amiloride
Metabolite
Developmental toxicity
Retinoic acid
animal cell
Acetates
Toxicology
fluorouracil
chemistry.chemical_compound
acidification
Mice
retinoic acid
phenoxyacetic acid
Glycol ethers
article
Cell Differentiation
Hydrogen-Ion Concentration
Amiloride
Intracellular pH
unclassified drug
stem-cell test
induced limb malformations
Teratogens
Biochemistry
ethoxyacetic acid
cell pH
Acetic Acids
acetic acid derivative
Ethylene Glycols
Mechanism
alkoxyacetic acid glycol ether derivative
methoxyacetic acid
medicine.drug
Embryonic stem cells
embryotoxicity
butoxyacetic acid
metabolite
Ether
in-vitro
valproic acid
BALB/c-3T3 cells
medicine
developmental toxicity
Animals
controlled study
Department of Agrotechnology and Food Sciences
cell strain 3T3
carbonic-anhydrase-ii
Biology
Toxicologie
Embryonic Stem Cells
mouse
VLAG
Pharmacology
monomethyl ether
nonhuman
Valproic Acid
pH measurement
animal cell culture
Embryo
Mammalian
embryonic stem cell
Glycolates
rats
Acetazolamide
Departement Agrotechnologie en Voedingswetenschappen
chemistry
Ethylene glycol
monoethyl ether
Zdroj: Toxicology and Applied Pharmacology, 2, 245, 236-243
Toxicology and Applied Pharmacology 245 (2010) 2
Toxicology and Applied Pharmacology, 245(2), 236. Academic Press Inc.
Toxicology and Applied Pharmacology, 245(2), 236-243
ISSN: 0041-008X
Popis: 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.
Databáze: OpenAIRE
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