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
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
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