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

Journal Article · Tue Jun 01 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.03.005· OSTI ID:21460169

Louisse, Jochem ^[1]; Yanqing, Bai ^[1]; Verwei, Miriam; Blaauboer, Bas J ^[2]

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1. Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen (Netherlands)
2. Institute for Risk Assessment Sciences (IRAS), Utrecht University, PO Box 80176, 3508 TD Utrecht (Netherlands)

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}) 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}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} 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 +}/H{sup +}-antiporter, corroborating an important role of the pH{sub i} in the embryotoxic mechanism of both compounds. Together, the results presented indicate that a decrease of the pH{sub i} may be the mechanism of embryotoxicity of the alkoxyacetic acid metabolites of the glycol ethers.

• OSTI ID: 21460169
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 245; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ALCOHOLS
ANIMAL CELLS
AZINES
CARBOXYLIC ACID ESTERS
CELL DIFFERENTIATION
EMBRYONIC CELLS
ESTERS
ETHERS
GLYCOLS
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
INHIBITION
METABOLITES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
PH VALUE
PYRIMIDINES
RETINOIC ACID
URACILS