Abstract
Methoxyacetic acid (MAA), a teratogenic toxin, is the major metabolite of ethylene glycol monomethyl ether (EGME, also referred to as 2-methoxyethanol, 2-ME). MAA causes a wide range of toxic effects in laboratory animals including reproductive and developmental toxicity, as well as hematotoxicity, by mechanisms that are not clear. In this study, we employed electron paramagnetic resonance (EPR) spin-labeling techniques in conjunction with spin labels specific for cytoskeletal proteins, bilayer lipids, cell-surface sialic acid, or cell-surface galactose and N-acetylgalactosamine residues of human erythrocyte membranes in order to gain insight into the mechanism of MAA toxicity. The major findings are: (1) MAA significantly increases the protein-protein interactions of skeletal proteins in a concentration-dependent manner (P < 0.001), while 2-ME has no effect (at even a 2.5-fold higher concentration). (2) Addition of MAA leads to significant increase in the rotational motion of spinlabeled terminal galactose and N-acetylgalactosamine residues (2.0 mM MAA, 38% decrease of the apparent rotational time τa, P < 0.01). (3) The rotational motion of spinlabeled sialic acid, 70% of which is on the major transmembrane sialoglycoprotein (glycophorin A or PAS 1), was not affected by MAA treatment. (4) MAA has no effect on the lipid bilayer fluidity, since no change in the motion of a lipid bilayer specific spin label (5-NS) in the erythrocyte membrane was observed. These results suggest that MAA may lead to teratologic toxicity by interacting not with lipid components but with certain, perhaps specific, protein components, i.e., transport proteins, cytoskeleton proteins or neurotransmitter receptors.
Original language | English |
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Pages (from-to) | 131-148 |
Number of pages | 18 |
Journal | Toxicology |
Volume | 83 |
Issue number | 1-3 |
DOIs | |
State | Published - Oct 25 1993 |
Bibliographical note
Funding Information:This work was supported in part by grants from NSF (EHR-9 108764) and NIH (AG-10836).
Funding
This work was supported in part by grants from NSF (EHR-9 108764) and NIH (AG-10836).
Funders | Funder number |
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U.S. Department of Energy Chinese Academy of Sciences Guangzhou Municipal Science and Technology Project Oak Ridge National Laboratory Extreme Science and Engineering Discovery Environment National Science Foundation National Energy Research Scientific Computing Center National Natural Science Foundation of China | EHR-9 108764 |
U.S. Department of Energy Chinese Academy of Sciences Guangzhou Municipal Science and Technology Project Oak Ridge National Laboratory Extreme Science and Engineering Discovery Environment National Science Foundation National Energy Research Scientific Computing Center National Natural Science Foundation of China | |
National Institutes of Health (NIH) | |
National Institute on Aging | P01AG010836 |
National Institute on Aging |
Keywords
- Cell-surface carbohydrates
- Cytoskeletal proteins
- EPR spin labeling
- Ethylene glycol monomethyl ether
- Methoxyacetic acid
- Teratology
ASJC Scopus subject areas
- Toxicology