2-Methoxyethanol metabolism in pregnant CD-1 mice and embryos.
Upon oxidation to 2-methoxyacetic acid (2-MAA), 2-methoxyethanol (2-ME) causes malformations in all animal species that have been examined. Commonly, 2-MAA is thought to be the proximate toxicant. However, our previous studies with [1,2-14C]2-ME and the present data obtained with [1-14C]2-MAA, [2-14C]2-ME and [methoxy-14C]2-ME revealed that metabolism beyond 2-MAA occurs. Regardless of the 14C position, dams exhaled approximately 5% of the radioactivity administered as a single teratogenic oral dose (3.3 mmol/kg on Gestation Day [gd] 11) as 14CO2. With all isotopic variants urine contained 70-80% of the dose within 24 hr after administration and 13-18% in the next 24 hr. Three labeled products were resolved using HPLC: an unidentified Peak A (12-18% of dose), 2-MAA (approximately 50%), and the glycine conjugate of 2-MAA (approximately 25%). Short-term (4 hr) whole embryo culture on gd 11 with 3 mM 2-MAA and a tracer dose of [1-14C]2-MAA, [2-14C]2-MAA, or [methoxy-14C]2-MAA showed that 14CO2 evolved from the former two substrates, while there was none detectable from the latter. The data indicate that dams metabolized [methoxy-14]2-MAA to 14CO2, while embryos apparently did not. The production of labeled CO2 from [2-14C]2-ME suggests that 2-methoxyacetyl approximately CoA (the precursor for amino acid conjugation with glycine) entered into the tricarboxylic acid (TCA) cycle. This interpretation is supported by the inhibition of 14CO2 evolution elicited by fluoroacetate (0.1 or 1.0 mM) and sodium acetate (5 mM). It is not yet clear whether entry of 2-methoxyacetyl approximately CoA as a "false substrate" in the TCA cycle is of significance for the embryotoxic effects of 2-ME/2MAA.
Mebus
C A
CA
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
Clarke
D O
DO
Stedman
D B
DB
Welsch
F
F
D000085:Acetates / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002250:Carbon Radioisotopes; D002952:Citric Acid Cycle; D004622:Embryo, Mammalian / Q000378:metabolism*; D005026:Ethylene Glycols / Q000378:metabolism* / Q000493:pharmacokinetics; D005260:Female; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*
D000085:Acetates; D002250:Carbon Radioisotopes; D005026:Ethylene Glycols; D002245:Carbon Dioxide; C005219:methyl cellosolve; C013598:methoxyacetic acid