Dose effects on the excretion of urinary metabolites of 2-[1,2,methoxy-13C]methoxyethanol in rats and mice.
The administration of 2-methoxyethanol (2-ME) to pregnant rats, mice, or primates results in developmental toxicity. To assess the role of metabolism in the adverse response of 2-ME, carbon-13 NMR spectroscopy was used to examine, directly in the urine, metabolites produced after administering high (250 mg/kg) and low (25 mg/kg) doses of 2-[1,2,methoxy-13C]ME to pregnant CD-1 mice and male Fischer 344 rats. The high dose elicits teratogenic effects in mice and testicular toxicity in rats. The urinary disposition was also examined after dosing pregnant CD-1 mice with a developmentally toxic level of 2-ME together with serine or acetate (known attenuators of 2-ME embryotoxicity). Seven novel metabolites were found in rat urine, consistent with those assigned in our previous studies with mice. Metabolite composition was compared for the different dosing regimens. A lower percentage of metabolites derived after conversion of 2-ME to 2-methoxyacetic acid (2-MAA) was found following concurrent administration of 2-ME with acetate, D-serine, or L-serine. These differences are mainly attributed to higher levels of ethylene glycol and/or glycolic acid that arise for the 2-ME administrations with any of the attenuators. Acetate together with 2-ME also reduced the percentage of metabolites incorporated into intermediary metabolism. These data indicate that attenuators of 2-ME teratogenic effects may alter metabolism and distribution by decreasing the conversion of 2-ME to 2-MAA, decreasing the conversion of 2-MAA to a coenzyme A thioester (2-methoxyacetyl approximately CoA), altering the utilization of the coenzyme A thioester, and/or increasing the conversion of 2-ME to ethylene glycol and its further metabolism. These changes in metabolism may contribute to the attenuating effects of these agents on 2-ME.
Sumner
S J
SJ
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.
Stedman
D B
DB
Cheng
S Y
SY
Welsch
F
F
Fennell
T R
TR
D000818:Animals; D002247:Carbon Isotopes; D004305:Dose-Response Relationship, Drug; D005026:Ethylene Glycols / Q000378:metabolism* / Q000652:urine; D005260:Female; D007166:Immunosuppressive Agents / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D013723:Teratogens / Q000378:metabolism*
D002247:Carbon Isotopes; D005026:Ethylene Glycols; D007166:Immunosuppressive Agents; D013723:Teratogens; C005219:methyl cellosolve