Several simple physiological compounds attenuate the teratogenic effects of
2-methoxyethanol (2-ME) when coadministered with
2-ME to mice. The mechanism of this protective action, however, has not been elucidated. Alteration of the kinetics of
2-ME and its oxidation product
2-methoxyacetic acid (2-MAA), the putative ultimate toxicant, was considered. D-
Serine, the most efficacious attenuator, and
L-serine (both 16.5 mmol/kg po) were examined for their abilities to mitigate
2-ME teratogenicity and to alter the disposition of an oral or sc bolus dose of
2-ME (3.3 mmol/kg containing 6 microCi 2-[methoxy-14C]
ethanol) given to CD-1 mice on Gestation Day 11.
L-Serine reduced the incidence of malformed fetuses from greater than or equal to 72% to 26-28%, while only 18 and 9% of fetuses were affected after coadministration of D-
serine with sc and po
2-ME, respectively. Changes in the metabolism of orally administered 2-[14C]ME were specific to each enantiomer. D-
Serine reduced the amount of 2-methoxy-N-acetylglycine eliminated in the urine to 70-75% of values observed with
2-ME alone, and concurrently increased the amount of urinary 2-MAA.
L-Serine induced an initially higher rate of 14CO2 exhalation. Both enantiomers delayed gastrointestinal absorption of
2-ME, and significantly reduced 2-MAA levels in maternal plasma during the first hour after dosing. This resulted in a nonsignificant decrease (10-17%) in total embryonic exposure to 2-MAA. However, when
2-ME was injected sc, maternal plasma 2-ME/2-MAA pharmacokinetics were not affected by
serine. In addition, dosing with 2.3 and 1.3 mmol 2-ME/kg sc alone showed that the embryo 2-MAA exposure levels which cause malformations in less than or equal to 35% fetuses were considerably lower than those measured following
serine plus 3.3 mmol 2-ME/kg (po or sc). These data infer that
serine does not protect against 2-ME-induced teratogenicity by altering
2-ME pharmacokinetics and reducing 2-MAA levels in the embryo.