The possible role of one-carbon moieties in 2-methoxyethanol and 2-methoxyacetic acid-induced developmental toxicity

The ethylene glycol ether, 2-methoxyethanol (2-ME), is rapidly (less than 1 hr) oxidized to 2-methoxyacetic acid (2-MAA). Both agents are selectively embryotoxic and equipotent in causing digit malformations when given to CD-1 mice on gestation Day 11. Previous observations have shown that simple physiological compounds such as formate, acetate, glycine, and glucose ameliorate the embryotoxicity of 2-ME. A common link for all of the attenuating agents may be oxidation pathways involving tetrahydrofolic acid (THF) as a catalyst for one-carbon transfer into purine and pyrimidine bases. In the present study serine at 16.5 mmol/kg, which reacts directly with THF, was as effective as formate in almost completely eliminating digit malformations resulting from treatment with 2-ME. Unlike formate, serine was equally effective against 2-MAA-induced dysmorphogenesis and the attenuating efficacy remained unchanged when serine administration was delayed for up to 8 hr after 2-ME or 2-MAA exposure. The protective effect of sarcosine, which is an intermediate in a pathway leading from choline to glycine and a structural analog of 2-MAA, was also determined. Both concomitant (43, 16.5, or 3.3 mmol/kg) and delayed (16.5 mmol/kg at 6 hr) sarcosine administration resulted in significantly less 2-ME-induced paw dysmorphogenesis. In addition, acetate administration was delayed for increasing intervals after 2-ME to determine the time at which attenuation would no longer occur, and acetate was effective for as long as 12 hr after 2-ME. These results support our hypothesis that 2-MAA, which has a long biological half-life, may interfere with the availability of one-carbon units for incorporation into purine and pyrimidine bases. Alterations in availability of these precursors might be expected to affect DNA and/or RNA synthesis and thereby influence normal cellular proliferation and differentiation in the developing embryo.