Attenuation of 2-methoxyethanol and methoxyacetic acid-induced digit malformations in mice by simple physiological compounds: implications for the role of further metabolism of methoxyacetic acid in developmental toxicity

Abstract

The ethylene glycol ether 2-methoxyethanol (ME) and its oxidation product methoxyacetic acid (MAA) are selective embryotoxins and equipotent as inducers of digit malformations when given by gavage to pregnant Crl:CD-1 ICR BR mice on gestation day 11. Earlier observations showed that the teratogenic effects were attenuated by delayed administrations of ethanol given at a time when all ME is already converted to MAA. That outcome suggested that acetate from ethanol catabolism might compete with methoxy-acetate in biosynthetic reactions relevant to MAA-induced malformations. Furthermore, 14C derived from [1,2-14C]-ME or [1-14C]-MAA is incorporated into all macromolecular fractions of the embryo, and 14C is exhaled by the dam in 14CO2. Those data indicate that 14C derived from 14C-ME catabolism enters into many metabolic reactions. The present study examined acetate and other simple physiological compounds with close relationships to carbon and one-carbon moiety metabolic pathways for their ability to attenuate digit malformations upon concomitant dosing with ME. All of the agents examined reduced the teratogenic effect significantly with a potency rank order of formate much greater than acetate = glycine much greater than D-glucose. The common link for their efficacy may be the one-carbon moiety oxidation pathway that involves tetrahydrofolic acid as a catalyst of one-carbon transfer into purines and thymidylate. Carbon from all of the attenuators administered is incorporated into those bases and then into DNA. It appears as if methoxyacetate enters into biochemical reactions analogous to those of acetate. This speculation is supported by the metabolic fate of 14C from 14C-ME in dam and embryo. Based on the indirect evidence obtained with all of the simple compounds that attenuate the ME-induced digit malformations, we postulate that abnormal macromolecules are generated by anabolic reactions and that those products disrupt normal paw development.