Prevention of neural tube defects by and toxicity of L‐homocysteine in cultured postimplantation rat embryos

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Abstract
Mild hyperhomocysteinemia is frequently observed in mothers who gave birth to a child with a neural tube defect (NTD). In a previous study we showed L-homocysteine was embryotoxic to gestational day 10 (GD 10) rat embryos in culture, however, no NTDs were observed. We therefore investigated the effect of L-homocysteine on the development of neural plate stage (GD9. 5) rat embryos. Other objectives of this study were investigation into whether the embryotoxicity of L-homocysteine could be attenuated by compounds related to its metabolism and clarification of the mechanism of L-homocysteine embryotoxicity. In GD9. 5 rat embryos L-homocysteine was not toxic at 1- and 2-mM concentrations. Rather at these concentrations it promoted development of the rat embryos in serum that without supplementation caused NTDs in the embryos. L-Methionine had the same preventive effect at even lower concentrations, but folinic acid (1mM) did not improve embryonic development. N5-Methyltetrahydrofolate (5-Ch3-THF)(100 μ,M)L-serine(6 mM), and L-methionine(6 and 12 mM) attenuated the embryotoxicity of L-homocysteine(6 mM) in GD10 rat embryos. Vitamin B12(10 μM) completely abolished the embryotoxicity of L-homocysteine, which was shown to be mediated by catalysis of the spontaneous oxidation of L-homocysteine, to the less toxic. L-homocysteine. In GD 11 rat embryos, both L-and D-homocysteine were readily and taken up when added to the culture (3 mM)and increased embryonic S-adenosylhomocysteine (SAH) levels 14-and 3-fold, respectively. This difference was shown to be caused by the stereospecific preference of SAH hydrolase. We propose the basis for L-homocysteine embryotoxicity is an inhibition of transmethylation reactions by increased embryonic SAH levels.