Prevention of neural tube defects by and toxicity of L-homocysteine in cultured postimplantation rat embryos.
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 (GD10) 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 (1 mM) did not improve embryonic development. N5-Methyltetrahydrofolate (5-CH3-THF) (100 microM), 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 microM) 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-homocystine. In GD11 rat embryos, both L- and D-homocysteine were readily 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.
Vanaerts
L A
LA
Department of Toxicology, Catholic University of Nijmegen, The Netherlands.
Blom
H J
HJ
Deabreu
R A
RA
Trijbels
F J
FJ
Eskes
T K
TK
Copius Peereboom-Stegeman
J H
JH
Noordhoek
J
J
D043383:Adenosylhomocysteinase; D000818:Animals; D002374:Catalase / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology; D019327:Copper Sulfate; D046508:Culture Techniques; D004347:Drug Interactions; D047108:Embryonic Development; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D006710:Homocysteine / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D006711:Homocystine / Q000378:metabolism / Q000494:pharmacology; D006867:Hydrolases / Q000378:metabolism; D008715:Methionine / Q000378:metabolism / Q000494:pharmacology; D009436:Neural Tube Defects / Q000517:prevention & control*; D010084:Oxidation-Reduction; D011247:Pregnancy; D051381:Rats; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D013237:Stereoisomerism; D013723:Teratogens / Q000633:toxicity; D014805:Vitamin B 12 / Q000494:pharmacology
D013723:Teratogens; D006710:Homocysteine; D006711:Homocystine; D003300:Copper; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D008715:Methionine; D002374:Catalase; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D019327:Copper Sulfate; D014805:Vitamin B 12