Inhibition of transmethylation disturbs neurulation in chick embryos.
Periconceptional folic acid supplementation can reduce the occurrence of neural tube defects. A low folate status will result in reduced remethylation of homocysteine (Hcy) to methionine and, subsequently, in a rise of Hcy levels. Indeed, elevated Hcy concentrations have been reported in mothers of children with neural tube defects. In our previous study, we showed that treatment of chick embryos with Hcy resulted in a delay of neural tube closure in an in vitro model. In the present study, we examined whether this effect of Hcy is due to inhibition of transmethylation via elevation of S-adenosylhomocysteine (AdoHcy). Transmethylation involves methylation of DNA, RNA and proteins by donation of a methyl group from S-adenosylmethionine (AdoMet). After application of inhibitors of S-adenosylhomocysteine hydrolase and of methionine adenosyltransferase, a delay of anterior neuropore closure, comparable to that observed after Hcy treatment, was observed. The changes in AdoMet and AdoHcy concentrations confirmed the inhibition of S-adenosylhomocysteine hydrolase or methionine adenosyltransferase, respectively, and the AdoMet/AdoHcy ratio was decreased in all cases, indicating reduced transmethylation. Moreover, the inhibition of methionine adenosyltransferase was prevented by pretreatment with methionine. This study, therefore, indicates that the Hcy-induced delay of the neural tube closure is caused by the inhibition of transmethylation via elevation of AdoHcy levels and a reduction of the AdoMet/AdoHcy ratio.
Afman
Lydia A
LA
Department of Anatomy and Embryology, Maastricht University, P.O. Box 616, 6200 MD, The Netherlands.
Blom
Henk J
HJ
Drittij
Marie-Jose
MJ
Brouns
Madeleine R
MR
van Straaten
Henny W M
HW
D000241:Adenosine / Q000494:pharmacology; D043383:Adenosylhomocysteinase / Q000378:metabolism; D000818:Animals; D002642:Chick Embryo / Q000502:physiology*; D003515:Cycloleucine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D047108:Embryonic Development / Q000187:drug effects*; D006710:Homocysteine / Q000494:pharmacology*; D008745:Methylation / Q000187:drug effects; D008954:Models, Biological; D009420:Nervous System / Q000196:embryology*; D038081:Organogenesis / Q000187:drug effects / Q000502:physiology*; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D013997:Time Factors; D014372:Tubercidin / Q000494:pharmacology
C018258:3-deazaadenosine; D006710:Homocysteine; D003515:Cycloleucine; D012435:S-Adenosylhomocysteine; D043383:Adenosylhomocysteinase; D000241:Adenosine; D014372:Tubercidin