Investigation, using rat embryo culture, of the role of methionine supply in folic acid-mediated prevention of neural tube defects.
Peri-conceptional folic acid supplementation has become a well established way to prevent neural tube defects (NTDs) and such supplementation reduces the prevalence of these defects by approximately 70%. However, the mechanism of the preventive effect of folic acid is not clear. This overview focuses on the biochemical basis of folic acid-preventable NTDs and on the results obtained with whole embryo culture that may help to shed some light on the mechanisms that underlie the preventive effect of folic acid. Culturing gestational day (GD) 9.5 rat embryos on diet-induced folate-deficient rat serum resulted in many malformations, but no NTDs and this embryotoxicity could only partly be overcome by supplementation with N(5)-methyltetrahydrofolate(5-methylTHF). This indicates that there may be an indirect effect of folate deficiency. Besides an important role in purine and thymidine synthesis, folate drives the methylation cycle in which the methyl group of 5-methylTHF is transferred to numerous biomolecules. In this process homocysteine and methionine are constantly interconverted. It was hypothesized that folate deficiency might lead to a toxic accumulation of homocysteine. However, only homocysteine levels 100-fold higher than physiological levels were embryotoxic to cultured GD10 rat embryos. Moreover, 1 and 2 mm l-homocysteine could prevent NTDs in GD9.5 rat embryos when they were cultured in human serum. Addition of 100 mum methionine had the same preventive effect, but addition of 1 mm folinic acid could not prevent the NTDs. When embryos were cultured in cow or canine serum, methionine had a similar preventive effect. These results suggest folic acid mediated prevention of NTDs may be based on an increase of the methionine supply and possibly its supportive action towards the methylation cycle.
Vanaerts
L A
LA
Department of Toxicology, University of Nijmegen, PO Box 9101, 6500 HB NijmegenThe Netherlands.