UPTAKE AND UTILIZATION OF DL-5-[METHYL-C-14] TETRAHYDROPTEROYLMONOGLUTAMATE BY CULTURED CYTOTROPHOBLASTS ASSOCIATED WITH NEURAL-TUBE DEFECTS

A significant advance in the primary prevention of neural tube defects (NTD) is the recent finding that the periconceptional supplementation with folate has a 72% preventive effect against recurrence of NTD. Ho wever, failure of folate supplements to prevent all recurrences suppor ts the multifactorial causation hypothesis, with inherited components exerting their influence, possibly through defects of storage, transpo rt, or metabolism of folate. We have assessed the kinetics of DL-5-[me thyl-C-14]tetrahydropteroylmonoglutamate ([C-14]MTHF) uptake and incor poration into the nucleic acid and protein pools by NTD-associated and control trophoblasts cultured in a medium lacking thymidine and other DNA precursors. We report a significant initial ''lag'' in the rate o f incorporation of C-14 label into the nucleic acid pool in NTD-associ ated trophoblasts. This we attribute to a defect in the de novo pathwa y of folate metabolism and its associated pathways, including the path way for methionine synthesis, although the rate of incorporation of C- 14 label into the protein pool was not significantly different from th at of the control cells. We discuss the possible pathways involved in the transfer of the label from the methyl group of [C-14]MTHF to the n ucleic acid pool, and argue that a slightly (but significantly) reduce d rate of uptake into the NTD-associated cells is a reflection of the lag in incorporation into the nucleic acid pool. It is concluded that in the absence of thymidine, most of the NTD-associated trophoblasts r equire a longer period than controls to adjust to utilization of [C-14 ]MTHF for synthesis of DNA, a period that could be crucial for complet ion of neural tube embryogenesis. We suggest that these findings could offer a way to a marker for risk of NTD.