Beyond Folate - a Supplementation Strategy to Prevent Neural Tube Defects

Diabetes during pregnancy increases the risk for structural birth defects, such heart defects and neural tube defects. The widely held view is that the teratogen is the excess blood glucose from the mother, because glycemic control in diabetic women is associated with lower birth defects incidence. Numerous studies with rodent embryos cultured in the presence of high glucose levels also have provided evidence for teratogenic action of glucose. We have experimental evidence that structural birth defects in diabetic pregnancies are caused by a glucose deficiency in embryonic cells: compelling transcriptome profiling data in a mouse diabetes model indicate that embryos exposed to maternal diabetes experience nutritional stress just as neural tube closure is about to commence. Intriguingly, a single bolus of glucose could reverse diabetes-affected gene pathways towards normal, implying a nutrient shortage, not an excess. Paradoxically, the diabetes-exposed embryo - despite the glucose-rich maternal environment - appears to be in a state of nutrient deficiency. In this exploratory project, we seek to investigate the biological significance of the glucose- mediated reversal of diabetes-driven transcriptome changes. It is clear that treatment with glucose is not a valid strategy in human diabetic pregnancies. However, we propose a treatment strategy that addresses the nutritional deficiency by supplementing downstream metabolites of glucose that (i) do not exacerbate the glycemic status of a diabetic mother, yet (ii) relieve the nutritional deficit so that embryos in diabetic pregnancies may develop normally. Therefore, this project falls into the NICHD priority area "Nutrition for Precision Health", by directing nutritional prevention strategies at the cellular, molecular and metabolic abnormalities that cause birth defects. We combine this approach with measurements designed to reveal the influence of supplements on cell migration processes in the early embryo. With this research, we provide a new perspective for developing approaches to reduce neural tube defect incidence: by improving the ‘biochemical fitness’ of embryonic cells, we seek to ensure accurate developmental performance. Such an approach may ultimately be useful to prevent neural tube defects in general, not just those of metabolically distressed pregnancies. Project Number: 1R21HD115906-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Johannes Salbaum | Institution: LSU PENNINGTON BIOMEDICAL RESEARCH CTR, BATON ROUGE, LA | Award Amount: $187,500 | Activity Code: R21 | Study Section: Pregnancy and Neonatology Study Section[PN] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21HD11590601A1