Maternal Circulatory NAD Precursor Levels and the Yolk Sac Determine NAD Deficiency-Driven Congenital Malformation...

Area of Science:

• Biochemistry
• Developmental Biology
• Metabolomics

Background:

• Nicotinamide adenine dinucleotide (NAD) is vital for cellular functions.
• Congenital NAD deficiency disorder (CNDD) arises from genetic defects in NAD synthesis, leading to severe developmental issues.
• Variability in CNDD patient outcomes is linked to maternal NAD precursor supply.

Purpose of the Study:

• To investigate how maternal NAD precursor levels impact embryonic NAD metabolism and pregnancy outcomes in a CNDD mouse model.
• To identify metabolic markers in maternal circulation that predict CNDD risk.
• To explore the bidirectional influence of embryonic and maternal NAD metabolism.

Main Methods:

• Quantification of NAD metabolomes in maternal plasma and yolk sacs.
• Measurement of embryonic NAD levels and assessment of pregnancy outcomes in a CNDD mouse model.
• Analysis of NAD precursor intake and metabolite levels in pregnant women.

Main Results:

• Maternal nicotinamide levels strongly correlated with embryonic NAD levels.
• Nicotinamide-derived metabolites in maternal circulation were the most effective predictors of adverse pregnancy outcomes.
• Mouse embryos with disrupted NAD synthesis showed increased CNDD susceptibility with limited maternal nicotinamide.
• Embryonic metabolites were detected in maternal plasma, indicating metabolic crosstalk.

Conclusions:

• Maternal nicotinamide is essential for embryonic NAD+ synthesis, particularly when embryonic de novo synthesis is impaired.
• Circulating metabolites in maternal blood serve as predictive markers for NAD deficiency-related adverse pregnancy outcomes.
• There is a significant interplay between maternal and embryonic NAD metabolism during pregnancy.