Prenatal Choline and Betaine Differentially Program Adult Hepatic One-Carbon Metabolism in Wistar Rats

Choline, an essential methyl donor nutrient, and its oxidation product betaine support one-carbon metabolism in early development, yet their prenatal effects on offspring hepatic metabolites and methyltransferase expression remain unknown. Gestational choline or betaine supplementation lowered Wistar rat offspring body weight, food intake, and relative adipose mass compared to the control. Both nutrients increased hepatic glycerophosphocholine in females and males, while betaine elevated sphingomyelin in males and dimethylglycine in both sexes. Choline and betaine raised hepatic S-adenosylmethionine (SAM), with males showing stepwise increases in SAM and the SAM/S-adenosylhomocysteine ratio. Betaine increased DNA methyltransferase (Dnmt) 1 and phosphatidylethanolamine N-methyltransferase gene expression in females, whereas males exhibited broader methyltransferase responses. Kinetic modeling indicated that SAM availability dominated local enzyme sensitivities. Regularized Canonical Correlation Analysis revealed a compact SAM-linked module in females versus a broader Dnmt1-centered module in males. Together, these findings demonstrate nutrient-specific programming of one-carbon metabolism, reflecting the unique metabolic roles of choline and betaine.