Exposure to prenatal excess or imbalanced micronutrients leads to long-term perturbations in one-carbon metabolism, trimethylamine-N-oxide and DNA methylation in Wistar rat offspring

• Published in: The FASEB journal Vol. 38; no. 16; p. e70032
• Main Authors: Shelp, Gia V, Dong, Jianzhang, Orlov, Nikolai O, Malysheva, Olga V, Bender, Erica, Shoveller, Anna K, Bakovic, Marica, Cho, Clara E
• Format: Journal Article
• Language: English
• Published: United States 31-08-2024
• Subjects: Animals; Carbon - metabolism; Choline - metabolism; Choline - pharmacology; DNA Methylation; Epigenesis, Genetic; Female; Folic Acid - metabolism; Hypothalamus - metabolism; Male; Methionine - metabolism; Methylamines - blood; Methylamines - metabolism; Micronutrients - metabolism; Pregnancy; Prenatal Exposure Delayed Effects - metabolism; Rats; Rats, Wistar; offspring; DNA methylation; trimethylamine‐N‐oxide; micronutrients; one‐carbon metabolism; pregnancy
• ISSN: 0892-6638; 1530-6860; 1530-6860
• DOI: 10.1096/fj.202401018RR

Prenatal multivitamins, including folic acid, are commonly consumed in excess, whereas choline, an essential nutrient and an important source of labile methyl groups, is underconsumed. Here, we characterized profiles of one-carbon metabolism and related pathways and patterns of DNA methylation in offspring exposed to excess or imbalanced micronutrients prenatally. Pregnant Wistar rats were fed either recommended 1× vitamins (RV), high 10× vitamins (HV), high 10× folic acid with recommended choline (HFolRC), or high 10× folic acid with no choline (HFolNC). Offspring were weaned to a high-fat diet for 12 weeks. Circulating metabolites were analyzed with a focus on the hypothalamus, an area known to be under epigenetic regulation. HV, HFolRC, and HFolNC males had higher body weight (BW) and lower plasma choline and methionine consistent with lower hypothalamic S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) and global DNA methylation compared with RV. HV and HFolNC females had higher BW and lower plasma 5-methyltetrahydrofolate and methionine consistent with lower hypothalamic global DNA methylation compared with RV. Plasma dimethylglycine (DMG) and methionine were higher as with hypothalamic SAM:SAH and global DNA methylation in HFolRC females without changes in BW compared with RV. Plasma trimethylamine and trimethylamine-N-oxide were higher in males but lower in females from HFolRC compared with RV. Network modeling revealed a link between the folate-dependent pathway and SAH, with most connections through DMG. Final BW was negatively correlated with choline, DMG, and global DNA methylation. In conclusion, prenatal intake of excess or imbalanced micronutrients induces distinct metabolic and epigenetic perturbations in offspring that reflect long-term nutritional programming of health.