Integration of metabolomics and proteomics to highlight altered neural development related pathways in the adult offspring after maternal folic acid supplement

Summary Background & aims Maternal folic acid (FA) supplement (FolS) programs the early development of an offspring. The onset of complex diseases at a later stage of life has been evidently linked with maternal FA ingestion. However, little is known regarding the underlying molecule fingerprints of the offspring. Here, we analyze the influence of maternal FolS on the metabolism of the adult offspring rats using the integrated metabolomics-proteomics. Methods Twenty pregnant female rats were randomly assigned to a FA supplement (FolS group) or control group which were fed AIN93G diet with 2 or 5 mg/kg FA, respectively. The blood samples from the offspring at 0, 3 and 7 weeks after birth were collected. The brain samples were obtained from the offspring at 7 weeks after birth. Serum and brain metabolite profiles were performed by UPLC–MS/MS and the brain proteomics analysis was obtained using iTRAQ-based quantitative proteomics. Results The metabolic change of the offspring for the maternal FA supplement is characterized by the phospholipids, fatty acid and amino acids, which are involved in linoleic acid, docosahexaenoic acid, glycerophosphocholine, lysophosphatidylcholine, tryptophan, glycine, arachidonic acid, γ-aminobutyric acid, and so on. Using iTRAQ-based quantitative proteomics analysis, 51 differential proteins in the brain are identified, which provides valuable insight into the underlying mechanisms of the offspring after the maternal FolS. These results demonstrate neural development related metabolites and proteins, such as docosahexaenoic acid, glycine, tryptophan, γ-aminobutyric acid, dopaminergic synapse related proteins including G protein, PPP1R1B and CAMK2G, are significantly altered, which suggests that the active neural conduction occurs in the offspring after maternal FA supplement. The behavioral testing demonstrates that the high level of memory is observed in rats with FA supplement. Conclusions We conceive that the alterations of metabolites and protein in the offspring are associated with the maternal FA supplement and these alterations are involved in the neural development, although such animal data are limited in their ability to mimic metabolic outcomes in humans.