Metabolomic and transcriptomic signatures of prenatal excessive methionine support nature rather than nurture in schizophrenia pathogenesis

Abstract

The imbalance of prenatal micronutrients may perturb one-carbon (C1) metabolism and increase the risk for neuropsychiatric disorders. Prenatal excessive methionine (MET) produces in mice behavioral phenotypes reminiscent of human schizophrenia. Whether in-utero programming or early life caregiving mediate these effects is, however, unknown. Here, we show that the behavioral deficits of MET are independent of the early life mother-infant interaction. We also show that MET produces in early life profound changes in the brain C1 pathway components as well as glutamate transmission, mitochondrial function, and lipid metabolism. Bioinformatics analysis integrating metabolomics and transcriptomic data reveal dysregulations of glutamate transmission and lipid metabolism, and identify perturbed pathways of methylation and redox reactions. Our transcriptomics Linkage analysis of MET mice and schizophrenia subjects reveals master genes involved in inflammation and myelination. Finally, we identify potential metabolites as early biomarkers for neurodevelopmental defects and suggest therapeutic targets for schizophrenia.

Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction

“…Metabolic profiling was carried out by the West Coast Metabolomics Center (University of California Davis). Three metabolic platforms were profiled: (1) primary metabolites including hydroxyl acids, purines, pyrimidines, carbohydrates and sugar phosphates, amino acids, and aromatics, (2) lipids, and (3) biogenic amines and methylated and acetylated amines 88 . mRNA microarray analysis.…”

“…Bioinformatic analysis of metabolomics and transcriptomics, and metabolitestranscriptomic Integration. The bioinformatic analysis of the differential metabolites differential genes was conducted as we described previously 88 . A differential analysis was performed between the s → S and c → C groups for both 24-h old pups and 13-week old adult mice groups using the Cyber-T program 91,92 to identify the top up-or downregulated metabolites, using p-value cutoff at 0.05.…”

Intergenerational Stress Transmission is Associated with Brain Metabotranscriptome Remodeling and Mitochondrial Dysfunction

“…Metabolic profiling was carried out by the West Coast Metabolomics Center (University of California Davis). Three metabolic platforms were profiled: 1) primary metabolites including hydroxyl acids, purines, pyrimidines, carbohydrates and sugar phosphates, amino acids, and aromatics; 2) lipids; and 3) biogenic amines and methylated and acetylated amines [28].…”

“…The bioinformatic analysis of the differential metabolites differential genes was conducted as we described previously [28]. A differential analysis was performed between the s→S and c→C groups for both 24-hour old pups and 13-week old adult mice groups using the Cyber-T program [31,32] to identify the top up-or down-regulated metabolites, using p-value cutoff at 0.05.…”

Rhea, the reaction knowledgebase in 2022

“…Rhea is now the reference vocabulary for enzyme annotation in the UniProt Knowledgebase UniProtKB ( https://www.uniprot.org ) ( 4–6 ) and provides reaction data for a host of other resources including the enzyme knowledgebases IntEnz ( 7 ) and the Enzyme Portal ( 8 ), the metabolomics data repository MetaboLights ( 9 ), the lipidomics knowledgebase SwissLipids ( 10 ), and the open chemistry database PubChem ( 11 ). Rhea reaction data is widely used for the annotation of genomes ( 12 , 13 ) and genome-scale metabolic models ( 14–19 ), for integrated analysis of metabolomics data ( 20 ), and for computational pathway design ( 21–23 ).…”