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Cytosine methylation profiling in small and large for gestational age newborns

ABSTRACT: In 1990, David Barker proposed that prenatal nutrition is directly linked to adult cardiovascular disease. Since then, the relationship between adult cardiovascular risk, metabolic syndrome and birth weight has been widely documented. Here we used the TruSeq Methyl Capture EPIC platform to compare the methylation patterns in cord blood from large for gestational age (LGA), small for gestational age (SGA) and adequate for gestational age/Control (AGA/Ctl) newborns. We found several differentially methylated CpGs (DMCs) and differentially methylated regions (DMRs) between LGA, SGA and AGA groups. A system biology approach identified several biological processes significantly enriched with genes in association with DMCs including Regulation of transcription, Regulation of epinephrine secretion, Norepinephrine biosynthesis, Receptor transactivation, Forebrain regionalization and several terms related with kidney and cardiovascular development. Gene ontology analysis of the genes in association with the DMRs identified several significantly enriched biological processes related with kidney development including Mesonephric duct development and Nephron tubule development. Furthermore, our dataset identified several DNA methylation markers enriched at gene networks involved in biological pathways and rare diseases of the cardiovascular system, kidneys and metabolism. Our study identified several DMCs/DMRs in association with fetal growth patterns. The use of cord blood as material for the identification of DNA methylation biomarkers gives us the possibility to perform follow up studies on the same patients as they enter childhood and puberty. These studies will not only help us understand how the methylome responds to continuum postnatal growth but also link early alterations of the DNA methylome with later clinical markers of growth and metabolic fitness.

ORGANISM(S): Homo sapiens

PROVIDER: GSE238155 | GEO | 2023/07/26

REPOSITORIES: GEO

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Project description:INTRODUCTION: Restricted or enhanced intrauterine growth is associated with elevated risks of early and late metabolic problems in humans. Metabolomics based on amino acid and carnitine/acylcarnitine profile may have a role in fetal and early postnatal energy metabolism. In this study, the relationship between intrauterine growth status and early metabolomics profile was evaluated.MATERIALS AND METHODS: A single center retrospective cohort study was conducted. Newborn infants were enrolled into the study and they were grouped according to their birth weight percentile as small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA) infants. In all infants amino acid and carnitine/acylcarnitine profile with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were recorded and compared between groups.RESULTS: LGA infants had higher levels of glutamic acid and lower levels of ornithine, alanine and glycine (p<0.05) when compared to AGA infants. SGA infants had higher levels of alanine and glycine levels when compared with AGA and LGA infants. Total carnitine, C0, C2, C4, C5, C10:1, C18:1, C18:2, C14-OH and C18:2-OH levels were significantly higher and C3 and C6-DC levels were lower in SGA infants (p<0.05). LGA infants had higher C3 and C5:1 level; and lower C18:2 and C16:1-OH levels (p<0.05). There were positive correlations between free carnitine and phenylalanine, arginine, methionine, alanine and glycine levels (p<0.05). Also a positive correlation between ponderal index and C3, C5-DC, C14, C14:1; and a negative correlation between ponderal index and ornithine, alanine, glycine, C16:1-OH, C18:2 were shown.CONCLUSION: We demonstrated differences in metabolomics possibly reflecting the energy metabolism in newborn infants with intrauterine growth problems in the early postnatal period. These differences might be the footprints of metabolic disturbances in future adulthood.

Project description:Intrauterine growth restriction is a common cause of small for gestational age (SGA) infants worldwide. SGA infants are deficient in digestive enzymes required for fat digestion and absorption compared to appropriate for gestational age (AGA), putting them at risk for impaired neurocognitive development. The objective was to determine if a hydrolyzed fat (HF) infant formula containing soy free fatty acids, 2-monoacylglycerolpalmitate, cholesterol, and soy lecithin could increase brain tissue incorporation of essential fatty acids or white matter to enhance brain development in SGA and AGA neonatal piglet models. Sex-matched, littermate pairs of SGA (0.5-0.9kg) and AGA (1.2-1.8kg) 2 day old piglets (N=60) were randomly assigned to control (CON) or HF formula diets in a 2 x 2 factorial design. On day 14, 24 piglets were used for hippocampal RNA-sequencing; the rest began a spatial learning task. On days 26-29, brain structure was assessed by magnetic resonance imaging (MRI). Cerebellum and hippocampus were analyzed for fatty acid content. SGA piglets grew more slowly than AGA piglets, with no effect of diet on daily weight gain or weight at MRI. HF diet did not affect brain weight. HF diet increased relative volumes of 7 brain regions and white matter (WM) volume in both SGA and AGA piglets. However, HF did not ameliorate SGA total WM integrity deficits. RNA sequencing revealed SGA piglets had increased gene expression of synapse and cell signaling pathways and decreased expression of ribosome pathways in the hippocampus compared to AGA. HF decreased expression of immune response related genes in the hippocampus of AGA and SGA piglets, but did not correct gene expression patterns in SGA piglets. Piglets learned the T-maze task at the same rate, but SGA HF, SGA CON, and AGA HF piglets had more accurate performance than AGA CON piglets on reversal day 2. HF increased arachidonic acid (ARA) percentage in the cerebellum and total ARA in the hippocampus. HF enhanced brain development in the neonatal piglet measured by brain volume and WM volume in specific brain regions; however, more studies are needed to assess long-term outcomes.

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Cytosine methylation profiling in small and large for gestational age newborns

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