Integrated Multi-Omics Analysis Reveals the Effect of Maternal Gestational Diabetes on Fetal Mouse Hippocampi

Abstract

Growing evidence suggests that adverse intrauterine environments could affect the long-term health of offspring. Recent evidence indicates that gestational diabetes mellitus (GDM) is associated with neurocognitive changes in offspring. However, the mechanism remains unclear. Using a GDM mouse model, we collected hippocampi, the structure critical to cognitive processes, for electron microscopy, methylome and transcriptome analyses. Reduced representation bisulfite sequencing (RRBS) and RNA-seq in the GDM fetal hippocampi showed altered methylated modification and differentially expressed genes enriched in common pathways involved in neural synapse organization and signal transmission. We further collected fetal mice brains for metabolome analysis and found that in GDM fetal brains, the metabolites displayed significant changes, in addition to directly inducing cognitive dysfunction, some of which are important to methylation status such as betaine, fumaric acid, L-methionine, succinic acid, 5-methyltetrahydrofolic acid, and S-adenosylmethionine (SAM). These results suggest that GDM affects metabolites in fetal mice brains and further affects hippocampal DNA methylation and gene regulation involved in cognition, which is a potential mechanism for the adverse neurocognitive effects of GDM in offspring.

The impact of maternal diabetes on the future health and neurodevelopment of the offspring: a review of the evidence

“…The differentially methylated genes are crucial in synaptogenesis, cognitive function, neuronal differentiation, neurotransmitter signaling, and dendritic development. Furthermore, significant changes in fetal brain metabolites associated with cognition and neurodevelopment, potentially attributed to DNA methylation changes, were noted (Graphical Abstract) ( 135 ).…”

Long-term outcomes and potential mechanisms of offspring exposed to intrauterine hyperglycemia

“…Reduced representation bisulfite sequencing (RRBS) of GDM fetal hippocampi showed that altered methylated genes were involved in cognitive function. Metabolic profiling in this article also identified differential metabolites in fetal brain targeting epigenetic modifications ( 108 ).…”

“…Additionally, in the radical Y-maze test, O-GDM adult mice made more re-entry mistakes, which indicated a deficiency in short-term memory ( 100 , 103 , 104 ); third, the cell cycle was altered to a stage where apoptosis-related genes were promoted in GDM neonate-derived cells ( 107 ). Hippocampi derived from the offspring of diabetic mothers were characterized by cell death and susceptibility to LPS stimulation ( 145 ); fourth, hyperglycemia led to malformation of the brain ( 105 ), especially disturbed neocortical lamination ( 106 ), neural tube malformation ( 107 ), and hippocampal synaptic derangement ( 101 , 108 ). Difference in the number of neurons in the ventromedial nucleus of the hypothalamus vanished after an islet transplantation in the diabetic group ( 187 ); fifth, fetal hippocampal formation was exposed to a neuroinflammatory environment because of hyperglycemia, so increased activated microglia and cytokines persisted into young adulthood ( 101 ), and O-GDM became more sensitive to an inflammatory response ( 145 ).…”

PHEVIR: an artificial intelligence algorithm that predicts the molecular role of pathogens in complex human diseases

“…STX7 is upregulated in T2D 54 , and STX10 is differentially methylated in the offspring of women with maternal diabetes 55 . CDIPT was hypomethylated and up-regulated in the fetus of mice with Maternal Gestational Diabetes 56 . SNRPA was found to be associated with metabolic syndromes 57 .…”