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

Si-Si Luo,He-Feng Huang,Jian-Zhong Sheng,Guo-Lian Ding,Yi Cheng,Ke-Xin Zou,Hong Zhu,Yi-Shang Yan

doi:10.3389/fcell.2022.748862

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.

Highlights

Accumulating human and animal studies have revealed that the early developmental environment is closely related to the long-term health of offspring (Hanson and Gluckman, 2014)
In a part of neurons, the chromatin aggregated into several clumps (Figure 1D, arrows); the shape of the nucleus was irregular; and the invaginations of nucleolemma became evident indicating the shrinkage of the nuclei (Figure 1D, asterisk), suggesting that the nuclei of neural cells were impaired in the gestational diabetes mellitus (GDM) group compared to the control group (Ctrl) group (Figure 1)
We performed representation bisulfite sequencing (RRBS) to search for DMRs in GDM group vs. Ctrl group

Summary

Introduction

Accumulating human and animal studies have revealed that the early developmental environment is closely related to the long-term health of offspring (Hanson and Gluckman, 2014). Previous studies have demonstrated that perinatal hyperglycemia could induce abnormal glucose metabolism in offspring (Ding et al, 2012; Chandna et al, 2015; Zhu and Zhang, 2016). Maternal diabetes cause abnormal glucose tolerance and insulin secretion and affects the development of the nervous system in offspring (Valle-Bautista et al, 2020; He. Multi-Omics Analysis of GDM Fetal Mouse et al, 2021). Multi-Omics Analysis of GDM Fetal Mouse et al, 2021) Both human cohort studies and experimental studies using rodent models have linked GDM with impaired cognitive abilities and decreased learning and memory in offspring (Kinney et al, 2003; Fraser et al, 2014; Bytoft et al, 2016; Daraki et al, 2017; He et al, 2017; de Sousa et al, 2019). The mechanisms that link GDM to the development of cognitive impairments in offspring have not been elucidated

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Discussion

Conclusion