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Epigenetic reprogramming of sperm in F1 adult male mice with intrauterine hyperglycemia exposure

ABSTRACT: Birth cohort studies and experimental investigations in animals link gestational diabetes mellitus (GDM) with impaired cognitive performance in the first filial generation (F1). We found that intrauterine hyperglycemia exposure resulted in behavior abnormality and cognitional functional disorder of both F1- and F2-GDM male mice. Methylome of sperm of F1 adult male mice from control pregnant mice (F1-C) and GDM pregnant mice (F1-GDM) revealed differentially methylated genes enriched in neurodevelopmental process.

ORGANISM(S): Mus musculus

PROVIDER: GSE142502 | GEO | 2021/08/25

REPOSITORIES: GEO

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Project description:Gestational diabetes mellitus (GDM) with intrauterine hyperglycemia induces a series of changes in the placenta, which have adverse effects on both the mother and fetus. Although some studies have examined these changes in the placenta, the differences resulting from fetal sex remain unelucidated. In this study, we established an intrauterine hyperglycemic model using ICR mice. We collected placental specimens before birth for histological observation using Hematoxylin and Eosin (HE) staining, along with Tandem Mass Tag (TMT) labeled proteomic analysis which was stratified by sex. In both male and female fetuses of the GDM group, body weight and placental weight were significantly lower compared to the control group. Additionally, the placenta-to-body weight ratio was higher, suggesting potential placental insufficiency. Histological analysis revealed smaller sizes and reduced thickness of the junctional zone and labyrinth in diabetic placentas at E18.5, along with ectopic accumulation of spongiotrophoblasts in the labyrinth. When the analysis was not segregated by sex, the GDM group showed 208 upregulated and 225 downregulated proteins in the placenta, primarily within the extracellular matrix and mitochondria. Altered biological processes included cholesterol metabolism and oxidative stress responses. After stratifying by sex, the male subgroup displayed 209 upregulated and 111 downregulated proteins, while the female subgroup exhibited 97 upregulated and 75 downregulated proteins. Among these, 64 differentially expressed proteins showed consistent trends across both sexes, primarily enriched in the JAK-STAT signaling pathway, complement and coagulation cascades, and metabolism-related modifications. The male subgroup showed a heightened tendency for immune-related pathway alterations, whereas the female subgroup manifested changes in branched-chain amino acid metabolism. The intrauterine hyperglycemic environment affects both placental morphology and proteomics, leading to shifts in energy metabolism, oxidative stress responses, and immune processes. Our study suggests that the observed differences in placental protein expression specific to each sex may provide an explanation for the varying impacts of GDM on offspring.

Project description:BackgroundThe existing reports about intergenerational or transgenerational effects of intrauterine hyperglycemia have included both intrauterine and postnatal metabolic exposure factors, while the impact of intrauterine hyperglycemia per se has not been assessed alone. A number of studies suggest DNA methylation reprogramming of gametes plays a crucial role in the metabolic inheritance, but it is unclear when and how DNA methylation patterns are altered when exposed to intrauterine hyperglycemia. In this study, we selected nondiabetic F1- and F2-gestational diabetes mellitus (GDM) male mice as founders to examine metabolic changes in the next generation and performed methylome sequencing of day 13.5 primordial germ cells (PGCs) from F1-GDM to explore the underlying epigenetic mechanism.ResultsWe found that intrauterine hyperglycemia exposure resulted in obesity, insulin resistance, and/or glucose intolerance in F2 male mice, but no metabolic changes in F3 male mice at 8 weeks. Using reduced representation bisulfite sequencing, we found DNA methylome of day 13.5 PGCs from F1-GDM fetuses revealed differently methylated genes enriched in obesity and diabetes. Methylation validation of the insulin resistance and fat accumulation gene Fyn showed a consistent hypomethylation status in F1 PGCs, F1 fetal testes, sperm from F1/C-GDM mice, and somatic cells from F2-GDM male mice. In contrast, no methylation alteration was observed in F2-GDM male germ cells and F3-GDM somatic cells.ConclusionWe provide evidence that intrauterine hyperglycemia exposure per se contributes to intergenerational metabolic changes in the F2 but not F3 generation. And the aberrant DNA methylation reprogramming occurs as early as day 13.5 in PGCs of the F1 generation. Our findings suggest that intrauterine exposure alone is sufficient to cause the epigenetic inheritance in F2 offspring, and the epigenetic memory carried by DNA methylation pattern could be erased by the second wave of methylation reprogramming in F2 PGCs during fetal development.