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Gestational diabetes in mice induces hematopoietic memory that impacts the long-term health of the offspring.

ABSTRACT: Gestational diabetes is a common medical complication of pregnancy that is associated with adverse perinatal outcomes and an increased risk of metabolic diseases and atherosclerosis in adult offspring. The mechanisms responsible for this delayed pathological transmission remain unknown. In mouse models, we found that the development of atherosclerosis in adult offspring born to diabetic pregnancy can be in part linked to hematopoietic alterations. Although they do not show any gross metabolic disruptions, the adult offspring maintain hematopoietic features associated with diabetes, indicating the acquisition of a lasting diabetic hematopoietic memory. We show that the induction of this hematopoietic memory during gestation relies on the activity of the pattern recognition receptor AGER and the NLRP3 inflammasome, which leads to increased placental inflammation. In adult offspring, we find that this memory is associated with DNMT1 upregulation and epigenetic changes in hematopoietic progenitors. Altogether, our results demonstrate that the hematopoietic system can acquire a lasting memory of gestational diabetes, and that this memory constitutes a new pathway connecting gestational health to adult pathologies.

ORGANISM(S): Mus musculus

PROVIDER: GSE244688 | GEO | 2023/11/13

REPOSITORIES: GEO

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Gestational diabetes in mice induces hematopoietic memory that impacts the long-term health of the offspring

Project description:Gestational diabetes is a common medical complication of pregnancy that is associated with adverse perinatal outcomes and an increased risk of metabolic diseases and atherosclerosis in adult offspring. The mechanisms responsible for this delayed pathological transmission remain unknown. In mouse models, we found that the development of atherosclerosis in adult offspring born to diabetic pregnancy can be in part linked to hematopoietic alterations. Although they do not show any gross metabolic disruptions, the adult offspring maintain hematopoietic features associated with diabetes, indicating the acquisition of a lasting diabetic hematopoietic memory. We show that the induction of this hematopoietic memory during gestation relies on the activity of the pattern recognition receptor AGER and the NLRP3 inflammasome, which leads to increased placental inflammation. In adult offspring, we find that this memory is associated with DNMT1 upregulation and epigenetic changes in hematopoietic progenitors. Altogether, our results demonstrate that the hematopoietic system can acquire a lasting memory of gestational diabetes, and that this memory constitutes a new pathway connecting gestational health to adult pathologies.

2023-11-13 | GSE244697 | GEO

Gestational diabetes in mice induces hematopoietic memory that impacts the long-term health of the offspring.

2023-11-13 | GSE244695 | GEO

Gene expression in the F1 and F2 mouse hippocampus with intrauterine hyperglycemia exposure

Project description:Studies on human and animals suggest associations between gestational diabetes mellitus (GDM) with impaired cognitive performance in offspring. Using a mouse model of diabetes during pregnancy, we found that intrauterine hyperglycemia exposure resulted in memory impairment in both the first filial (F1) males and the second filial (F2) males from the F1 male offspring. The effects of intrauterine hyperglycemia exposure on F1 and F2 hippocampus gene expression were also examined.

2021-08-25 | GSE147039 | GEO

Methylation arrays (MethylationEPIC) of cord and peripheral whole blood from children born to mothers with obesity or gestational diabetes, with longitudinal follow-up during their first year of life

Project description:Epidemiological studies have associated maternal metabolic conditions such as obesity and gestational diabetes with poor health outcomes in the offspring. Epigenetic mechanisms may help explain the intrauterine influence that mothers have on their offspring during pregnancy. Here, using Illumina's MethylationEPIC array technology, we have longitudinally profiled the blood methylomes of children born to mothers with obesity and obesity with gestational diabetes, and healthy controls, during the first year of life (measurements at 0, cord blood; 6 and 12 months, peripheral blood).

2023-03-01 | E-MTAB-12728 | biostudies-arrayexpress

Gestational diabetes and human amniocytes

Project description:Context: Context: Gestational diabetes (GDM) has profound effects on the intrauterine metabolic milieu and is linked to obesity and diabetes in offspring, but the mechanisms driving these effects remain largely unknown. Alterations gene expression in amniocytes exposed to GDM in utero may identify potential mechanisms leading to metabolic dysfunction later in life. Objective: Objective: To profile changes in the transcriptome in human amniocytes exposed to GDM Methods: A nested case-control study was performed in second trimeseter amniocytes matched for offspring sex, maternal race/ethnicity, maternal age, gestational age at amniocentesis, gestational age at birth and gestational diabetes status. Sex-specific RNA-sequencing was completed and gene expression changes were identified. Results: Expression of interferon-stimulated genes was increased in GDM amniocytes accounting for 6 of the top 10 altered genes (q<0.05). Enriched biological pathways in GDM anmiocytes included pathways involving inflammation, the interferon response, fatty liver disease, monogenic diabetes and atherosclerosis. Conclusion: In a unique repository of human amniocytes exposed to GDM in utero, trancriptome analysis identified enrichment of inflammation and interferon-related pathways.

2020-05-15 | GSE150621 | GEO

Gestational diabetes exposure induces an altered cardiac transcriptome that is associated with impaired cardiac function in the rat offspring

Project description:Gestational diabetes mellitus (GDM) is the most common complication of pregnancy. Children of mothers with GDM are at an increased risk for the development of cardiometabolic disease later in life, though the mechanisms responsible for this observation are unknown. We propose that an altered cardiac transcriptome, programmed in utero, may be a contributing mechanism to cardiometabolic disease development and hypothesize that the hearts of offspring exposed to GDM will exhibit altered gene expression pathways. The purpose of this project will be to study alterations in the cardiac transcriptome of young adult rat offspring after exposure to GDM to investigate the mechanisms responsible for the developmental origins of cardiovascular disease.

2021-07-31 | GSE136737 | GEO

Neutrophil Extracellular Traps (NETs) promote macrophage inflammation and impair atherosclerosis resolution in mice with diabetes

Project description:Neutrophil extracellular traps (NETs) promote inflammation and atherosclerosis progression. In diabetes they are increased and impair wound healing, during which inflammation normally resolves. Atherosclerosis regression, a process resembling wound healing, is also impaired in diabetes. Thus, we hypothesized that NETs impede atherosclerosis regression in diabetes through unresolved inflammation. Objective: To investigate in diabetes the effect of NETs on plaque macrophage inflammation and whether NETs reduction improves atherosclerosis regression. Findings: Transcriptomic profiling of plaque macrophages from NET positive and negative areas in Ldlr-/- mice revealed inflammasome and glycolysis pathway upregulation, indicating a pro-inflammatory phenotype. During atherosclerosis regression in non-diabetic mice, plaque NET content decreased. In contrast, in diabetic mouse plaques NETs were enriched and persisted after lipid-lowering. DNase1 treatment (to degrade NETs) of diabetic mice reduced plaque NETs and macrophage inflammation and improved atherosclerosis regression after lipid-lowering. Conclusions: NETs decline during atherosclerosis regression in non-diabetic mice, but persist in diabetes and impair regression by exacerbating macrophage inflammation. DNase1 reduced diabetic plaque NETs and macrophage inflammation, and restored atherosclerosis resolution after lipid-lowering, despite ongoing hyperglycemia. Given that humans with diabetes also exhibit impaired atherosclerosis resolution with lipid-lowering, these data suggest that NETs contribute to the increased CVD risk in this population.

2020-05-12 | GSE145200 | GEO

Fetal metabolic programing increases the susceptibility of cardiovascular diseases in the offspring due to maternal high-fat-diet during diabetic pregnancy

Project description:Increasing trends of obesity in childbearing women with a concurrent gestational diabetes are often associated with adverse fetal metabolic cues. Not only the carbohydrates but also fats are considered to contribute additional dietary fuels to the fetal hearts. To examine the hitherto unknown epigenetic mechanisms on the offspring’s cardiometabolic health due to maternal high-fat (HF) diet (40% kcal) or streptozotocin (STZ)-induced diabetic pregnancy, or both, we carried out an epigenetic characterization of neonatal heart tissue using chromatin immunoprecipitation (ChIP) sequening and a previously validated rat model. Chromatin landscape of offspring’s heart tissue revealed differential peaks distribution on various promoter regions mapped to the rat genome due to histone (H3) modifications by acetylation (H3Ac) or trimethylations of lysine 4 and 27 (H3K4me3 and H3K27me3, respectively). Ongoing evaluations include gene ontology and disease ontology analyses. Together, it is expected that the findings will show that maternal HF-diet with or without gestational diabetes changes the cardiac histone signature in rat offspring, potentially leading to development of novel disease prevention strategies.

2017-06-12 | GSE84831 | GEO

Effects of GDM involves alterations in gene specific DNA methylation

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2015-02-10 | E-GEOD-65779 | biostudies-arrayexpress

Perinatal malnutrition in male mice influences gene expression in the next generation offspring: Potential role of epigenetics.

Project description:Perinatal nutritional imbalances may have long-lasting consequences on health and disease, increasing risk of obesity, insulin resistance, type 2 diabetes or cardiovascular disease. This idea has been conceptualized in the Developmental Origins of Health and Disease Hypothesis (DOHaD). In addition, there is evidence that such early-programmed phenotypes can be transmitted to the following generation(s). It is proposed that, environmentally induced, transmission of disease risk is mediated by epigenetic mechanisms. The aim of this study was to determine whether patterns of gene expression in the first generation offspring are also present in the following generation offspring, via the paternal lineage. Paternal transmission of patterns of gene expression strongly suggest epigenetic inheritance of disease risk. Liver tissue was obtained from the follwing experimental groups: a) control male mice, b) adult male mice previously exposed to 50% caloric restriction in utero (IUGR), c) adult male mice overfed during lactation (ON), d) adult male offspring from control mice, e) adult male offspring from IUGR mice and f) adult male offspring from ON mice.RNA was extracted and processed for further hybridization on Affymetrix microarrays (GeneChip Mouse Genome 430 2.0 (Affymetrix, Santa Clara, CA)).

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