Effect of intrauterine growth restriction on the transcriptome of microglia in hippocampus
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE317999 | GEO | 2026/01/30
REPOSITORIES: GEO
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Project description:Microglia exhibit an overactivated phenotype in a variety of FGR animal models. Further studies have shown that the excessive activation of microglia can last from the perinatal period to adolescence. In recent years, breakthroughs in single-cell sequencing technologies have revealed the high heterogeneity of microglia, and previous studies have identified multiple pathological microglial subpopulations in neuropsychiatric disorders. Nevertheless, in the context of FGR-associated cognitive impairment in offspring, the mechanistic contributions of hippocampal microglia, their heterogeneity at single-cell resolution have not been elucidated.
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Project description:Fetal growth restriction (FGR) is a condition that affects 5-10% of pregnancies and is the second most common cause of perinatal mortality. Peptidomics, as an emerging branch of proteomics, is more applied in screening of disease biomarkers, diagnosis, treatment and monitoring. However, there is still little in-depth analysis about peptidomics study in FGR. The purpose of this study was to explore the significance of maternal placenta polypeptide omics in FGR.
2022-10-08 | PXD037214 |
Project description:Fetal growth restriction (FGR) affects approximately 5–10% of pregnancies and remains a leading cause of perinatal morbidity and mortality. The condition is characterized by the failure of the fetus to achieve its genetically determined growth potential, most commonly as a consequence of placental dysfunction. Despite extensive research, the molecular mechanisms underlying FGR remain incompletely understood. In this study, we investigated whether alterations in placental DNA methylation are associated with early-onset FGR and may contribute to its pathophysiology.
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Project description:Fetal growth restriction (FGR) is a risk factor for obesity in adult life. Importantly, growth-restricted females are more prone to obesity than males. The mechanisms involved in this sexually dimorphic programming are not known. Previously, we have demonstrated that ambient hyperthermia (40° C) led to placental insufficiency and significant FGR, and the perirenal adipose tissue undergoes sexually dimorphic gene expression. We demonstrated that males undergo significant changes in gene expression with growth restriction. This was not the case in females. We have also demonstrated that the isolated preadipocytes from male FGR (MFGR) have reduced differentiation potential compared to control males & females and female FGR (FFGR). Thus, we hypothesized that growth restriction differentially programs gene expression and genetic pathways in perirenal preadipocytes, which reduces their differentiation potential in male fetuses in a sexually dimorphic manner. We created fetal growth restriction by exposing pregnant sheep to ambient hyperthermia. After isolating preadipocytes from perirenal adipose tissue, we differentiated them following published protocols. We examined the gene expression before and after differentiation from control male, control female, MFGR, and FFGR female. We also compared our data with other published studies in mouse and human preadipocytes. Our results demonstrate that a set of 21 genes altered with preadipocyte differentiation to mature adipocytes is common in adipose tissue from both sexes, humans, mice, and sheep, at different organismal ages (embryonic, fetal, and adult) and different sites (subcutaneous inguinal, pancreatic, perirenal). We also demonstrate that female FFGR fetuses demonstrate all these 21 genes altered similar to control males and females; however, MFGR fetuses have six genes (Dgat2, Fabp4, Lipe, Lrrfip1, Spred3, and Thrsp) that are not changed with preadipocyte differentiation to mature adipocyte. These genes may be responsible for reduced differentiation potential and obesity in FGR males compared to FGR females. Another important finding of the present study is that Lrrfip1, known to be associated with obesity, was upregulated with FGR and requires further investigation. Overall, our studies provide several target genes that may play a crucial role in reducing the risk of MFGR for obesity.
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Project description:Fetal growth restriction (FGR) is associated with adverse perinatal outcomes. Pre-eclampsia (PreE) increases the associated perinatal morbidity and mortality. The structure of the umbilical cord in the setting of FGR and PreE has yet to be determined. This study aimed to examine changes in the umbilical cord (UC) composition in pregnancies complicated by FGR and FGR with PreE. UC from gestational age-matched pregnancies with isolated FGR (n = 5), FGR with PreE (n = 5) and controls (n = 5) were collected, and a portion of the UC was processed for histologic and proteomic analysis. Manual segmentation analysis was performed to measure cross-section areas of umbilical cord regions. Wharton's Jelly samples were analyzed on a tims-TOF Pro. Spectral count and ion abundance data were analyzed simultaneously, creating an intersection dataset from a combination of multiple mass spectrometry search and inference engines. UCs from FGR and FGR with PreE had lower cross-sectional area and Wharton's Jelly area compared with control (p = ;0.03). When comparing isolated FGR to control, 28 proteins were significantly different in abundance analysis and 34 in spectral count analysis (p-value < 0.05). Differential expression analysis between PreE with FGR vs controls, demonstrated 48 proteins were significantly different in abundance and 5 in spectral count (p-value < 0.05). The majority of proteomic changes occur in proteins associated with extracellular matrix, cellular process, inflammatory, and angiogenesis pathways.
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Project description:Fetal growth restriction (FGR) is associated with perinatal death and adverse birth outcomes, as well as long-term complications, including increased childhood morbidity, abnormal neurodevelopment, and cardio-metabolic diseases in adulthood. Placental epigenetic reprogramming associated with FGR may mediate these long-term outcomes. Placental malaria (PM), characterized by sequestration of Plasmodium falciparum-infected erythrocytes in placental intervillous space, is the leading global cause of FGR, but its impact on placental epigenetics is unknown. We hypothesized that placental methylomic profiling would reveal common and distinct mechanistic pathways of non-malarial and PM-associated FGR. We analyzed placentas from a US cohort with no malaria exposure (n = 12) and a cohort from eastern Uganda, a region with a high prevalence of malaria (n = 12). From each site, 8 cases of FGR and 4 healthy controls were analyzed. PM was diagnosed by placental histopathology. We compared the methylation levels of over 850K CpGs of the placentas using Infinium MethylationEPIC v1 microarray. Non-malarial FGR was associated with 65 differentially methylated CpGs (DMCs), whereas PM-FGR was associated with 133 DMCs, compared to their corresponding controls without FGR. One DMC (cg16389901, located in the promoter region of BMP4) was commonly hypomethylated in both groups. We identified 522 DMCs between non-malarial FGR vs. PM-FGR placentas, independent of differing geographic location or cellular composition. Placentas with PM-associated FGR have distinct methylation profiles compared to placentas with non-malarial FGR, suggesting novel epigenetic reprogramming in response to malaria. Larger cohort studies are needed to determine the distinct long-term health outcomes in PM-associated FGR pregnancies.
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Project description:Fetal growth restriction (FGR) increases the risk for impaired cognitive function later in life. However, the precise mechanisms remain elusive. Using dexamethasone-induced FGR and protein restriction-influenced FGR mouse models, we observed learning and memory deficits in adult FGR offspring. FGR induces decreased hippocampal neurogenesis from the early postnatal period to adulthood by reducing the proliferation of neural stem cells (NSCs). We further found a persistent decrease of Tet1 expression in hippocampal NSCs of FGR mice. Mechanistically, Tet1 downregulation results in hypermethylation of the Dll3 and Notch1 promoters and inhibition of Notch signaling, leading to reduced NSC proliferation. Overexpression of Tet1 activates Notch signaling, offsets the decline in neurogenesis, and enhances learning and memory abilities in FGR offspring. Our data indicate that a long-term decrease in Tet1/Notch signaling in hippocampal NSCs contributes to impaired neurogenesis following FGR and could serve as potential targets for the intervention of FGR-related cognitive disorders.
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Project description:Early-life exposures (spanning from the gamete stage to childhood) to adverse environmental factors can exert long-term effects on offspring health through epigenetic modifications, significantly increasing susceptibility to chronic diseases such as neuropsychiatric disorders in adulthood. Previous studies have shown that fetal growth restriction can lead to excessive activation of microglia in the individual's brain, but there is still a lack of research on its epigenetic mechanisms. Our data supplements the changes in chromatin accessibility of microglia in the hippocampus of individuals with fetal growth restriction, and explores the epigenetic basis of microglial activation
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Project description:Early-life exposures (spanning from the gamete stage to childhood) to adverse environmental factors can exert long-term effects on offspring health through epigenetic modifications, significantly increasing susceptibility to chronic diseases such as neuropsychiatric disorders in adulthood. Previous studies have shown that fetal growth restriction can lead to excessive activation of microglia in the individual's brain, but there is still a lack of research on its epigenetic mechanisms. Our data supplements the changes in DNA methylation of microglia in the hippocampus of individuals with fetal growth restriction, and explores the epigenetic basis of microglial activation
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Project description:Fetal growth restriction (FGR) is associated with aberrant placentation and accounts for a significant proportion of perinatal deaths. microRNAs have been shown to be dysregulated in FGR. The purpose of this study was to determine microRNA-regulated molecular pathways altered using a caloric restricted mouse model of FGR. Pregnant mice were subjected to a 50% caloric restricted diet beginning at E9. At E18.5, RNA sequencing of placental tissue was performed to identify differences in gene expression between caloric restricted and control placentas. Significant differences in gene expression between caloric restricted and control placentas were observed in 228 of the 1546 (14.7%) microRNAs. Functional analysis of microRNA-mRNA interactions demonstrated enrichment of several biological pathways with oxidative stress, apoptosis, and autophagy pathways upregulated and angiogenesis and signal transduction pathways downregulated. Ingenuity pathway analysis also suggested that ID1 signaling, a pathway integral for trophoblast differentiation, is also dysregulated in caloric restricted placentas. Thus, a maternal caloric restriction mouse model of FGR results in aberrant microRNA-regulated molecular pathways associated with angiogenesis, oxidative stress, signal transduction, apoptosis, and cell differentiation. As several of these pathways are dysregulated in human FGR, our findings suggest that this model may provide an excellent means to study placental microRNA derangements seen in FGR.
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