Effects of Maternal Diabetes and Diet on Gene Expression in the Murine Placenta.
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ABSTRACT:
SUBMITTER: Kappen C
PROVIDER: S-EPMC8775503 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Diet during pregnancy influences the future health of a woman's offspring, with outcomes differing depending on the child's sex. Because the placenta buffers the fetus from the mother, we examined the impact of diet and fetal sex on placental gene expression in mice fed either a very-high-fat, low-fat, chow diet of intermediate caloric density. At day 12.5 of pregnancy, placental RNA was extracted and analyzed by microarray. The expression of 1,972 genes was changed more than 2-fold (P < 0.05) in comparisons across diet in at least one of the three groups. Female placentae demonstrated more striking alterations in gene expression in response to maternal diet than male placentae. Notably, each diet provided a distinctive signature of sexually dimorphic genes, with expression generally higher in genes (651 out of 700) from female placentae than those from male placentae. Several genes normally considered as characteristic of kidney function were affected by diet, including genes regulating ion balance and chemoreception. The placenta also expressed most of the known olfactory receptor genes (Olfr), which may allow the placenta to sense odorant molecules and other minor dietary components, with transcript levels of many of these genes influenced by diet and fetal sex. In conclusion, gene expression in the murine placenta is adaptive and shaped by maternal diet. It also exhibits pronounced sexual dimorphism, with placentae of females more sensitive to nutritional perturbations than placentae of males.
| S-EPMC2851754 | biostudies-literature
Project description:Unfavorable maternal diet during pregnancy can predispose the offspring to diseases later in life, such as hypertension, metabolic syndrome, and obesity. However, the molecular basis for this phenomenon of "developmental programming" is poorly understood. We have recently shown that a diet nutritionally optimized for pregnancy can nevertheless be harmful in the context of diabetic pregnancy in the mouse, associated with a high incidence of neural tube defects and intrauterine growth restriction. We hypothesized that placental abnormalities may contribute to impaired fetal growth in these pregnancies, and therefore investigated the role of maternal diet in the placenta. LabDiet 5015 diet was associated with reduced placental growth, commencing at midgestation, when compared to pregnancies in which the diabetic dam was fed LabDiet 5001 maintenance chow. Furthermore, by quantitative RT-PCR we identify 34 genes whose expression in placenta at midgestation is modulated by diet, diabetes, or both, establishing biomarkers for gene-environment interactions in the placenta. These results implicate maternal diet as an important factor in pregnancy complications and suggest that the early phases of placenta development could be a critical time window for developmental origins of adult disease.
| S-EPMC3372526 | biostudies-literature
Project description:BackgroundMaternal diet is an important factor in prenatal development that also has implications for disease risk later in life. The adipokine leptin is a key regulator of energy homeostasis and may be involved in the association between maternal nutrition, maternal obesity, and infant outcomes. DNA methylation of placenta genes may occur in response to exposures and may program subsequent infant development. This study examined maternal diet, placenta leptin gene DNA methylation, and neonatal growth in a sample of healthy neonates and their mothers.MethodsMothers and their healthy neonates (N = 135) were recruited within 1-2 days following delivery at Women and Infants Hospital in Providence, RI. A structured interview was conducted to assess maternal dietary intake. Maternal pre-pregnancy weight, weight gain during pregnancy, maternal health, medications, and vitamin use were obtained from medical records. Bisulfite pyrosequencing was used to measure methylation of CpG sites in the promoter region of the placenta leptin gene and determine genotype of the leptin single nucleotide polymorphism (SNP) rs2167270, which is known to influence leptin methylation. Bivariate analyses and linear regression models were used to evaluate associations of demographics, diet, and mean leptin methylation.ResultsGenotype was a significant predictor of placenta leptin DNA methylation (p < .01), and after controlling for this and other relevant maternal and infant covariates, lower levels of leptin methylation were significantly associated with greater intake of carbohydrates (p < .05), in particular added sugars (p < .05) and white/refined carbohydrates (p < .05). Total caloric intake was also associated with placenta leptin methylation (p < .05), however after controlling for relevant covariates, significance diminished to trend-level. There were no significant associations of placenta leptin methylation and intake of protein (p > .05) or fat (p > .05).ConclusionThese findings underline the importance of intake of carbohydrate consumption for methylation of the placenta leptin gene. Because methylation reduces gene transcription, lower methylation may indicate a placenta response to high caloric intake and carbohydrate food that would result in higher levels of this hormone during fetal development. Further investigation of the developmental ramifications of epigenetic changes to placenta leptin methylation should be pursued.
| S-EPMC7185035 | biostudies-literature
Project description:BackgroundExposure to diabetes in utero influences future metabolic health of the offspring. MicroRNAs (miRNA) are small noncoding RNAs that may contribute mechanistically to the effects on offspring imparted by diabetes mellitus (DM) during pregnancy. We hypothesized that exposure to DM during pregnancy influences select miRNAs in fetal circulation, in human umbilical vein endothelial cells (HUVEC), and placenta.MethodsmiRNA abundance was quantified using real-time PCR from RNA isolated from umbilical cord serum exosomes, HUVEC, and placenta exposed to diabetes or normoglycemia during pregnancy. The abundance of each of these miRNAs was determined by comparison to a known standard and the relative expression assessed using the 2-ΔΔCt method. Multivariable regression models examined the associations between exposure to diabetes during pregnancy and miRNA expression.ResultsmiR-126-3p was highly abundant in fetal circulation, HUVEC, and placenta. Diabetes exposure during pregnancy resulted in lower expression of miR-148a-3p and miR-29a-3p in the HUVEC. In the placenta, for miR-126-3p, there was a differential effect of DM by birth weight between DM versus control group, expression being lower at the lower birth weight, however not different at the higher birth weight.ConclusionExposure to DM during pregnancy alters miRNA expression in the offspring in a tissue-specific manner.ImpactmiRNAs are differentially expressed in fetal tissues from offspring exposed to in utero diabetes mellitus compared to those who were not exposed. miRNA expression differs among tissue types (human umbilical vein endothelial cells, placenta and circulation exosomes) and response to diabetes exposure varies according to tissue of origin. miRNA expression is also affected by maternal and infant characteristics such as infant birth weight, infant sex, maternal age, and maternal BMI. miRNAs might be one of the potential mechanisms by which offspring's future metabolic status may be influenced by maternal diabetes mellitus.
| S-EPMC7854929 | biostudies-literature
Project description:Antenatal steroids like dexamethasone (DEX) are used to augment fetal lung maturity and there is a major concern that they impair fetal growth. If delivery is delayed after using antenatal DEX, placental function and hence fetal growth may be compromised even further. To investigate the effects of DEX on placental function, we treated 9 pregnant C57/BL6 mice with DEX and 9 pregnant mice were injected with saline to serve as controls. Placental gene expression was studied using microarrays in 3 pairs and other 6 pairs were used to confirm microarray results by semi-quantitative RT-PCR, real-time PCR, in situ hybridization, western blot analysis and Oligo ApopTaq assay. DEX-treated placentas were hydropic, friable, pale, and weighed less (80.0+/-15.1mg compared to 85.6.8+/-7.6mg, p=0.05) (n=62 placentas). Fetal weight was significantly reduced after DEX use (940+/-32mg compared to 1162+/-79mg, p=0.001) (n=62 fetuses). There was >99% similarity within and between the three gene chip data sets. DEX led to down-regulation of 1212 genes and up-regulation of 1382 genes. RT-PCR studies showed that DEX caused a decrease in expression of genes involved in cell division such as cyclins A2, B1, D2, cdk 2, cdk 4 and M-phase protein kinase along with growth-promoting genes such as EGF-R, BMP4 and IGFBP3. Oligo ApopTaq assay and western blot studies showed that DEX-treatment increased apoptosis of trophoblast cells. DEX-treatment led to up-regulation of aquaporin 5 and tryptophan hydroxylase genes as confirmed by real-time PCR, and in situ hybridization studies. Thus antenatal DEX treatment led to a reduction in placental and fetal weight, and this effect was associated with a decreased expression of several growth-promoting genes and increased apoptosis of trophoblast cells.
| S-EPMC2040329 | biostudies-literature
Project description:Maternal obesity is associated with placental oxidative stress. However, the mechanism underlying this association remains poorly understood. In the present study, a gilt obesity model was developed by exposure to different energy diets and used to investigate the role of NADPH oxidase 2 (Nox2) in the placenta. Specifically, 99 gilts (Guangdong Small-ear Spotted pig) at day 60 of gestation were randomly assigned to one of the following three treatments: low-energy group (L, DE = 11.50 MJ/kg), medium-energy group (M, DE = 12.41 MJ/kg), and high-energy group (H, DE = 13.42 MJ/kg), with 11 replicate pens per treatment and 3 gilts per pen. At the start of the study, maternal body weight and backfat thickness were not significantly different in the three treatments. After the study, data indicated that the H group had higher body weight and backfat thickness gain for gilts during gestation and lower piglet birth weight compared with the other two groups. Additionally, the H group showed glucolipid metabolic disorders and increased triglyceride and nonesterified fatty acid contents in the placenta of gilts. Compared with the L group, the H group exhibited lower mitochondrial biogenesis and increased oxidative damage in the placenta. Importantly, increased mRNA expression and protein abundance of Nox2 were observed for the first time in H group placentae. Furthermore, compared with the L group, the H group showed a decrease in the density of placental vessels and the protein levels of vascular endothelial cadherin (VE-cadherin), vascular endothelial growth factor A (VEGF-A), and phosphorylation of vascular endothelial growth factor receptor 2 (p-VEGFR2) as well as the immunostaining intensity of platelet endothelial cell adhesion molecule-1 (CD31). Our findings suggest that maternal high-energy diet-induced obesity increases placental oxidative stress and decreases placental angiogenesis possibly through the upregulation of Nox2.
| S-EPMC6791269 | biostudies-literature
Project description:The high fat content in Western diets probably affects placental function during pregnancy with potential consequences for the offspring in the short and long term. The aim of the present study was to compare genome-wide placental gene expression between rat dams fed a high-fat diet (HFD) and those fed a control diet for 3 weeks before conception and during gestation. Gene expression was measured by microarray and pathway analysis was performed. Gene expression differences were replicated by real-time PCR and protein expression was assessed by Western blot analysis. Placental and fetal weights at E17.25 were not altered by exposure to the maternal HFD. Gene pathways targeting placental growth, blood supply and chemokine signalling were up-regulated in the placentae of dams fed the HFD. The up-regulation in messenger RNA expression for five genes Ptgs2 (fatty acid cyclo-oxidase 2; COX2), Limk1 (LIM domain kinase 1), Pla2g2a (phospholipase A2), Itga1 (integrin ?-1) and Serpine1 was confirmed by real-time PCR. Placental protein expression for COX2 and LIMK was also increased in HFD-fed dams. In conclusion, maternal HFD feeding alters placental gene expression patterns of placental growth and blood supply and specifically increases the expression of genes involved in arachidonic acid and PG metabolism. These changes indicate a placental response to the altered maternal metabolic environment.
| S-EPMC4153320 | biostudies-other
Project description:The role of extracellular vesicles (EVs), specifically exosomes, in intercellular communication likely plays a key role in placental orchestration of pregnancy and maternal immune sensing of the fetus. While murine models are powerful tools to study pregnancy and maternal-fetal immune interactions, in contrast to human placental exosomes, the content of murine placental and pregnancy exosomes remains largely understudied. Using a recently developed in vitro culture technique, murine trophoblast stem cells derived from B6 mice were differentiated into syncytial-like cells. EVs from the conditioned media, as well as from pregnant and non-pregnant sera, were enriched for exosomes. The RNA composition of these murine trophoblast-derived and pregnancy-associated exosome-enriched-EVs (ExoE-EVs) was determined using RNA-sequencing analysis and expression levels confirmed by qRT-PCR. Differentially abundant miRNAs were detected in syncytial differentiated ExoE-EVs, particularly from the X chromosome cluster (mmu-miR-322-3p, mmu-miR-322-5p, mmu-miR-503-5p, mmu-miR-542-3p, and mmu-miR-450a-5p). These were confirmed to be increased in pregnant mouse sera ExoE-EVs by qRT-PCR analysis. Interestingly, fifteen miRNAs were only present within the pregnancy-derived ExoE-EVs compared to non-pregnant controls. Mmu-miR-292-3p and mmu-miR-183-5p were noted to be some of the most abundant miRNAs in syncytial ExoE-EVs and were also present at higher levels in pregnant versus non-pregnant sera ExoE-EVs. The bioinformatics tool, MultiMir, was employed to query publicly available databases of predicted miRNA-target interactions. This analysis reveals that the X-chromosome miRNAs are predicted to target ubiquitin-mediated proteolysis and intracellular signaling pathways. Knowing the cargo of placental and pregnancy-specific ExoE-EVs as well as the predicted biological targets informs studies using murine models to examine not only maternal-fetal immune interactions but also the physiologic consequences of placental-maternal communication.
| S-EPMC6366741 | biostudies-literature
Project description:Maternal obesity is associated with an increased risk of obesity and metabolic disease in offspring. Increasing evidence suggests that the placenta plays an active role in fetal programming. In this study, we used a mouse model of diet-induced obesity to demonstrate that the abnormal metabolic milieu of maternal obesity sets the stage very early in pregnancy by altering the transcriptome of placenta progenitor cells in the preimplantation (trophectoderm [TE]) and early postimplantation (ectoplacental cone [EPC]) placenta precursors, which is associated with later changes in placenta development and function. Sphingolipid metabolism was markedly altered in the plasma of obese dams very early in pregnancy as was expression of genes related to sphingolipid processing in the early placenta. Upregulation of these pathways inhibits angiogenesis and causes endothelial dysfunction. The expression of many other genes related to angiogenesis and vascular development were disrupted in the TE and EPC. Other key changes in the maternal metabolome in obese dams that are likely to influence placenta and fetal development include a marked decrease in myo and chiro-inositol. These early metabolic and gene expression changes may contribute to phenotypic changes in the placenta, as we found that exposure to a high-fat diet decreased placenta microvessel density at both mid and late gestation. This is the first study to demonstrate that maternal obesity alters the transcriptome at the earliest stages of murine placenta development.
| S-EPMC6454478 | biostudies-literature
Project description:ObjectiveTo elucidate and categorize the murine placental hormones expressed across gestation, including the expression of hormones with previously undescribed roles.Study designExpression levels of all genes with known or predicted hormone activity expressed in two separate tissues, the placenta and maternal decidua, were assessed across a timecourse spanning the full lifetime of the placenta. Novel expression patterns were confirmed by in situ hybridization and protein level measurements.ResultsA combination of temporal and spatial information defines five groups that can accurately predict the patterns of uncharacterized hormones. Our analysis identified Secretin, a novel placental hormone that is expressed specifically by the trophoblast at levels many times greater than in any other tissue.ConclusionsThe characteristics of Secretin fit the paradigm of known placental hormones and suggest that it may play an important role during pregnancy.
| S-EPMC3725973 | biostudies-literature