Prenatal psychophysical and metabolic stress investigation on placenta tissue (MOMINFLAM)
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion ETD
ORGANISM(S): Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
FEDERICA FRATINI
PROVIDER: MSV000092388 | MassIVE | Mon Jul 10 00:38:00 BST 2023
REPOSITORIES: MassIVE
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Project description:Maternal obesity in mice negatively affects placental functionand maternal and fetal liver function. We performed a global proteomic analysis using a liquid-chromatography/mass-spectrometry system to investigate total and phosphorylated proteins in the placenta and fetal liver in a mouse model that combines maternal obesity with maternal androgen excess to identify changes in molecular pathways that might promote diseases in adulthood.
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Project description:Activation of the maternal immune system during pregnancy can fetal development, which can lead to postnatal susceptibility to a wide range of diseases, including cardiovascular, metabolic and psychiatric disorders. During maternal immune activation (MIA), the maternal body must balance its ressources between mounting an immune response and investing resources into continued metabolism and growth : both essential for survival of the fetus and a successful pregnancy. How the placenta responds to MIA over time and how it can protect the fetus is not well understood, and neither are the fetal consequences of MIA. Here, we characterised the response to an induced acute inflammation in maternal lungs over time across maternal and fetal organs, using a combination of omics-methods, imaging and integrative computational analysis. We found that the placenta, unlike other maternal organs, did not react by inducing a typical inflammatory response, but instead initially induced genes associated to strengthen tissue integrity and simultaneously reduced growth to prevent exposure to potential infections. Afterwards, a return to homeostasis was observed, with heightened biosynthesis and expression of endoplasmic reticulum (ER) stress genes. This mechanism likely protects the fetus from inflammation, as we observed no immune response in the fetal liver transcriptome. Instead, we observed metabolic adaptations in the fetus, including a release of docosahexaenoic acid (DHA) Notably, DHA has a crucial function for fetal brain development , and levels of triglyceride and phosphatidylcholine lipids that are necessary for transportation of DHA to the brain were also increased. This metabolic response is likely a combination of the placental MIA response and temporary maternal fasting, caused by MIA-induced fever and lack of nutrient intake. Our study shows, for the first time, the temporal and systemic response to MIA in lungs across maternal and fetal organs.
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Project description:There is increasing concern regarding the adverse effects of air pollution on human health, and benzene is a major toxic compound in air pollution. Maternal benzene exposure has been associated with reproductive complications, such as preterm birth, low birth weight, and immunological and neurological complications in the offspring. However, it is poorly understood how benzene induces these complications. Our objective was to establish a full body inhalation mouse model for maternal benzene exposure that mimics clinical phenotypes observed in human populations, and characterize the maternal immune activation and placental response in our model. Here, we report that maternal immune activation triggered by benzene exposure during pregnancy leads to increased resorptions, abnormal placenta development and low birth weight of fetus. More importantly, there is a sexual dimorphic response to benzene exposure in female and male placentas. In the male placenta, the transcriptome changes reveal a more immunologically relevant profile, while females have a metabolically related profile. Furthermore, we discover the sexual dimorphic response could be a consequence of the sexual dimorphism of placenta at baseline, which indicates the significant difference between sexes in terms of the immunological processes in the placenta, both in human and mouse. Therefore, our findings established a benzene exposure mouse model and indicated the sexual dimorphism of placenta, which provides valuable reference for the future pregnancy studies.
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Project description:Maternal obesity has both a direct effect on the outcome of pregnancy but also programs the fetus for obesity and metabolic syndrome in later life. Due to its roles at the interface between mother and fetus, the placenta transduces and mediates the effects of the obese intrauterine environment on the fetus. Here we have generated genome-scale high-resolution maps of 5mC and 5hmC in human placentas of obese and healthy weight pregnancies. Widespread alterations to the placental epigenome identified across the genome in the setting of maternal adiposity are primarily characterized by increase in 5mC and reciprocal decrease in 5hmC. This is also evident at the two pregnancy-associated gene clusters on chromosomes 17 and 19. In addition, maternal adiposity is associated with downregulation of ten-eleven translocation (TET) and isocitrate dehydrogenase (IDH) family genes and is accompanied by decreased levels of α-ketoglutarate (αKG) in the placenta. Of note, αKG levels exhibit a close positive correlation with both ascorbate and aconitate levels and less substantial but significant association with global 5hmC levels and placenta-specific gene expression. These observations suggest a mechanistic linkage between obesogenic environment and conversion efficiency of 5mC to 5hmC and highlight the idea that TET-mediated active DNA demethylation pathway can sense and respond to metabolic derangements and plays a role in subsequent cellular adaptation. Collectively, this study demonstrates that altered DNA demethylation process is likely one of the mechanisms underlying metabolic modulation of the placental epigenome with maternal adiposity. Comparison of lean vs obese epigenomes in human pregnancies
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Project description:Some neuropsychiatric disease, including schizophrenia, may originate during prenatal development, following periods of gestational hypoxia and placental oxidative stress. Here we investigated if gestational hypoxia promotes damaging secretions from the placenta that affect fetal development and whether a mitochondria-targeted antioxidant MitoQ might prevent this. Gestational hypoxia caused low birth-weight and changes in young adult offspring brain, mimicking those in human neuropsychiatric disease. Exposure of cultured neurons to fetal plasma or to secretions from the placenta or from model trophoblast barriers that had been exposed to altered oxygenation caused similar morphological changes. The secretions and plasma contained altered microRNAs whose targets were linked with changes in gene expression in the fetal brain and with human schizophrenia loci. Molecular and morphological changes in vivo and in vitro were prevented by a single dose of MitoQ bound to nanoparticles, which were shown to localise and prevent oxidative stress in the placenta but not in the fetus. We suggest the possibility of developing preventative treatments that target the placenta and not the fetus to reduce risk of psychiatric disease in later life.
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Project description:The placenta regulates maternal-fetal communication, and its defect leads to significant pregnancy complications. The maternal and embryonic circulations are primitively connected in early placentation, but the function of the placenta during this developmentally essential period is relatively unknown. We thus performed a comparative proteomic analysis of the placenta before and after primary placentation and found that the metabolism and transport of lipids were characteristically activated in this period. The placental fatty acid (FA) carriers in specific placental compartments were upregulated according to gestational age, and metabolomic analysis also showed that the placental transport of FAs increased in a time-dependent manner. Further analysis of two mutant mice models with embryonic lethality revealed that lipid-related signatures could reflect the functional state of the placenta. Our findings highlight the importance of the nutrient transport function of the primary placenta in the early gestational period and the role of lipids in embryonic development.
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Project description:Obesity during pregnancy is associated with fetal growth restriction in the offspring. We used RNA next generation sequencing analysis (HiSeq2000) to have a snapshot of the placenta transcriptome at embryonic day 19 to examine whether mice exposed to maternal obesity had significant changes in their transcriptome which may lead to growth restriction in the fetus.
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Project description:Previous studies have suggested that increases in maternal cortisol or maternal stress in late pregnancy increase the risk of stillbirth at term. In an ovine model with increased maternal cortisol over the last 0.20 of gestation, we have previously found evidence of disruption of fetal serum and cardiac metabolomics, and of expression of genes related to mitochondrial function and metabolism in biceps femoris, diaphragm and cardiac muscle. The present studies were designed to test for effects of chronically increased maternal cortisol on gene expression and metabolomics in placentomes near term. We hypothesized that changes in placenta may underlie or contribute to the alterations in fetal serum metabolomics, and thereby contribute to changes in striated muscle metabolism. Multi-omic analysis indicates that amino acid metabolism, particularly of branched chain amino acids and glutamate occur in placenta; changes in amino acid metabolism, degradation or biosynthesis in placenta were consistent changes in valine, isoleucine, leucine and glycine in fetal serum. The analysis also indicates changes in glycerophospholipid metabolism, and suggests changes in ER stress and antioxidant status in the placenta. These findings suggest that changes in placental function occurring with excess maternal cortisol in late gestation may contribute to metabolic dysfunction in the fetus at birth.
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Project description:Maternal exposure to stress during pregnancy is associated with an increased risk of psychiatric disorders in the offspring in later life. The mechanisms through which the effects of maternal stress are transmitted to the fetus are unclear, however the placenta, as the interface between mother and fetus, is likely to play a key role. Using a rat model, we investigated a role for placental oxidative stress in conveying the effects of maternal social stress to the fetus and the potential for treatment using a nanoparticle-bound antioxidant to prevent adverse outcomes in the offspring. Maternal psychosocial stress increased circulating corticosterone in the mother, but not in the fetuses. Maternal stress also induced oxidative stress in the placenta, but not in the fetal brain. Blocking oxidative stress using an antioxidant prevented the prenatal stress-induced anxiety phenotype in the male offspring, and prevented sex-specific neurobiological changes, specifically a reduction in dendrite lengths in the hippocampus, as well as reductions in the number of parvalbumin-positive neurons and GABA receptor subunits in the hippocampus and basolateral amygdala of the male offspring. Importantly, many of these effects were mimicked in neuronal cultures by application of placental-conditioned medium or fetal plasma from stressed pregnancies, indicating molecules released from the placenta may mediate the effects of prenatal stress on the fetal brain. Indeed, both placenta-conditioned medium and fetal plasma contained differentially abundant microRNAs following maternal stress, and their predicted targets were enriched for genes relevant to nervous system development and psychiatric disorders. The results highlight placental oxidative stress as a key mediator in transmitting the maternal social stress effects on the offspring's brain and behaviour, and offer a potential intervention to prevent stress-induced fetal programming of affective disorders.
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