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The impact of maternal obesity in pregnancy on placental glucocorticoid and macronutrient transport and metabolism.
Johns, EC, Denison, FC, Reynolds, RM
Biochimica et biophysica acta. Molecular basis of disease. 2020;(2):165374
Abstract
Maternal obesity is the most common metabolic disturbance in pregnancy affecting >1 in 5 women in some countries. Babies born to obese women are heavier with more adiposity at birth, and are vulnerable to obesity and metabolic disease across the lifespan suggesting offspring health is 'programmed' by fetal exposure to an obese intra-uterine environment. The placenta plays a major role in dictating the impact of maternal health on prenatal development. Maternal obesity impacts the function of integral placental receptors and transporters for glucocorticoids and nutrients, key drivers of fetal growth, though mechanisms remain poorly understood. This review aims to summarise current knowledge in this area, and considers the impact of obesity on the epigenetic machinery of the placenta at this vital juncture in offspring development. Further research is required to advance understanding of these areas in the hope that the trans-generational cycle of obesity can be alleviated.
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Is there evidence for bacterial transfer via the placenta and any role in the colonization of the infant gut? - a systematic review.
Gil, A, Rueda, R, Ozanne, SE, van der Beek, EM, van Loo-Bouwman, C, Schoemaker, M, Marinello, V, Venema, K, Stanton, C, Schelkle, B, et al
Critical reviews in microbiology. 2020;(5):493-507
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With the important role of the gut microbiome in health and disease, it is crucial to understand key factors that establish the microbial community, including gut colonization during infancy. It has been suggested that the first bacterial exposure is via a placental microbiome. However, despite many publications, the robustness of the evidence for the placental microbiome and transfer of bacteria from the placenta to the infant gut is unclear and hence the concept disputed. Therefore, we conducted a systematic review of the evidence for the role of the placental, amniotic fluid and cord blood microbiome in healthy mothers in the colonization of the infant gut. Most of the papers which were fully assessed considered placental tissue, but some studied amniotic fluid or cord blood. Great variability in methodology was observed especially regarding sample storage conditions, DNA/RNA extraction, and microbiome characterization. No study clearly considered transfer of the normal placental microbiome to the infant gut. Moreover, some studies in the review and others published subsequently reported little evidence for a placental microbiome in comparison to negative controls. In conclusion, current data are limited and provide no conclusive evidence that there is a normal placental microbiome which has any role in colonization of infant gut.
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Oxidative stress markers in preeclamptic placentas: A systematic review with meta-analysis.
Ferreira, RC, Fragoso, MBT, Bueno, NB, Goulart, MOF, de Oliveira, ACM
Placenta. 2020;:89-100
Abstract
INTRODUCTION Oxidative stress (OS) is the basis of several diseases. Preeclampsia (PE) is a multisystemic syndrome, considered one of the major causes of maternal and fetal mortality. The placenta is considered the main anatomical pathogenetic substrate for the disease, being the placental OS a likely critical pathway in the pathogenesis of PE. This meta-analysis aimed to verify whether there is OS in the preeclamptic placenta and which markers are altered in this condition. METHODS The search was conducted in the following databases: MEDLINE (via PubMed), Lilacs and Scopus. Relevant studies were identified until May 2020. The quality of the studies was evaluated according to the Newcastle-Ottawa scale. RESULTS From the 3998 screened records, 43 were finally included in the systematic review, and 23 in the meta-analysis. The biomarkers evaluated were related to cell and macromolecules' damage, such as malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OH-dG), lipid peroxides, isoprostane, total oxidant status (TOS), carbonylated proteins and some of the reactive oxygen and nitrogen species (RONS), like hydrogen peroxide and nitric oxide. It was also related to antioxidant activity, both enzymatic, including superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione S-transferase and total antioxidant status, and non-enzymatic, through quantification of reduced glutathione, vitamin C and E, zinc and copper. CONCLUSION It was observed that there was OS in the preeclamptic placentas, based on results, like lower activity of some of the enzymes of the antioxidant system (SOD and GPx) as well as the increase in oxidative damage markers (MDA and lipid peroxide), corroborating literature data.
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Antiviral properties of placental growth factors: A novel therapeutic approach for COVID-19 treatment.
Joshi, MG, Kshersagar, J, Desai, SR, Sharma, S
Placenta. 2020;:117-130
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The current challenge of the COVID-19 pandemic is complicated by the limited therapeutic options against the virus, with many being anecdotal or still undergoing confirmatory trials, underlining the urgent need for novel strategies targeting the virus. The pulmotropic virus causes loss of oxygenation in severe cases with acute respiratory distress syndrome (ARDS) and need for mechanical ventilation. This work seeks to introduce placental extract-derived biologically active components as a therapeutic option and highlights their mechanism of action relevant to COVID-19 virus. Human placenta has been used in clinical practice for over a century and there is substantial experience in clinical applications of placental extract for different indications. Aqueous extract of human placentacontains growth factors, cytokines/chemokines, natural metabolic and other compounds, anti-oxidants, amino acids, vitamins, trace elements and biomolecules, which individually or in combination show accelerated cellular metabolism, immunomodulatory and anti-inflammatory effects, cellular proliferation and stimulation of tissue regeneration processes. Placental extract treatment is proposed as a suitable therapeutic approach consideringthe above properties which could protect against initial viral entry and acute inflammation of alveolar epithelial cells, reconstitute pulmonary microenvironment and regenerate the lung. We reviewed useful therapeutic information of placental biomolecules in relation to COVID-19 treatment. We propose the new approach of using placental growth factors, chemokines and cytokine which will execute antiviral activity in coordination with innate and humoral immunity and improve patient's immunological responses to COVID-19. Executing a clinical trial using placental extract as preventive, protective and/or therapeutic approach for COVID-19treatment could advance the development of a most promising therapeutic candidate that can join the armamentaria against the COVID-19 virus.
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Maternal dietary fatty acids and their roles in human placental development.
Duttaroy, AK, Basak, S
Prostaglandins, leukotrienes, and essential fatty acids. 2020;:102080
Abstract
Fatty acids are essential for feto-placental growth and development. Maternal fatty acids and their metabolites are involved in every stage of pregnancy by supporting cell growth and development, cell signaling, and modulating other critical aspects of structural and functional processes. Early placentation process is critical for placental growth and function. Several fatty acids modulate angiogenesis as observed by increased tube formation and secretion of angiogenic growth factors in first-trimester human placental trophoblasts. Long-chain fatty acids stimulate angiogenesis in these cells via vascular endothelium growth factor (VEGF), angiopoietin-like protein 4 (ANGPTL4), fatty acid-binding proteins (FABPs), or eicosanoids. Inadequate placental angiogenesis and trophoblast invasion of the maternal decidua and uterine spiral arterioles leads to structural and functional deficiency of placenta, which contributes to preeclampsia, pre-term intrauterine growth restriction, and spontaneous abortion and also affects overall fetal growth and development. During the third trimester of pregnancy, placental preferential transport of maternal plasma long-chain polyunsaturated fatty acids is of critical importance for fetal growth and development. Fatty acids cross the placental microvillous and basal membranes by mainly via plasma membrane fatty acid transport system (FAT, FATP, p-FABPpm, & FFARs) and cytoplasmic FABPs. Besides, a member of the major facilitator superfamily-MFSD2a, present in the placenta is involved in the supply of DHA to the fetus. Maternal factors such as diet, obesity, endocrine, inflammation can modulate the expression and activity of the placental fatty acid transport activity and thereby impact feto-placental growth and development. In this review, we discuss the maternal dietary fatty acids, and placental transport and metabolism, and their roles in placental growth and development.
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Associations between the activity of placental nutrient-sensing pathways and neonatal and postnatal metabolic health: the ECHO Healthy Start cohort.
Keleher, MR, Erickson, K, Kechris, K, Yang, IV, Dabelea, D, Friedman, JE, Boyle, KE, Jansson, T
International journal of obesity (2005). 2020;(11):2203-2212
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OBJECTIVE Our hypothesis was that the activity of placental nutrient-sensing pathways is associated with adiposity and metabolic health in childhood. RESEARCH DESIGN AND METHODS Using placental villus samples from healthy mothers from the Healthy Start Study, we measured the abundance and phosphorylation of key intermediates in the mTOR, insulin, AMPK, and ER stress signaling pathways. Using multivariate multiple regression models, we tested the association between placental proteins and offspring adiposity (%fat mass) at birth (n = 109), 4-6 months (n = 104), and 4-6 years old (n = 64), adjusted for offspring sex and age. RESULTS Placental mTORC1 phosphorylation was positively associated with adiposity at birth (R2 = 0.13, P = 0.009) and 4-6 years (R2 = 0.15, P = 0.046). The mTORC2 target PKCα was positively associated with systolic blood pressure at 4-6 years (β = 2.90, P = 0.005). AMPK phosphorylation was positively associated with adiposity at birth (β = 2.32, P = 0.023), but the ratio of phosphorylated to total AMPK was negatively associated with skinfold thickness (β = -2.37, P = 0.022) and body weight (β = -2.92, P = 0.005) at 4-6 years. CONCLUSIONS This is the first report of associations between key placental protein activity measures and longitudinal child outcomes at various life stages. Our data indicate that AMPK and mTOR signaling are linked to cardiometabolic measures at birth and 4-6 years, providing novel insight into potential mechanisms underpinning how metabolic signaling in the placenta is associated with future risk of cardiovascular disease.
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DNA methylation loci in placenta associated with birthweight and expression of genes relevant for early development and adult diseases.
Tekola-Ayele, F, Zeng, X, Ouidir, M, Workalemahu, T, Zhang, C, Delahaye, F, Wapner, R
Clinical epigenetics. 2020;(1):78
Abstract
BACKGROUND Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. The placenta, a transient organ at the maternal-fetal interface, regulates fetal growth. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life. RESULTS We performed placental epigenome-wide association study (EWAS) of birthweight in an ethnic diverse cohort of pregnant women (n = 301). Methylation at 15 cytosine-(phosphate)-guanine sites (CpGs) was associated with birthweight (false discovery rate (FDR) < 0.05). Methylation at four (26.7%) CpG sites was associated with placental transcript levels of 15 genes (FDR < 0.05), including genes known to be associated with adult lipid traits, inflammation and oxidative stress. Increased methylation at cg06155341 was associated with higher birthweight and lower FOSL1 expression, and lower FOSL1 expression was correlated with higher birthweight. Given the role of the FOSL1 transcription factor in regulating developmental processes at the maternal-fetal interface, epigenetic mechanisms at this locus may regulate fetal development. We demonstrated trans-tissue portability of methylation at four genes (MLLT1, PDE9A, ASAP2, and SLC20A2) implicated in birthweight by a previous study in cord blood. We also found that methylation changes known to be related to maternal underweight, preeclampsia and adult type 2 diabetes were associated with lower birthweight in placenta. CONCLUSION We identified novel placental DNA methylation changes associated with birthweight. Placental epigenetic mechanisms may underlie dysregulated fetal development and early origins of adult cardiometabolic diseases. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT00912132.
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Differences of DNA methylation patterns in the placenta of large for gestational age infant.
Shen, Z, Tang, Y, Song, Y, Shen, W, Zou, C
Medicine. 2020;(39):e22389
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To investigate the molecular mechanisms of later metabolic health changes in large for gestational age (LGA) newborns by analyzing deoxyribonucleic acid (DNA) methylation patterns in the placenta of LGA and appropriate for gestational age (AGA) newborns.A total of 6 placentas of LGA and 6 placentas of AGA newborns were enrolled as LGA group and AGA group. DNA methylation was analyzed using the Illumina Infinium Human MethylationEPIC BeadChip microarrays and verified via pyrosequencing and reverse transcription-quantitative real-time polymerase chain reaction. Functional enrichment analysis were constructed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis based on the differentially methylated regions between LGA and AGA groups.Clinical investigation showed that LGA newborns had significantly lower hemoglobin and blood glucose compared to AGA newborns. Birth weight was negatively correlated to hemoglobin and blood glucose. Genome-wide DNA methylation analysis identified 17 244 methylation variable positions achieving genome-wide significance (adjusted P < .05). 34% methylation variable positions were located in the gene promoter region. A total of 117 differentially methylated regions were revealed by bump hunting analysis, which mapped to 107 genes. Function analysis showed 13 genes enriched in "adhesion and infection process, endocrine and other factor-regulated calcium reabsorption, calcium signaling pathway and transmembrane transport". Four genes linked to type II diabetes mellitus. Among the 13 genes, we selected GNAS and calcium voltage-gated channel subunit alpha1 G for independent verification of pyrosequencing, and the messenger ribonucleic acid levels of guanine nucleotide binding protein, calcium voltage-gated channel subunit alpha1 G, DECR1, and FK506 binding protein 11 were verified by reverse transcription-quantitative real-time polymerase chain reaction.DNA methylation variation and gene expression differences in placental samples were associated with LGA newborns, which linking the effect of intrauterine environment to regulation of the offspring's gene expression. Furthermore, pathway analysis suggested that intrauterine environment affecting fetal growth might had a functional impact on multiple signaling pathways involved in fetal growth, metabolism, and inflammation. Further studies were required to understand the differences of methylation patterns.
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Maternal stress and placental function; ex vivo placental perfusion studying cortisol, cortisone, tryptophan and serotonin.
Mathiesen, L, Bay-Richter, C, Wegener, G, Liebenberg, N, Knudsen, LE
PloS one. 2020;(6):e0233979
Abstract
BACKGROUND Exposure to maternal stress during pregnancy can have adverse effects on the fetus, which has potential long-term effects on offspring´s development and health. We investigated the kinetics and metabolism of the hormones and amino acids: cortisol, cortisone, tryptophan and serotonin in the term placenta in an ex vivo human placental perfusion model. The placentas used in the experiments were donated from families participating in the Maternal Stress and Placental Function project with a known maternal stress background. METHOD Cortisol, cortisone, tryptophan and serotonin were added simultaneously to the maternal side in the 6 hour ex vivo term human recirculating placental perfusion model, in four experimental set-ups: without inhibitors, with carbenoxolone -that inhibits cortisol metabolism into cortisone, with fluoxetine that inhibits the serotonin transporter, and with PCPA that inhibits metabolism of tryptophan into serotonin. The concentration of cortisol and cortisone, and tryptophan and serotonin were quantified using UPLC and HPLC-MS respectively. RESULTS Cortisol was rapidly metabolized into cortisone in the placenta, to a somewhat lesser degree when adding the inhibitor carbenoxolone, resulting in higher fetal exposure to cortisol. Serotonin was also rapidly metabolized in the placenta. When adding fluoxetine a peak of fetal serotonin levels was seen in the first hour of the perfusion. No effect was seen of the maternal stress levels on placental transport kinetics in this study. CONCLUSION Inhibiting the metabolism of cortisol in the placenta increased fetal exposure to cortisol as expected. Unexpectedly we saw an increased fetal exposure to serotonin when inhibiting the serotonin transporter, which may be related to the increased serotonin concentration on the maternal side of the placenta. No effect on placental kinetics were evident on maternal stress levels during the pregnancy as the majority of participating mothers had normal stress levels.
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Placental Regulation of Energy Homeostasis During Human Pregnancy.
Armistead, B, Johnson, E, VanderKamp, R, Kula-Eversole, E, Kadam, L, Drewlo, S, Kohan-Ghadr, HR
Endocrinology. 2020;(7)
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Successful pregnancies rely on sufficient energy and nutrient supply, which require the mother to metabolically adapt to support fetal needs. The placenta has a critical role in this process, as this specialized organ produces hormones and peptides that regulate fetal and maternal metabolism. The ability for the mother to metabolically adapt to support the fetus depends on maternal prepregnancy health. Two-thirds of pregnancies in the United States involve obese or overweight women at the time of conception. This poses significant risks for the infant and mother by disrupting metabolic changes that would normally occur during pregnancy. Despite well characterized functions of placental hormones, there is scarce knowledge surrounding placental endocrine regulation of maternal metabolic trends in pathological pregnancies. In this review, we discuss current efforts to close this gap of knowledge and highlight areas where more research is needed. As the intrauterine environment predetermines the health and wellbeing of the offspring in later life, adequate metabolic control is essential for a successful pregnancy outcome. Understanding how placental hormones contribute to aberrant metabolic adaptations in pathological pregnancies may unveil disease mechanisms and provide methods for better identification and treatment. Studies discussed in this review were identified through PubMed searches between the years of 1966 to the present. We investigated studies of normal pregnancy and metabolic disorders in pregnancy that focused on energy requirements during pregnancy, endocrine regulation of glucose metabolism and insulin resistance, cholesterol and lipid metabolism, and placental hormone regulation.