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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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Abstract
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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Early pregnancy dyslipidemia is associated with placental DNA methylation at loci relevant for cardiometabolic diseases.
Ouidir, M, Zeng, X, Workalemahu, T, Shrestha, D, Grantz, KL, Mendola, P, Zhang, C, Tekola-Ayele, F
Epigenomics. 2020;(11):921-934
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Aim: To identify placental DNA methylation changes that are associated with early pregnancy maternal dyslipidemia. Materials & methods: We analyzed placental genome-wide DNA methylation (n = 262). Genes annotating differentially methylated CpGs were evaluated for gene expression in placenta (n = 64). Results: We found 11 novel significant differentially methylated CpGs associated with high total cholesterol, low-density lipoprotein cholesterol and triglycerides, and low high-density lipoprotein cholesterol. High triglycerides were associated with decreased methylation of cg02785814 (ALX4) and decreased expression of ALX4 in placenta. Genes annotating the differentially methylated CpGs play key roles in lipid metabolism and were enriched in dyslipidemia pathways. Functional annotation found cis-methylation quantitative trait loci for genetic loci in ALX4 and EXT2. Conclusion: Our findings lend novel insights into potential placental epigenetic mechanisms linked with maternal dyslipidemia. 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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Mitochondrial implications in human pregnancies with intrauterine growth restriction and associated cardiac remodelling.
Guitart-Mampel, M, Juarez-Flores, DL, Youssef, L, Moren, C, Garcia-Otero, L, Roca-Agujetas, V, Catalan-Garcia, M, Gonzalez-Casacuberta, I, Tobias, E, Milisenda, JC, et al
Journal of cellular and molecular medicine. 2019;(6):3962-3973
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Intrauterine growth restriction (IUGR) is an obstetric complication characterised by placental insufficiency and secondary cardiovascular remodelling that can lead to cardiomyopathy in adulthood. Despite its aetiology and potential therapeutics are poorly understood, bioenergetic deficits have been demonstrated in adverse foetal and cardiac development. We aimed to evaluate the role of mitochondria in human pregnancies with IUGR. In a single-site, cross-sectional and observational study, we included placenta and maternal peripheral and neonatal cord blood mononuclear cells (PBMC and CBMC) from 14 IUGR and 22 control pregnancies. The following mitochondrial measurements were assessed: enzymatic activities of mitochondrial respiratory chain (MRC) complexes I, II, IV, I + III and II + III, oxygen consumption (cell and complex I-stimulated respiration), mitochondrial content (citrate synthase [CS] activity and mitochondrial DNA copy number), total ATP levels and lipid peroxidation. Sirtuin3 expression was evaluated as a potential regulator of bioenergetic imbalance. Intrauterine growth restriction placental tissue showed a significant decrease of MRC CI enzymatic activity (P < 0.05) and CI-stimulated oxygen consumption (P < 0.05) accompanied by a significant increase of Sirtuin3/β-actin protein levels (P < 0.05). Maternal PBMC and neonatal CBMC from IUGR patients presented a not significant decrease in oxygen consumption (cell and CI-stimulated respiration) and MRC enzymatic activities (CII and CIV). Moreover, CS activity was significantly reduced in IUGR new-borns (P < 0.05). Total ATP levels and lipid peroxidation were preserved in all the studied tissues. Altered mitochondrial function of IUGR is especially present at placental and neonatal level, conveying potential targets to modulate obstetric outcome through dietary interventions aimed to regulate Sirtuin3 function.
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A clinical research study on the respective relationships between visfatin and human fetuin A and pregnancy outcomes in gestational diabetes mellitus.
Lu, D, Yang, M, Yao, Y, Xie, Y
Taiwanese journal of obstetrics & gynecology. 2019;(6):808-813
Abstract
OBJECTIVE The aim was to determine the role of visfatin (VF) and human fetuin A (AHSG) in the development of gestational diabetes mellitus (GDM) and to explore the association between these variables and adverse outcomes. MATERIALS AND METHODS We carried out our study on 68 cases of GDM pregnant women and 42 cases of healthy pregnant women, including 56 cases with diet control and 12 cases with insulin treatment. Enzyme-linked immunoassay (ELISA) was used to test the expression levels of VF and AHSG in maternal and umbilical cord serum. Immunohistochemistry (ICH) was used to test the expression level of the VF protein in placental tissue. RESULTS The expression levels of VF and AHSG in maternal and umbilical cord serum and the expression level of VF in placental tissue in GDM pregnant women were higher than those in healthy pregnant women. The incidence of adverse outcomes in the GDM pregnant women was higher than that in healthy pregnant women, and these differences were statistically significant (P < 0.05). Those who had higher expression levels of VF or AHSG had a higher incidence of adverse outcomes (P < 0.05). CONCLUSION The expression of VF and AHSG may participate in the development of GDM. A test of VF and AHSG in GDM pregnant women may have some predictive value for the occurrence of adverse outcomes.
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Placental MFSD2a transporter is related to decreased DHA in cord blood of women with treated gestational diabetes.
Prieto-Sánchez, MT, Ruiz-Palacios, M, Blanco-Carnero, JE, Pagan, A, Hellmuth, C, Uhl, O, Peissner, W, Ruiz-Alcaraz, AJ, Parrilla, JJ, Koletzko, B, et al
Clinical nutrition (Edinburgh, Scotland). 2017;(2):513-521
Abstract
BACKGROUND & AIMS Maternal-fetal transfer of docosahexaenoic acid (DHA) is impaired by gestational diabetes mellitus (GDM), but the underlying mechanisms are still unknown. MFSD2a was recently recognized as a lyso-phospholipid (lyso-PL) transporter that facilitates DHA accretion in brain. The role of this transporter in placenta is uncertain. We evaluated effects of GDM and its treatment (diet or insulin) on phospholipid species, fatty acid profile in women, cord blood and placental fatty acid carriers. METHODS Prospective observational study of pregnant women recruited in the third trimester (25 controls, 23 GDM-diet, 20 GDM-insulin). Fetal ultrasound was performed at gestational week 38. At delivery, maternal and neonatal anthropometry was performed, and fatty acids in total lipids and phospholipid species were analyzed in placenta, maternal and venous cord blood. Western-blot analyses were performed for placental fatty acid carriers. RESULTS Fetal abdominal circumference z-score at 38 weeks tended to higher values in GDM (P = 0.071), pointing toward higher fetal fat accretion in these babies. DHA percentage in cord serum total lipids (P = 0.029) and lyso-PL (P = 0.169) were reduced in GDM. Placental MFSD2a was reduced in both GDM groups and was positively correlated to DHA values in cord serum total lipids (r = 0.388, P = 0.003). Among established placental lipid carriers, only FATP4 was correlated to DHA concentration in placental lyso-PL. In all compartments, DHA percentage was inversely correlated to fetal abdominal circumference. CONCLUSIONS In offspring of women with GDM treated either with diet or insulin, higher fetal fat accretion and lower placental MFSD2a contribute to reduce DHA availability. Lyso-PL appear to contribute to materno-fetal DHA transport.
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Effects of obesity and gestational diabetes mellitus on placental phospholipids.
Uhl, O, Demmelmair, H, Segura, MT, Florido, J, Rueda, R, Campoy, C, Koletzko, B
Diabetes research and clinical practice. 2015;(2):364-71
Abstract
Gestational diabetes mellitus (GDM) is associated with adverse effects in the offspring. The composition of placental glycerophospholipids (GPL) is known to be altered in GDM and might reflect an aberrant fatty acid transfer across the placenta and thus affect the foetal body composition. The aim of this study was to investigate possible effects of obesity and GDM, respectively, on placental GPL species composition. We investigated molecular species of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS) in term placentas from controls (lean non-diabetic, body-mass-index [BMI] 18-24.9k g/m(2), n=31), obese non-diabetics (BMI ≥30 kg/m(2), n=17) and lean diabetics (n=15), using liquid chromatography - triple quadrupole mass spectrometry. PE(16:0/22:6) and PE(18:0/20:4) were increased in GDM and decreased species were PC(18:0/20:3), PC(18:1/20:3) and PS(18:0/18:2). A consistent difference between BMI related changes and changes caused by GDM was not observed. Arachidonic acid percentages of cord blood correlated with placental PC(16:0/20:4), whereas foetal docosahexaenoic acid correlated to placental PE species. Furthermore, a positive correlation of placental weight was found to levels of PE containing arachidonic acid. We demonstrated that obesity and GDM are associated with decreased dihomo-gamma-linolenic acid and increased arachidonic acid and docosahexaenoic acid contents of placental GPL, with unknown consequences for the foetus. PC(16:0/20:4) was identified as the major component for the supply of arachidonic acid to the foetal circulation, whereas PE containing arachidonic acid was found to be associated to the placental and infant growth.
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There is no difference in nitric oxide metabolites and neonatal outcome between premature infants born to pre-eclamptic and those born to normotensive women.
Rugolo, LM, de Sá, MP, Kurokawa, CS, Madoglio, RJ, Bentlin, MR, Rugolo, A, Corrente, JE
Paediatrics and international child health. 2015;(1):47-52
Abstract
BACKGROUND The pathophysiology of pre-eclampsia (PE) is complex, and nitric oxide (NO) may be a factor. The neonatal outcome in pregnancies complicated by PE is controversial, and the PE/NO/neonatal diseases relationship has not been well established. AIMS To measure nitrate and nitrite levels in the placenta, umbilical cord blood, blood and urine of preterm neonates born to pre-eclamptic and normotensive women and to investigate the relationship between placental, fetal and neonatal NO metabolites and neonatal outcome. METHODS A prospective study was undertaken of 30 preterm infants <34 weeks of gestation, born to pre-eclamptic mothers and matched by gestational age with 30 infants born to normotensive mothers. Samples from the placental tissue, venous cord blood and the newborns' blood on day 4 and urine on days 1 and 4 were assayed for NO metabolites (nitrate and nitrite). Clinical variables and NO metabolites were compared between the groups. Generalised linear models were fitted to associate NO metabolites levels with adverse neonatal outcomes. RESULTS There were no differences in NO metabolites and neonatal outcomes between the two groups. Increased levels of NO metabolites were found in the placenta and cord blood of small-for-gestational-age infants, and in the cord blood of newborns with necrotising enterocolitis and those who died. CONCLUSION NO metabolite levels in the placenta and fetal and neonatal circulation were not associated with PE; however, cord blood levels of NO metabolites differed according to fetal growth and neonatal outcome.
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Back to the future: examining type 2 diabetic vasculature using the gestational diabetic placenta.
Samuel, R, Ramanathan, K, Mathews, JE, Seshadri, MS
Diabetes & vascular disease research. 2014;(5):363-5
Abstract
Understanding the association between the intrauterine hyperglycemic milieu and the development of adult diabetic vasculopathy is of particular relevance in India, where diabetes and vascular disease are prevalent. The gestational diabetes mellitus placenta is a valuable tool to examine blood vessels that have been exposed to hyperglycemic cues. We report an interesting observation in a cohort of gestational diabetes mellitus foetal placental vasculature from South India. Transmission electron microscopy demonstrated pericyte detachment and pericyte ghost cells reminiscent of adult type 2 diabetic retinopathy, in gestational diabetes mellitus foetal placental blood vessels that were not observed in non-gestational diabetes mellitus placentas (p ≤0.001). Endothelial cell irregularity was observed in 76% gestational diabetes mellitus foetal blood vessels as compared with 10.4% non-gestational diabetes mellitus placental vasculature (p ≤0.001). Other abnormalities noted in gestational diabetes mellitus placenta included mitochondrial abnormalities, increased micro vessel density and thickening of basement membranes. These results suggest that adult type 2 diabetic vasculopathy has developmental origins in utero.