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In vivo kinetic study of materno-fetal fatty acid transfer in obese and normal weight pregnant women.
Gázquez, A, Prieto-Sánchez, MT, Blanco-Carnero, JE, van Harskamp, D, Perazzolo, S, Oosterink, JE, Demmelmair, H, Schierbeek, H, Sengers, BG, Lewis, RM, et al
The Journal of physiology. 2019;(19):4959-4973
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Abstract
KEY POINTS Placental structure and function can be modified as a result of maternal obesity affecting materno-fetal fatty acids (FA) transport. We report for the first time, in humans and in vivo, the kinetics of placental FA transfer in normo-weight and in normolipemic obese pregnant women using stable isotopes. The administration of different tracer FA with similar behaviour to the mother at different time points allows the collection of kinetic information on materno-fetal transfer of FA despite only one sample of placenta and cord can be collected per subject. Computational modelling showed a good fit to the data when considering all maternal plasma lipid classes but not when based only on non-esterified FA. The novel approach using multiple tracer FA administration combined with computational modelling shows a consistent time course of placental tracer FA and predicted total FA accumulation. ABSTRACT We analyse for the first time the in vivo materno-fetal kinetic transfer of fatty acids (FA) labelled with stable isotopes in control and obese (OB) pregnant women. Labelled FA with a similar metabolism (stearic acid: 13 C-SA; palmitic acid: 13 C-PA; oleic acid: 13 C-OA) were orally administered at -4 h, -8 h and -12 h, respectively prior to elective caesarean section to 10 pregnant women with a body mass index >30 (OB) and 10 with a body mass index in the range 20-25 (NW). Placenta, venous and arterial cord blood were collected obtaining a wide range of FA enrichments. A combined experimental and computational modelling analysis was applied. FA fractional synthesis rate (FSR) in placenta was 11-12% h-1 . No differences were observed between NW and normo-lipidemic OB. It was not possible to estimate FA FSR in cord blood with this oral bolus dose approach. Computational modelling demonstrated a good fit to the data when all maternal plasma lipid classes were included but not with modelling based only on the non-esterified FA fraction. The estimated materno-fetal 13 C-FA transfer was ∼1%. In conclusion, our approach using multiple 13 C-FA tracers allowed us to estimated FSR in placental/maternal plasma but not in fetal/maternal compartments. Computational modelling showed a consistent time course of placental 13 C-FA transfer and predicted total fetal FA accumulation during the experiment. We conclude that, in addition to non-esterified FA fraction in the maternal circulation, maternal plasma very low-density lipoprotein and other lipoproteins are important contributors to placental FA transfer to the fetus.
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Steroid hormones and pregnancy.
Noyola-Martínez, N, Halhali, A, Barrera, D
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2019;(5):376-384
Abstract
Pregnancy is associated with physiological adjustments in order to allow adequate growth and fetal development. In particular, steroids are necessary to maintain in balance numerous functions during gestation. Steroidogenesis in the maternal, placental and fetal compartments and the biological effects of progestins and estrogens that play a pivotal role before and during pregnancy are described. Although it is well-known that androgens are considered as substrate for estrogens biosynthesis, their biosynthesis and functionality in placental and other tissues have been questioned. As compared with healthy pregnancy, steroid hormones levels have been found altered in complicated pregnancies and hormonal treatments have been used is some pathologies. Therefore, the aim of this work was to review the biosynthesis, function and regulation of progestins, androgens and estrogens during gestation. Furthermore, steroid hormones concentrations during healthy and complicated pregnancy as well hormonal therapies for the prevention of miscarriages and preterm deliveries are discussed in the present review.
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Latest findings on the placenta from the point of view of immunology, tolerance and mesenchymal stem cells.
Macholdová, K, Macháčková, E, Prošková, V, Hromadníková, I, Klubal, R
Ceska gynekologie. 2019;(2):154-160
Abstract
OBJECTIVE Overview of current placental findings from the point of view of immunology, tolerance and mesenchymal stem cells. TYPE OF STUDY Review. SETTING Medicínské centrum Praha. CONCLUSION The placenta is an important organ that connects mother and developing fetus during pregnancy. For the uncomplicated course of pregnancy and fetal development the placental function is crucial. The placenta provides not only the replacement of breathing gases, nutrients and waste materials, but also creates an immunological interface between the mother and the fetus. Maternal tolerance towards the fetus carrying paternal antigens is induced at the fetomaternal interface due to the mutual molecular interactions. Immune tolerance at the interface between placenta and decidua is ensured mainly due to the expression of HLA-C, HLA-E, HLA-F, and HLA-G on trophoblasts and their interactions with receptors expressed on uterine NK cells. Regulatory T cells and DC-10 cells also play an important role at the fetomaternal interface on the mothers side of placenta. However, some fetal cells, such as Hofbauer cells or granulocytic myeloid-derived suppressor cells are also partially involved in inducement of maternal tolerance towards the fetus. Recently, considerable attention is also paid to mesenchymal stem cells derived from both placental and umbilical tissues. These mesenchymal stem cells play an important role in inducement of immune tolerance and exhibit better immunomodulatory properties than mesenchymal stem cells isolated from adult human tissues.
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Integrating Autism Spectrum Disorder Pathophysiology: Mitochondria, Vitamin A, CD38, Oxytocin, Serotonin and Melatonergic Alterations in the Placenta and Gut.
Maes, M, Anderson, G, Betancort Medina, SR, Seo, M, Ojala, JO
Current pharmaceutical design. 2019;(41):4405-4420
Abstract
BACKGROUND A diverse array of data has been associated with autism spectrum disorder (ASD), reflecting the complexity of its pathophysiology as well as its heterogeneity. Two important hubs have emerged, the placenta/prenatal period and the postnatal gut, with alterations in mitochondria functioning crucial in both. METHODS Factors acting to regulate mitochondria functioning in ASD across development are reviewed in this article. RESULTS Decreased vitamin A, and its retinoic acid metabolites, lead to a decrease in CD38 and associated changes that underpin a wide array of data on the biological underpinnings of ASD, including decreased oxytocin, with relevance both prenatally and in the gut. Decreased sirtuins, poly-ADP ribose polymerase-driven decreases in nicotinamide adenine dinucleotide (NAD+), hyperserotonemia, decreased monoamine oxidase, alterations in 14-3-3 proteins, microRNA alterations, dysregulated aryl hydrocarbon receptor activity, suboptimal mitochondria functioning, and decreases in the melatonergic pathways are intimately linked to this. Many of the above processes may be modulating, or mediated by, alterations in mitochondria functioning. Other bodies of data associated with ASD may also be incorporated within these basic processes, including how ASD risk factors such as maternal obesity and preeclampsia, as well as more general prenatal stressors, modulate the likelihood of offspring ASD. CONCLUSION Such a mitochondria-focussed integrated model of the pathophysiology of ASD has important preventative and treatment implications.
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Risk of Ischemic Placental Disease in Relation to Family History of Preeclampsia.
Ananth, CV, Jablonski, K, Myatt, L, Roberts, JM, Tita, ATN, Leveno, KJ, Reddy, UM, Varner, MW, Thorp, JM, Mercer, BM, et al
American journal of perinatology. 2019;(6):624-631
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OBJECTIVE To assess the risk of ischemic placental disease (IPD) including preeclampsia, small for gestational age (SGA), and abruption, in relation to preeclampsia in maternal grandmother, mother, and sister(s). STUDY DESIGN We performed a secondary analysis of data from a randomized trial of vitamins C and E for preeclampsia prevention. Data on family history of preeclampsia were based on recall by the proband. The associations between family history of preeclampsia and the odds of IPD were evaluated from alternating logistic regressions. RESULTS Of the 9,686 women who delivered nonmalformed, singleton live births, 17.1% had IPD. Probands provided data on preeclampsia in 55.5% (n = 5,374) on all three family members, 26.5% (n = 2,562) in mother and sister(s) only, and 11.6% (n = 1,125) in sister(s) only. The pairwise odds ratio (pOR) of IPD was 1.16 (95% confidence interval [CI]: 1.00-1.36) if one or more of the female relatives had preeclampsia. The pORs of preeclampsia were 1.54 (95% CI: 1.12-2.13) and 1.35 (95% CI: 1.03-1.77) if the proband's mother or sister(s) had a preeclamptic pregnancy, respectively, but no associations were seen for SGA infant or abruption. CONCLUSION This study suggests that IPD may share a predisposition with preeclampsia, suggesting a familial inheritance.
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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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Analysis of correlations between the placental expression of glucose transporters GLUT-1, GLUT-4 and GLUT-9 and selected maternal and fetal parameters in pregnancies complicated by diabetes mellitus.
Stanirowski, PJ, Szukiewicz, D, Pyzlak, M, Abdalla, N, Sawicki, W, Cendrowski, K
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2019;(4):650-659
Abstract
PURPOSE The aim of the study was to analyze the correlations between the expression of glucose transporters GLUT-1, GLUT-4, and GLUT-9 in human term placenta and selected maternal and fetal parameters in pregnancies complicated by diabetes mellitus (DM). MATERIALS AND METHODS Placental samples were obtained from healthy control (n = 25) and diabetic pregnancies, including diet-controlled gestational diabetes mellitus (GDMG1) (n = 16), insulin-controlled gestational diabetes mellitus (GDMG2) (n = 6), and pregestational DM (PGDM) (n = 6). Computer-assisted quantitative morphometry of stained placental sections was performed to determine the expression of selected glucose transporter proteins. For the purposes of correlation analysis, the following parameters were selected: type of diabetes, gestational age, maternal prepregnancy body mass index (BMI), gestational weight gain, third trimester glycated hemoglobin concentration, placental weight, fetal birth weight (FBW) as well as ultrasonographic indicators of fetal adiposity, including subscapular (SSFM), abdominal (AFM), and midthigh (MTFM) fat mass measurements. RESULTS In the PGDM group, the analysis demonstrated positive correlations between the placental expression of GLUT-1, GLUT-4, and GLUT-9 and FBW, AFM, and SSFM measurements (p < .05). Similarly in the GDMG2 patients positive correlations between GLUT-4 expression, FBW and SSFM were observed (p < .05). In the multivariate regression analysis, only the type of diabetes and FBW were significantly associated with GLUTs expression (p < .001). In addition, maternal prepregnancy BMI significantly contributed to GLUT-1 expression (p < .001). CONCLUSIONS The study results revealed that placental expression of GLUT-1, GLUT-4, and GLUT-9 may be involved in the intensification of the fetal growth in pregnancies complicated by GDM/PGDM.
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Quantification of Calcyclin and Heat Shock Protein 90 in Sera from Women with and without Preeclampsia by Mass Spectrometry.
Güzel, C, van den Berg, CB, Duvekot, JJ, Stingl, C, van den Bosch, TPP, van der Weiden, M, Steegers, EAP, Steegers-Theunissen, RPM, Luider, TM
Proteomics. Clinical applications. 2019;(3):e1800181
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PURPOSE The objective of present study is to determine serum levels and placental distribution of two interacting proteins calcyclin and heat shock protein 90 in preeclampsia. EXPERIMENTAL DESIGN Maternal serum levels of calcyclin and heat shock protein 90 are compared throughout pregnancy from the first trimester till term among women with preeclampsia (n = 43) and age-matched normotensive pregnant controls (n = 46). A serum-based 2D LC-MS assay using Parallel Reaction Monitoring is applied to quantify both calcyclin and heat shock protein 90. RESULTS Serum levels of calcyclin are significantly lower in patients with preeclampsia in the second trimester of pregnancy as compared to controls (p < 0.05). Serum levels of heat shock protein 90 are significantly higher in patients with preeclampsia in the third trimester as compared to controls (p < 0.001). CONCLUSION AND CLINICAL RELEVANCE Both interacting proteins calcyclin and heat shock protein 90 are notably changed in preeclamptic patients compared to controls. Calcyclin is already decreased before the onset of preeclampsia in the second trimester and HSP90 is strongly increased in the third trimester. This suggests that these proteins may play a role in the pathogenesis of preeclampsia and ought to be investigated in large cohort studies as molecular biomarkers.
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The choice of amniotic fluid in metabolomics for the monitoring of fetus health - update.
Bardanzellu, F, Fanos, V
Expert review of proteomics. 2019;(6):487-499
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Introduction: In recent years, several studies have highlighted the promising role of metabolomics in the analysis of amniotic fluid (AF), to describe and characterize the interactions occurring between the mother and the fetus during prenatal development. Among the available biological fluids, AF represents an ideal substrate to provide dynamic information regarding fetal organogenesis and metabolism through pregnancy, since it originates from both maternal and fetal tissues and contains substances derived from placenta, fetal skin, lungs, gastric fluid, and fetal urine. Areas covered: In this paper, we provide an update reporting the most recent results on AF metabolomics in the assessment of feto-maternal health, regarding physiological pregnancies but even fields such as prematurity, bronchopulmonary dysplasia, fetal malformations, chromosomopathies, maternal diseases, placental inflammation or infections, maternal diet or exposure to exogenous substances, according to the literature found on MEDLINE since 2015. Expert opinion: Metabolomics shows a promising role in describing both physiology and disease; the goal would be the identification of biomarkers able to precociously and efficaciously detect pathological conditions, allowing the identification of complicated pregnancy and improving their management. However, this field is under development and its reliability still needs to be clarified, especially through more numerous and accurate studies.
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Competition for nutrients in pregnant adolescents: consequences for maternal, conceptus and offspring endocrine systems.
Wallace, JM
The Journal of endocrinology. 2019;(1):T1-T19
Abstract
The competition for nutrients that arises when pregnancy coincides with continuing or incomplete growth in young adolescent girls increases the risk of preterm delivery and low birthweight with negative after-effects for mother and child extending beyond the perinatal period. Sheep paradigms involving nutritional management of weight and adiposity in young, biologically immature adolescents have allowed the consequences of differential maternal growth status to be explored. Although nutrient reserves at conception play a modest role, it is the dietary manipulation of the maternal growth trajectory thereafter which has the most negative impact on pregnancy outcome. Overnourishing adolescents to promote rapid maternal growth is particularly detrimental as placental growth, uteroplacental blood flows and fetal nutrient delivery are perturbed leading to a high incidence of fetal growth restriction and premature delivery of low birthweight lambs, whereas in undernourished adolescents further maternal growth is prevented, and depletion of the maternal body results in a small reduction in birthweight independent of placental size. Maternal and placental endocrine systems are differentially altered in both paradigms with downstream effects on fetal endocrine systems, organ development and body composition. Approaches to reverse these effects have been explored, predominantly targeting placental growth or function. After birth, growth-restricted offspring born to overnourished adolescents and fed to appetite have an altered metabolic phenotype which persists into adulthood, whereas offspring of undernourished adolescents are largely unaffected. This body of work using ovine paradigms has public health implications for nutritional advice offered to young adolescents before and during pregnancy, and their offspring thereafter.