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International Journal of Molecular... Jul 2022Minerals are required for the establishment and maintenance of pregnancy and regulation of fetal growth in mammals. Lentiviral-mediated RNA interference (RNAi) of...
Minerals are required for the establishment and maintenance of pregnancy and regulation of fetal growth in mammals. Lentiviral-mediated RNA interference (RNAi) of chorionic somatomammotropin hormone (CSH) results in both an intrauterine growth restriction (IUGR) and a non-IUGR phenotype in sheep. This study determined the effects of CSH RNAi on the concentration and uptake of calcium, phosphate, and vitamin D, and the expression of candidate mRNAs known to mediate mineral signaling in caruncles (maternal component of placentome) and cotyledons (fetal component of placentome) on gestational day 132. CSH RNAi Non-IUGR pregnancies had a lower umbilical vein−umbilical artery calcium gradient (p < 0.05) and less cotyledonary calcium (p < 0.05) and phosphate (p < 0.05) compared to Control RNAi pregnancies. CSH RNAi IUGR pregnancies had less umbilical calcium uptake (p < 0.05), lower uterine arterial and venous concentrations of 25(OH)D (p < 0.05), and trends for lower umbilical 25(OH)D uptake (p = 0.059) compared to Control RNAi pregnancies. Furthermore, CSH RNAi IUGR pregnancies had decreased umbilical uptake of calcium (p < 0.05), less uterine venous 25(OH)D (vitamin D metabolite; p = 0.055), lower caruncular expression of SLC20A2 (sodium-dependent phosphate transporter; p < 0.05) mRNA, and lower cotyledonary expression of KL (klotho; p < 0.01), FGFR1 (fibroblast growth factor receptor 1; p < 0.05), FGFR2 (p < 0.05), and TRPV6 (transient receptor potential vanilloid member 6; p < 0.05) mRNAs compared to CSH RNAi Non-IUGR pregnancies. This study has provided novel insights into the regulatory role of CSH for calcium, phosphate, and vitamin D utilization in late gestation.
Topics: Animals; Calcium; Calcium, Dietary; Female; Fetal Growth Retardation; Humans; Mammals; Phosphates; Placenta; Placental Lactogen; Pregnancy; RNA, Messenger; Sheep; Sodium-Phosphate Cotransporter Proteins, Type III; Uterus; Vitamin D
PubMed: 35887141
DOI: 10.3390/ijms23147795 -
Frontiers in Cell and Developmental... 2022Cytotrophoblasts are progenitor cells that proliferate and fuse to form the multinucleated syncytiotrophoblast layer, implicated in placental endocrine and transport...
Cytotrophoblasts are progenitor cells that proliferate and fuse to form the multinucleated syncytiotrophoblast layer, implicated in placental endocrine and transport functions. While membrane transporters play a critical role in the distribution of nutrients, hormones, and xenobiotics at the maternal-fetal interface, their selectivity to the syncytiotrophoblast layer is poorly characterized. We aimed to evaluate the regulation of placental transporters in response to trophoblast differentiation . Experiments were carried out in isolated primary human trophoblast cells before and after syncytialization. Gene expression of six molecular markers and thirty membrane transporters was investigated by qPCR analysis. Subsequently, functional expression was evaluated for proteins involved in the transplacental transfer of essential nutrients i.e., cholesterol (ABCA1, ABCG1), glucose (SLC2A1), leucine (SLC3A2, SLC7A5), and iron (transferrin receptor, TfR1). We identified that human chorionic gonadotropin, placental lactogen, endoglin, and cadherin-11 serve as optimal gene markers for the syncytialization process. We showed that trophoblast differentiation was associated with differential gene expression (mostly up-regulation) of several nutrient and drug transporters. Further, we revealed enhanced protein expression and activity of ABCG1, SLC3A2, SLC7A5, and TfR1 in syncytialized cells, with ABCA1 and GLUT1 displaying no change. Taken together, these results indicate that the syncytiotrophoblast has a dominant role in transporting essential nutrients cholesterol, leucine, and iron. Nonetheless, we present evidence that the cytotrophoblast cells may also be linked to transport functions that could be critical for the cell fusion processes. Our findings collectively yield new insights into the cellular functions associated with or altered by the trophoblast fusion. Importantly, defective syncytialization could lead to nutrient transfer imbalance, ultimately compromising fetal development and programming.
PubMed: 35273963
DOI: 10.3389/fcell.2022.820286 -
Journal of the Endocrine Society Apr 2022Hormonal factors affecting the vascular adaptions of the uteroplacental unit in noncomplicated and complicated pregnancies are of interest. Here, 4 human placentas from...
Hormonal factors affecting the vascular adaptions of the uteroplacental unit in noncomplicated and complicated pregnancies are of interest. Here, 4 human placentas from women with and without preeclampsia (PE) were investigated for the presence of placental lactogen (PL)-derived, antiangiogenic vasoinhibin. Western blotting and mass spectrometry of placental tissue revealed the presence of a 9-kDa PL-derived vasoinhibin, the normal 22-kDa full-length PL, and a 28-kDa immunoreactive protein of undetermined nature. The sequence of the 9-kDa vasoinhibin includes the antiangiogenic determinant of vasoinhibin and could constitute a relevant factor in normal pregnancy and PE.
PubMed: 35265784
DOI: 10.1210/jendso/bvac029 -
Biomolecules Jan 2022As patients recently diagnosed with T1D and patients with T2D have residual beta cell mass, there is considerable effort in beta cell biology to understand the...
As patients recently diagnosed with T1D and patients with T2D have residual beta cell mass, there is considerable effort in beta cell biology to understand the mechanisms that drive beta cell regeneration as a potential cellular therapy for expanding patients' residual beta cell population. Both mouse and human studies have established that beta cell mass expansion occurs rapidly during pregnancy. To investigate the mechanisms of beta cell mass expansion during pregnancy, we developed a novel in vivo and in vitro models of pseudopregnancy. Our models demonstrate that pseudopregnancy promotes beta cell mass expansion in parous mice, and this expansion is driven by beta cell proliferation rather than hypertrophy. Importantly, estrogen, progesterone, and placental lactogen induce STAT5A signaling in the pseudopregnancy model, demonstrating that this model successfully recapitulates pregnancy-induced beta cell replication. We then created an in vitro model of pseudopregnancy and found that the combination of estrogen and placental lactogen induced beta cell replication in human islets and rat insulinoma cells. Therefore, beta cells both in vitro and in vivo increase proliferation when subjected to the pseudopregnancy cocktail compared to groups treated with estradiol or placental lactogen alone. The pseudopregnancy models described here may help inform novel methods of inducing beta cell replication in patients with diabetes.
Topics: Animals; Cell Division; Female; Humans; Insulin-Secreting Cells; Islets of Langerhans; Mice; Placenta; Placental Lactogen; Pregnancy; Rats
PubMed: 35204716
DOI: 10.3390/biom12020215 -
BMJ Open Feb 2022Maternal metabolic disease states (such as gestational and pregestational diabetes and maternal obesity) are reaching epidemic proportions worldwide and are associated...
INTRODUCTION
Maternal metabolic disease states (such as gestational and pregestational diabetes and maternal obesity) are reaching epidemic proportions worldwide and are associated with adverse maternal and fetal outcomes. Despite this, their aetiology remains incompletely understood. Lactogenic hormones, namely, human placental lactogen (hPL) and prolactin (PRL), play often overlooked roles in maternal metabolism and glucose homeostasis during pregnancy and (in the case of PRL) postpartum, and have clinical potential from a diagnostic and therapeutic perspective. This paper presents a protocol for a systematic review which will synthesise the available scientific evidence linking these two hormones to maternal and fetal metabolic conditions/outcomes.
METHODS AND ANALYSIS
MEDLINE (via OVID), CINAHL and Embase will be systematically searched for all original observational and interventional research articles, published prior to 8 July 2021, linking hPL and/or PRL levels (in pregnancy and/or up to 12 months postpartum) to key maternal metabolic conditions/outcomes (including pre-existing and gestational diabetes, markers of glucose/insulin metabolism, postpartum glucose status, weight change, obesity and polycystic ovary syndrome). Relevant fetal outcomes (birth weight and placental mass, macrosomia and growth restriction) will also be included. Two reviewers will assess articles for eligibility according to prespecified selection criteria, followed by full-text review, quality appraisal and data extraction. Where possible, meta-analysis will be performed; otherwise, a narrative synthesis of findings will be presented.
ETHICS AND DISSEMINATION
Formal ethical approval is not required as no primary data will be collected. The results will be published in a peer-reviewed journal and presented at conference meetings, and will be used to inform future research directions.
PROSPERO REGISTRATION NUMBER
CRD42021262771.
Topics: Diabetes, Gestational; Female; Glucose; Humans; Meta-Analysis as Topic; Placenta; Postpartum Period; Pregnancy; Prolactin
PubMed: 35190436
DOI: 10.1136/bmjopen-2021-055257 -
Reproduction & Fertility Dec 2021Prolactin and placental lactogens increase during pregnancy and are involved with many aspects of maternal metabolic adaptation to pregnancy, likely to impact on fetal...
UNLABELLED
Prolactin and placental lactogens increase during pregnancy and are involved with many aspects of maternal metabolic adaptation to pregnancy, likely to impact on fetal growth. The aim of this study was to determine whether maternal plasma prolactin or placental lactogen concentrations at 20 weeks of gestation were associated with later birth of small-for-gestational-age babies (SGA). In a nested case-control study, prolactin and placental lactogen in plasma samples obtained at 20 weeks of gestation were compared between 40 women who gave birth to SGA babies and 40 women with uncomplicated pregnancies and size appropriate-for-gestation-age (AGA) babies. Samples were collected as part of the 'screening of pregnancy endpoints' (SCOPE) prospective cohort study. SGA was defined as birthweight <10th customized birthweight centile (adjusted for maternal weight, height, ethnicity, parity, infant sex, and gestation age) in mothers who remained normotensive. No significant differences were observed in concentrations of prolactin or placental lactogen from women who gave birth to SGA babies compared with women with uncomplicated pregnancies. However, a sex-specific association was observed in SGA pregnancies, whereby lower maternal prolactin concentration at 20 weeks of gestation was observed in SGA pregnancies that were carrying a male fetus (132.0 ± 46.7 ng/mL vs 103.5 ± 38.3 ng/mL, mean ± s.d., = 0.036 Student's -test) compared to control pregnancies carrying a male fetus. Despite the implications of these lactogenic hormones in maternal metabolism, single measurements of either prolactin or placental lactogen at 20 weeks of gestation are unlikely to be useful biomarkers for SGA pregnancies.
LAY SUMMARY
Early identification during pregnancy of small for gestational age (SGA) babies would enable interventions to lower risk of complications around birth (perinatal), but current detection rates of these at risk babies is low. Pregnancy hormones, prolactin and placental lactogen, are involved in metabolic changes that are required for the mother to support optimal growth and development of her offspring during pregnancy. The levels of these hormones may provide a measurable indicator (biomarker) to help identify these at risk pregnancies. Levels of these hormones were measured in samples from week 20 of gestation from women who went on to have SGA babies and control pregnancies where babies were born at a size appropriate for gestation age. Despite the implications of prolactin and placental lactogen in maternal metabolism, no significant differences were detected suggesting that single measures of either prolactin or placental lactogen at 20 weeks gestation are unlikely to be useful biomarker to help detect SGA pregnancies.
Topics: Biomarkers; Birth Weight; Case-Control Studies; Female; Humans; Male; Placenta; Placental Lactogen; Pregnancy; Prolactin; Prospective Studies
PubMed: 35118402
DOI: 10.1530/RAF-21-0020 -
Frontiers in Global Women's Health 2021Transition into motherhood involves profound physiological and behavioral adaptations that ensure the healthy development of offspring while maintaining maternal health.... (Review)
Review
Transition into motherhood involves profound physiological and behavioral adaptations that ensure the healthy development of offspring while maintaining maternal health. Dynamic fluctuations in key hormones during pregnancy and lactation induce these maternal adaptations by acting on neural circuits in the brain. Amongst these hormonal changes, lactogenic hormones (e.g., prolactin and its pregnancy-specific homolog, placental lactogen) are important regulators of these processes, and their receptors are located in key brain regions controlling emotional behaviors and maternal responses. With pregnancy and lactation also being associated with a marked elevation in the risk of developing mood disorders, it is important to understand how hormones are normally regulating mood and behavior during this time. It seems likely that pathological changes in mood could result from aberrant expression of these hormone-induced behavioral responses. Maternal mental health problems during pregnancy and the postpartum period represent a major barrier in developing healthy mother-infant interactions which are crucial for the child's development. In this review, we will examine the role lactogenic hormones play in driving a range of specific maternal behaviors, including motivation, protectiveness, and mother-pup interactions. Understanding how these hormones collectively act in a mother's brain to promote nurturing behaviors toward offspring will ultimately assist in treatment development and contribute to safeguarding a successful pregnancy.
PubMed: 34927138
DOI: 10.3389/fgwh.2021.767467 -
Frontiers in Endocrinology 2021Adaptive changes in glucose homeostasis during pregnancy require proliferation of insulin-secreting beta-cells in the pancreas, together with increased sensitivity for...
Adaptive changes in glucose homeostasis during pregnancy require proliferation of insulin-secreting beta-cells in the pancreas, together with increased sensitivity for glucose-stimulated insulin secretion. Increased concentrations of maternal prolactin/placental lactogen contribute to these changes, but the site of action remains uncertain. Use of Cre-lox technology has generated pancreas-specific prolactin receptor (Prlr) knockouts that demonstrate the development of a gestational diabetic like state. However, many Cre-lines for the pancreas also express Cre in the hypothalamus and prolactin could act centrally to modulate glucose homeostasis. The aim of the current study was to examine the relative contribution of prolactin action in the pancreas and brain to these pregnancy-induced adaptations in glucose regulation. Deletion of prolactin receptor (Prlr) from the pancreas using Pdx-cre or Rip-cre led to impaired glucose tolerance and increased non-fasting blood glucose levels during pregnancy. Prlr /Pdx-Cre mice also had impaired glucose-stimulated insulin secretion and attenuated pregnancy-induced increase in beta-cell fraction. Varying degrees of Prlr recombination in the hypothalamus with these Cre lines left open the possibility that central actions of prolactin could contribute to the pregnancy-induced changes in glucose homeostasis. Targeted deletion of Prlr specifically from the forebrain, including areas of expression induced by Pdx-Cre and Rip-cre, had no effect on pregnancy-induced adaptations in glucose homeostasis. These data emphasize the pancreas as the direct target of prolactin/placental lactogen action in driving adaptive changes in glucose homeostasis during pregnancy.
Topics: Adaptation, Physiological; Animals; Female; Glucose; Glucose Intolerance; Homeostasis; Hypothalamus; Insulin-Secreting Cells; Male; Mice; Pancreas; Placenta; Pregnancy; Prolactin; Prosencephalon; Receptors, Prolactin; Signal Transduction
PubMed: 34867810
DOI: 10.3389/fendo.2021.765976 -
Biology of Sex Differences Nov 2021Current methods fail to accurately predict women at greatest risk of developing fetal growth restriction (FGR) or related adverse outcomes, including stillbirth. Sexual...
BACKGROUND
Current methods fail to accurately predict women at greatest risk of developing fetal growth restriction (FGR) or related adverse outcomes, including stillbirth. Sexual dimorphism in these adverse pregnancy outcomes is well documented as are sex-specific differences in gene and protein expression in the placenta. Circulating maternal serum microRNAs (miRNAs) offer potential as biomarkers that may also be informative of underlying pathology. We hypothesised that FGR would be associated with an altered miRNA profile and would differ depending on fetal sex.
METHODS
miRNA expression profiles were assessed in maternal serum (> 36 weeks' gestation) from women delivering a severely FGR infant (defined as an individualised birthweight centile (IBC) < 3rd) and matched control participants (AGA; IBC = 20-80th), using miRNA arrays. qPCR was performed using specific miRNA primers in an expanded cohort of patients with IBC < 5th (n = 15 males, n = 16 females/group). Maternal serum human placental lactogen (hPL) was used as a proxy to determine if serum miRNAs were related to placental dysfunction. In silico analyses were performed to predict the potential functions of altered miRNAs.
RESULTS
Initial analyses revealed 11 miRNAs were altered in maternal serum from FGR pregnancies. In silico analyses revealed all 11 altered miRNAs were located in a network of genes that regulate placental function. Subsequent analysis demonstrated four miRNAs showed sexually dimorphic patterns. miR-28-5p was reduced in FGR pregnancies (p < 0.01) only when there was a female offspring and miR-301a-3p was only reduced in FGR pregnancies with a male fetus (p < 0.05). miR-454-3p was decreased in FGR pregnancies (p < 0.05) regardless of fetal sex but was only positively correlated to hPL when the fetus was female. Conversely, miR-29c-3p was correlated to maternal hPL only when the fetus was male. Target genes for sexually dimorphic miRNAs reveal potential functional roles in the placenta including angiogenesis, placental growth, nutrient transport and apoptosis.
CONCLUSIONS
These studies have identified sexually dimorphic patterns for miRNAs in maternal serum in FGR. These miRNAs may have potential as non-invasive biomarkers for FGR and associated placental dysfunction. Further studies to determine if these miRNAs have potential functional roles in the placenta may provide greater understanding of the pathogenesis of placental dysfunction and the differing susceptibility of male and female fetuses to adverse in utero conditions.
Topics: Circulating MicroRNA; Female; Fetal Growth Retardation; Humans; Male; Placenta; Pregnancy; Pregnancy Outcome; Sex Factors
PubMed: 34789323
DOI: 10.1186/s13293-021-00405-z -
The American Journal of Case Reports Nov 2021BACKGROUND When a woman becomes pregnant, the placenta produces human placental lactogen (hPL). The anti-insulin effect of hPL raises maternal blood glucose levels,...
BACKGROUND When a woman becomes pregnant, the placenta produces human placental lactogen (hPL). The anti-insulin effect of hPL raises maternal blood glucose levels, allowing the fetus to use glucose as a nutrient. Because hPL is produced by the placenta until delivery, insulin requirements in patients with gestational diabetes mellitus (GDM) typically increase, but in some cases, they may decrease. We retrospectively examined data from women with GDM who received insulin and delivered at our hospital. CASE REPORT From April 2019 to March 2020, we targeted patients who were diagnosed with GDM, received insulin, and delivered at our hospital. GDM was diagnosed based on the guidelines from the Japanese Society of Obstetrics and Gynecology. The rate of change in insulin dosage was calculated as: (insulin dosage at delivery - insulin dosage 14 days before delivery) divided by 14. Two patients whose insulin dosage was significantly reduced developed a syndrome of hemolysis, elevated liver enzymes, and low platelet count or acute fatty liver of pregnancy and underwent emergency cesarean section. CONCLUSIONS The present case report suggests that a decrease in insulin requirement in pregnant patients with GDM can predict maternal abnormalities due to placental dysfunction.
Topics: Blood Glucose; Cesarean Section; Diabetes, Gestational; Female; Hemolysis; Humans; Insulin; Liver; Placenta; Platelet Count; Pregnancy; Retrospective Studies
PubMed: 34744160
DOI: 10.12659/AJCR.933460