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The Journal of Endocrinology Dec 2020Chorionic somatomammotropin (CSH) is a placenta-specific hormone associated with fetal growth, and fetal and maternal metabolism in both humans and sheep. We...
Chorionic somatomammotropin (CSH) is a placenta-specific hormone associated with fetal growth, and fetal and maternal metabolism in both humans and sheep. We hypothesized that CSH deficiency could impact sheep fetal liver glucose utilization. To generate CSH-deficient pregnancies, day 9 hatched blastocysts were infected with lentiviral particles expressing CSH-specific shRNA (RNAi) or scramble control shRNA (SC) and transferred to synchronized recipients. CSH RNAi generated two distinct phenotypes at 135 days of gestational age (dGA); pregnancies with IUGR (RNAi-IUGR) or with normal fetal weight (RNAi-NW). Fetal body, fetal liver and placental weights were reduced (P < 0.05) only in RNAi-IUGR pregnancies compared to SC. Umbilical artery plasma insulin and insulin-like growth factor 1 (IGF1) concentrations were decreased, whereas insulin receptor beta (INSR) concentration in fetal liver was increased (P < 0.05) in both RNAi phenotypes. The mRNA concentrations of IGF1, IGF2, IGF binding protein 2 (IGFBP2) and IGFBP3 were decreased (P < 0.05) in fetal livers from both RNAi phenotypes. Fetal liver glycogen concentration and glycogen synthase 1 (GYS1) concentration were increased (P < 0.05), whereas fetal liver phosphorylated-GYS (inactive GYS) concentration was reduced (P < 0.05) in both RNAi phenotypes. Lactate dehydrogenase B (LDHB) concentration was increased (P < 0.05) and IGF2 concentration was decreased (P < 0.05) in RNAi-IUGR fetal livers only. Our findings suggest that fetal liver glucose utilization is impacted by CSH RNAi, independent of IUGR, and is likely tied to enhanced fetal liver insulin sensitivity in both RNAi phenotypes. Determining the physiological ramifications of both phenotypes, may help to differentiate direct effect of CSH deficiency or its indirect effect through IUGR.
Topics: Animals; Female; Fetal Growth Retardation; Glucose; Glycogen; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Liver; Placental Lactogen; Pregnancy; RNA Interference; Sheep
PubMed: 33108344
DOI: 10.1530/JOE-20-0375 -
Diabetes Jan 2021Hypoadiponectinemia is a risk factor of gestational diabetes mellitus (GDM). Our previous study reported that adiponectin gene knockout mice ( ) develop GDM due to...
Hypoadiponectinemia is a risk factor of gestational diabetes mellitus (GDM). Our previous study reported that adiponectin gene knockout mice ( ) develop GDM due to insulin insufficiency. The main objective of this study was to elucidate the underlying mechanism through which adiponectin controls islet expansion during pregnancy. A significant reduction in β-cell proliferation rates, β-cell areas, and blood insulin concentrations was detected in mice at midpregnancy. Surprisingly, conditionally knocking down adiponectin receptor 1 () or genes in β-cells during pregnancy did not reduce β-cell proliferation rates or blood insulin concentrations. In vitro adiponectin treatment also failed to show any effect on β-cell proliferation of isolated pancreatic islets. It was reported that placental lactogen (PL) plays a crucial role in pregnancy-induced maternal β-cell proliferation. A significant decrease in phosphorylation of signal transducer and activator of transcription 5, a downstream molecule of PL signaling, was observed in islets from dams. The mRNA levels of mouse PL genes were robustly decreased in the placentas of dams. In contrast, adiponectin treatment increased PL expression in human placenta explants and JEG3 trophoblast cells. Most importantly, bovine PL injection restored β-cell proliferation and blood insulin concentrations in dams. Together, these results demonstrate that adiponectin plays a vital role in pregnancy-induced β-cell proliferation by promoting PL expression in trophoblast cells.
Topics: Adiponectin; Animals; Cell Line; Cell Proliferation; Female; Humans; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Mice; Mice, Knockout; Placenta; Placental Lactogen; Pregnancy; Receptors, Adiponectin; Trophoblasts
PubMed: 33087456
DOI: 10.2337/db20-0471 -
Journal of Neuroendocrinology Nov 2020Pregnancy represents a period of remarkable adaptive physiology throughout the body, with many of these important adaptations mediated by changes in gene transcription...
Pregnancy represents a period of remarkable adaptive physiology throughout the body, with many of these important adaptations mediated by changes in gene transcription in the brain. A marked activation of the transcription factor signal transducer and activator of transcription 5 (STAT5) has been described in the brain during pregnancy and likely drives some of these changes. We aimed to investigate the physiological mechanism causing this increase in phosphorylated STAT5 (pSTAT5) during pregnancy. In various tissues, STAT5 is known to be activated by a number of different cytokines, including erythropoietin, growth hormone and prolactin. Because the lactogenic hormones that act through the prolactin receptor (PRLR), prolactin and its closely-related placental analogue placental lactogen, are significantly increased during pregnancy, we hypothesised that this receptor was primarily responsible for the pregnancy-induced increase in pSTAT5 in the brain. By examining temporal changes in plasma prolactin levels and the pattern of pSTAT5 immunoreactivity in the hypothalamus during early pregnancy, we found that the level of pSTAT5 was sensitive to circulating levels of endogenous prolactin. Using a transgenic model to conditionally delete PRLRs from forebrain neurones (Prlr /CamK-Cre), we assessed the relative contribution of the PRLR to the up-regulation of pSTAT5 in the brain of pregnant mice. In the absence of PRLRs on most forebrain neurones, a significant reduction in pSTAT5 was observed throughout the hypothalamus and amygdala in late pregnancy, confirming that PRLR is key in mediating this response. The exception to this was the hypothalamic paraventricular nucleus, where only 17% of pSTAT5 immunoreactivity during pregnancy was in PRLR-expressing cells. Taken together, these data indicate that, although there are region-specific mechanisms involved, lactogenic activity through the PRLR is the primary signal activating STAT5 in the brain during pregnancy.
Topics: Amygdala; Animals; Brain Chemistry; Cytokines; Female; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Paraventricular Hypothalamic Nucleus; Phosphorylation; Placenta; Placental Lactogen; Pregnancy; Prolactin; Receptors, Prolactin; STAT5 Transcription Factor; Signal Transduction
PubMed: 33000513
DOI: 10.1111/jne.12901 -
International Journal of Molecular... Jul 2020Activating mutations in the human KIT receptor is known to drive severe hematopoietic disorders and tumor formation spanning various entities. The most common mutation...
Activating mutations in the human KIT receptor is known to drive severe hematopoietic disorders and tumor formation spanning various entities. The most common mutation is the substitution of aspartic acid at position 816 to valine (D816V), rendering the receptor constitutively active independent of ligand binding. As the role of the KIT receptor in placental signaling cascades is poorly understood, we analyzed the impact of KIT expression on placental development using a humanized mouse model. Placentas from KIT animals present with a grossly changed morphology, displaying a reduction in labyrinth and spongiotrophoblast layer and an increase in the Parietal Trophoblast Giant Cell (P-TGC) layer. Elevated differentiation to P-TGCs was accompanied with reduced differentiation to other Trophoblast Giant Cell (TGC) subtypes and by severe decrease in proliferation. The embryos display growth retardation and die in utero. KIT-trophoblast stem cells (TSC) differentiate much faster compared to wild type (WT) controls. In undifferentiated KIT-TSCs, levels of Phosphorylated Extracellular-signal Regulated Kinase (P-ERK) and Phosphorylated Protein Kinase B (P-AKT) are comparable to wildtype cultures differentiating for 3-6 days. Accordingly, P-TGC markers Placental Lactogen 1 (PL1) and Proliferin (PLF) are upregulated as well. The results reveal that KIT signaling orchestrates the fine-tuned differentiation of the placenta, with special emphasis on P-TGC differentiation. Appropriate control of KIT receptor action is therefore essential for placental development and nourishment of the embryo.
Topics: Animals; Female; Gene Expression Regulation, Developmental; Homeobox A10 Proteins; Humans; MAP Kinase Signaling System; Mice; Neoplasm Invasiveness; Placenta; Placental Lactogen; Placentation; Pregnancy; Prolactin; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-kit; Trophoblasts
PubMed: 32752102
DOI: 10.3390/ijms21155503 -
Handbook of Clinical Neurology 2020The hormonal fluctuations in pregnancy drive a wide range of adaptive changes in the maternal brain. These range from specific neurophysiological changes in the patterns... (Review)
Review
The hormonal fluctuations in pregnancy drive a wide range of adaptive changes in the maternal brain. These range from specific neurophysiological changes in the patterns of activity of individual neuronal populations, through to complete modification of circuit characteristics leading to fundamental changes in behavior. From a neurologic perspective, the key hormone changes are those of the sex steroids, estradiol and progesterone, secreted first from the ovary and then from the placenta, the adrenal glucocorticoid cortisol, as well as the anterior pituitary peptide hormone prolactin and its pregnancy-specific homolog placental lactogen. All of these hormones are markedly elevated during pregnancy and cross the blood-brain barrier to exert actions on neuronal populations through receptors expressed in specific regions. Many of the hormone-induced changes are in autonomic or homeostatic systems. For example, patterns of oxytocin and prolactin secretion are dramatically altered to support novel physiological functions. Appetite is increased and feedback responses to metabolic hormones such as leptin and insulin are suppressed to promote a positive energy balance. Fundamental physiological systems such as glucose homeostasis and thermoregulation are modified to optimize conditions for fetal development. In addition to these largely autonomic changes, there are also changes in mood, behavior, and higher processes such as cognition. This chapter summarizes the hormonal changes associated with pregnancy and reviews how these changes impact on brain function, drawing on examples from animal research, as well as available information about human pregnancy.
Topics: Animals; Cognition; Female; Humans; Insulin; Leptin; Placenta; Pregnancy; Prolactin
PubMed: 32736755
DOI: 10.1016/B978-0-444-64239-4.00002-3 -
Physiological Reports Jul 2020The psychoactive component in cannabis, delta-9-tetrahydrocannabinol, can restrict fetal growth and development. Delta-9-tetrahydrocannabinol has been shown to...
The psychoactive component in cannabis, delta-9-tetrahydrocannabinol, can restrict fetal growth and development. Delta-9-tetrahydrocannabinol has been shown to negatively impact cellular proliferation and target organelles like the mitochondria resulting in reduced cellular respiration. In the placenta, mitochondrial dysfunction leading to oxidative stress prevents proper placental development and function. A key element of placental development is the proliferation and fusion of cytotrophoblasts to form the syncytium that comprises the materno-fetal interface. The impact of delta-9-tetrahydrocannabinol on this process is not well understood. To elucidate the nature of the mitochondrial dysfunction and its consequences on trophoblast fusion, we treated undifferentiated and differentiated BeWo human trophoblast cells, with 20 µM delta-9-tetrahydrocannabinol for 48 hr. At this concentration, delta-9-tetrahydrocannabinol on BeWo cells reduced the expression of markers involved in syncytialization and mitochondrial dynamics, but had no effect on cell viability. Delta-9-tetrahydrocannabinol significantly attenuated the process of syncytialization and induced oxidative stress responses in BeWo cells. Importantly, delta-9-tetrahydrocannabinol also caused a reduction in the secretion of human chorionic gonadotropin and the production of human placental lactogen and insulin growth factor 2, three hormones known to be important in facilitating fetal growth. Furthermore, we also demonstrate that delta-9-tetrahydrocannabinol attenuated mitochondrial respiration, depleted adenosine triphosphate, and reduced mitochondrial membrane potential. These changes were also associated with an increase in cellular reactive oxygen species, and the expression of stress responsive chaperones, HSP60 and HSP70. These findings have important implications for understanding the role of delta-9-tetrahydrocannabinol-induced mitochondrial injury and the role this might play in compromising human pregnancies.
Topics: Cannabinoid Receptor Agonists; Cell Line, Tumor; Cell Survival; Chaperonin 60; Dronabinol; Female; Giant Cells; Gonadotropins; HSP70 Heat-Shock Proteins; Humans; Insulin-Like Growth Factor II; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Oxidative Stress; Trophoblasts
PubMed: 32628362
DOI: 10.14814/phy2.14476 -
Journal of Neuroendocrinology Nov 2020The four genes coding for placental members of the human (h) growth hormone (GH) family include two that code independently for placental lactogen (PL), also known as... (Review)
Review
The four genes coding for placental members of the human (h) growth hormone (GH) family include two that code independently for placental lactogen (PL), also known as chorionic somatomammotrophin hormone, one that codes for placental growth hormone (PGH) and a pseudogene for which RNA but no protein product is reported. These genes are expressed preferentially in the villus syncytiotrophoblast of the placenta in pregnancy. In higher primates, the placental members, including hPL and PGH, are the result of multiple duplication events of the GH gene. This contrasts with rodents and ruminants, where PLs result from duplication of the prolactin (PRL) gene. Thus, unlike their mouse counterparts, the hPL and PGH hormones bind both lactogenic and somatogenic receptors with varying affinity. Roles influenced by nutrient availability in both metabolic control in pregnancy and maternal behaviour are supported. However, the effect maternal obesity has on the activation of placental members of the hGH gene family, particularly the expression and function of those genes, is poorly understood. Evidence from partially humanised hGH/PL transgenic mice indicates that both the remote upstream hPL locus control region (LCR) and more gene-related regulatory regions are required for placental expression in vivo. Furthermore, a specific pattern of interactions between the LCR and hPL gene promoter regions is detected in term placenta chromatin from women with a normal body mass index (BMI) in the range 18.5-25 kg m by chromosome conformation capture assay. This pattern is disrupted with maternal obesity (class II BMI > 35 kg m ) and associated with a > 40% decrease in term hPL RNA levels, as well as serum hPL but not PRL levels, during pregnancy. The relative importance of the chromosomal architecture and predicted properties for transcription factor participation in terms of hPL production and response to obesity are considered, based on comparison with components required for efficient human pituitary GH gene expression.
Topics: Animals; Female; Gene Expression Regulation; Humans; Obesity; Placenta; Placental Lactogen; Pregnancy
PubMed: 32500948
DOI: 10.1111/jne.12859 -
Placenta Jun 2020The impala is a widely distributed African ungulate. Detailed studies of the placenta and ovaries in impala undertaken in the 1970s did not address the endocrine...
INTRODUCTION
The impala is a widely distributed African ungulate. Detailed studies of the placenta and ovaries in impala undertaken in the 1970s did not address the endocrine functions of the placenta.
METHODS
The uteri of 25 pregnant impala estimated to be between 49 and 113 days of the 190 day gestation were examined grossly, histologically and immunohistochemically.
RESULTS
A single corpus luteum was present in either maternal ovary but the conceptus was always situated in the right uterine horn. The fetal membranes extended to the tips of both uterine horns. The amnion was in intimate contact with, but not fused to, the allantochorion. Placentation was typically ruminant with fetal macrocotyledons attached to the rows of maternal caruncles. The fetal villi were highly branched, especially in the centre of each placentome where the attenuated maternal epithelium lining the placental crypts was absent in some places. Both the corpus luteum and the uninucleate trophoblast cells of the interplacentomal allantochorion stained strongly for 3-β hydroxysteroid dehydrogenase, and progestagen concentrations in allantoic and amniotic fluids increased significantly as gestation progressed, with a tendency to do likewise in maternal serum. Binucleate trophoblast cells stained positively for bovine placental lactogen, but neither the placenta nor the maternal corpus luteum showed evidence of oestrogen synthesis.
DISCUSSION
Despite exhibiting the same basic type of placentation, both the gross and histological structure of the impala placenta, along with its immunohistochemical properties, demonstrates that great variation exists across ruminant placentas.
Topics: 3-Hydroxysteroid Dehydrogenases; Animals; Antelopes; Female; Placenta; Placentation; Pregnancy; Progesterone; Trophoblasts; Uterus
PubMed: 32452408
DOI: 10.1016/j.placenta.2020.04.009 -
Reproductive Toxicology (Elmsford, N.Y.) Aug 2020Using JEG-3 and BeWo cells, we examined the effect of "real life" mixtures of polycyclic aromatic hydrocarbons (PAHs), at doses reported in maternal blood (Mix I) and in...
"Real life" polycyclic aromatic hydrocarbon (PAH) mixtures modulate hCG, hPL and hPLGF levels and disrupt the physiological ratio of MMP-2 to MMP-9 and VEGF expression in human placenta cell lines.
Using JEG-3 and BeWo cells, we examined the effect of "real life" mixtures of polycyclic aromatic hydrocarbons (PAHs), at doses reported in maternal blood (Mix I) and in placental tissue (Mix II), on human chorionic gonadotropin (hCG), placental lactogen (hPL) and placental growth factor (hPLGF) secretion, protein expression and immunolocalization. Additionally, the action of PAH mixtures on basal and hormone-stimulated matrix metalloproteinase-2 (MMP-2), MMP-9 and vascular endothelial growth factor (VEGF) protein expression was evaluated. Under basal conditions, the PAH mixtures increased hCG and decreased hPLGF levels in both cell lines, while hPL expression was stimulated in JEG-3 and inhibited in BeWo. There was no effect on the MMP-2/MMP-9 ratio or VEGF expression. In hormone-stimulated cells, PAH mixtures changed the MMP-2/MMP-9 ratio in JEG-3 cells in favor of MMP-9, while in BeWo MMP-2 was favored. The effect on VEGF expression was cell specific and dependent on the mixture. In hCG-treated cells, only Mix II inhibited VEGF expression in JEG-3 cells. Neither PAH mixtures affected this protein in BeWo cells. In hPL-treated cells, Mix I had a stimulatory effect in JEG-3 cells, while Mix II exerted an inhibitory effect in BeWo cells. In hPLGF-treated cells, Mix II decreased in JEG-3 cells, but in BeWo cells, both mixtures increased VEGF expression. Considering that the evaluated protein hormones play crucial roles in angiogenesis and neovascularization in the placenta, "real life" PAH mixtures by disrupting protein hormones levels, the MMP-2/MMP-9 ratio and VEGF expression can lead to insufficiency and many pregnancy-related disorders.
Topics: Cell Line; Chorionic Gonadotropin; Female; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Placenta; Placenta Growth Factor; Placental Lactogen; Polycyclic Aromatic Hydrocarbons; Pregnancy; Vascular Endothelial Growth Factor A
PubMed: 32418891
DOI: 10.1016/j.reprotox.2020.02.006 -
IScience May 2020We evaluated the contribution of organic anion transporting polypeptide 2A1 (OATP2A1/SLCO2A1), a high-affinity carrier for prostaglandins (PGs), to the parturition...
We evaluated the contribution of organic anion transporting polypeptide 2A1 (OATP2A1/SLCO2A1), a high-affinity carrier for prostaglandins (PGs), to the parturition process. At gestational day (GD) 15.5, OATP2A1 is co-localized with 15-hydroxy-PG dehydrogenase in the mouse placental junctional zone and facilitates PG degradation by delivering PGs to the cytoplasm. Slco2a1 (+/-) females mated with Slco2a1 (-/-) males frequently showed elevated circulating progesterone at GD18.5 and delayed parturition. Progesterone receptor inhibition by RU486 treatment at GD18.5 blocked the delay of parturition. In the junctional zone, PGE stimulated placental lactogen II (PL-II) production, resulting in higher expression of PL-II in Slco2a1 (-/-) placenta at GD18.5. Indomethacin treatment at GD15.5 suppressed the PL-II overproduction at GD18.5 in Slco2a1 (-/-) embryo-bearing dams, which promoted progesterone withdrawal and corrected the delayed parturition. These results suggest that extracellular PGE reduction by OATP2A1 at mid-pregnancy would be associated with progesterone withdrawal by suppressing PL-II production, triggering parturition onset.
PubMed: 32408168
DOI: 10.1016/j.isci.2020.101098