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Francis EC, Dumolt JH, Zemski-Berry K, Jansson T, Powell TL. Maternal Plasma Choline Levels Are Positively Correlated with Maternal and Placental Phospholipid-DHA Content in Females with Obesity Who Receive DHA Supplementation. J Nutr 2025; 155:880-889. [PMID: 39742970 PMCID: PMC11934244 DOI: 10.1016/j.tjnut.2024.12.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 12/20/2024] [Accepted: 12/27/2024] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND Pregnancies complicated by maternal obesity are characterized by metabolic differences affecting placental nutrient transport and fetal development. Docosahexaenoic acid (DHA) is critical for fetal brain development and is primarily incorporated into phosphatidylcholine (PC). Recent evidence suggests that choline may enhance PC-DHA synthesis; however, data on the impact of maternal plasma choline on placental phospholipid DHA content in females with obesity are limited. METHODS We conducted a secondary analysis of a DHA supplementation trial (800 mg/d) in 38 pregnant females with obesity (body mass index ≥30 kg/m2). Blood samples at 36 wk gestation and term placentas were analyzed for phospholipids using mass spectrometry. Choline transporter-like (CTL) proteins in the syncytiotrophoblast microvillous (MVM) and basal plasma membranes were quantified by Western blot. RESULTS Daily DHA supplementation from 25 wk gestation was associated with higher maternal plasma and placental PC- and lysophosphatidylcholine (LPC)-DHA. A significant interaction (P interaction <0.05) between DHA supplementation and choline indicated that higher choline enhanced the incorporation of DHA into plasma PC. MVM CTL-1 expression was correlated with placental total PC-DHA and LPC-DHA content, suggesting that CTL-1 has a predominate role in placental choline uptake and phospholipid synthesis. CONCLUSIONS These findings suggest that choline may influence maternal PC- and LPC-DHA synthesis and plasma levels, as well as the expression of placental choline transporters and the resulting PC- and LPC-DHA content in females with obesity. These relationships may have implications for DHA transport to the fetus and overall fetal development.
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Affiliation(s)
- Ellen C Francis
- Biostatistics and Epidemiology Department, Rutgers School of Public Health, Piscataway, NJ, United States
| | - Jerad H Dumolt
- Division of Reproductive Sciences, Department of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Karin Zemski-Berry
- Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Thomas Jansson
- Division of Reproductive Sciences, Department of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Theresa L Powell
- Division of Reproductive Sciences, Department of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States; Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
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2
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Cao M, Bai L, Wei H, Guo Y, Sun G, Sun H, Shi B. Dietary supplementation with pterostilbene activates the PI3K-AKT-mTOR signalling pathway to alleviate progressive oxidative stress and promote placental nutrient transport. J Anim Sci Biotechnol 2024; 15:133. [PMID: 39369257 PMCID: PMC11456245 DOI: 10.1186/s40104-024-01090-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 08/14/2024] [Indexed: 10/07/2024] Open
Abstract
BACKGROUND Progressive oxidative stress easily occurs as a result of a gradual increase in the intensity of maternal metabolism due to rapid foetal development and increased intensity of lactation. However, studies on the effects of processive oxidative stress on nutrient transport in the placenta have received little attention. The present study was conducted on sows at 85 days of gestation to study the effects of pterostilbene (PTE) on maternal oxidative stress status and placental nutrient transport. RESULTS PTE increased the antioxidant capacity and immunoglobulin content in mothers' blood and milk, reduced the level of inflammatory factors, and improved the nutrient content of milk. PTE also reduced sow backfat loss and the number of weak sons, and increased piglet weaning weight and total weaning litter weight. We subsequently found that PTE enhanced placental glucose and fatty acid transport and further affected glycolipid metabolism by increasing the expression of LAL, PYGM, and Gbe-1, which activated the PI3K phosphorylation pathway. Moreover, PTE addition altered the relative abundance of the Firmicutes, Proteobacteria, Parabacillus, and Bacteroidetes-like RF16 groups in sow faeces. PTE increased the levels of acetate, propionate, butyrate and isovalerate in the faeces. CONCLUSIONS These findings reveal that the addition of PTE during pregnancy and lactation mitigates the effects of processive oxidative stress on offspring development by altering maternal microbial and placental nutrient transport capacity.
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Affiliation(s)
- Mingming Cao
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, PR China
| | - Liyun Bai
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, PR China
| | - Haoyun Wei
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, PR China
| | - Yantong Guo
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, PR China
| | - Guodong Sun
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, PR China
| | - Haoyang Sun
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, PR China.
| | - Baoming Shi
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, PR China.
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Yi Y, Wang T, Xu W, Zhang SH. Epigenetic modifications of placenta in women with gestational diabetes mellitus and their offspring. World J Diabetes 2024; 15:378-391. [PMID: 38591094 PMCID: PMC10999040 DOI: 10.4239/wjd.v15.i3.378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 12/30/2023] [Accepted: 02/06/2024] [Indexed: 03/15/2024] Open
Abstract
Gestational diabetes mellitus (GDM) is a pregnancy-related complication characterized by abnormal glucose metabolism in pregnant women and has an important impact on fetal development. As a bridge between the mother and the fetus, the placenta has nutrient transport functions, endocrine functions, etc., and can regulate placental nutrient transport and fetal growth and development according to maternal metabolic status. Only by means of placental transmission can changes in maternal hyperglycemia affect the fetus. There are many reports on the placental pathophysiological changes associated with GDM, the impacts of GDM on the growth and development of offspring, and the prevalence of GDM in offspring after birth. Placental epigenetic changes in GDM are involved in the programming of fetal development and are involved in the pathogenesis of later chronic diseases. This paper summarizes the effects of changes in placental nutrient transport function and hormone secretion levels due to maternal hyperglycemia and hyperinsulinemia on the development of offspring as well as the participation of changes in placental epigenetic modifications due to maternal hyperglycemia in intrauterine fetal programming to promote a comprehensive understanding of the impacts of placental epigenetic modifications on the development of offspring from patients with GDM.
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Affiliation(s)
- Yan Yi
- Department of Ultrasonography, The First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei Province, China
| | - Tao Wang
- Clinical Molecular Immunology Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Wei Xu
- Department of Ultrasonography, The First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei Province, China
| | - San-Hong Zhang
- Department of Pediatric, Xiantao First People’s Hospital, Xiantao 433000, Hubei Province, China
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Huang Y, Qiu F, Dziegielewska KM, Koehn LM, Habgood MD, Saunders NR. Effects of paracetamol/acetaminophen on the expression of solute carriers (SLCs) in late-gestation fetal rat brain, choroid plexus and the placenta. Exp Physiol 2024; 109:427-444. [PMID: 38059686 PMCID: PMC10988763 DOI: 10.1113/ep091442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 11/21/2023] [Indexed: 12/08/2023]
Abstract
Solute carriers (SLCs) regulate transfer of a wide range of molecules across cell membranes using facilitative or secondary active transport. In pregnancy, these transporters, expressed at the placental barrier, are important for delivery of nutrients to the fetus, whilst also limiting entry of potentially harmful substances, such as drugs. In the present study, RNA-sequencing analysis was used to investigate expression of SLCs in the fetal (embryonic day 19) rat brain, choroid plexus and placenta in untreated control animals and following maternal paracetamol treatment. In the treated group, paracetamol (15 mg/kg) was administered to dams twice daily for 5 days (from embryonic day 15 to 19). In untreated animals, overall expression of SLCs was highest in the placenta. In the paracetamol treatment group, expression of several SLCs was significantly different compared with control animals, with ion, amino acid, neurotransmitter and sugar transporters most affected. The number of SLC transcripts that changed significantly following treatment was the highest in the choroid plexus and lowest in the brain. All SLC transcripts that changed in the placenta following paracetamol treatment were downregulated. These results suggest that administration of paracetamol during pregnancy could potentially disrupt fetal nutrient homeostasis and affect brain development, resulting in major consequences for the neonate and extending into childhood.
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Affiliation(s)
- Yifan Huang
- Department of NeuroscienceMonash UniversityMelbourneVictoriaAustralia
| | - Fiona Qiu
- Department of NeuroscienceMonash UniversityMelbourneVictoriaAustralia
| | | | - Liam M. Koehn
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleVictoriaAustralia
| | - Mark D. Habgood
- Department of NeuroscienceMonash UniversityMelbourneVictoriaAustralia
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Silva E, Ferchaud‐Roucher V, Kramer A, Madi L, Pantham P, Chassen S, Jansson T, Powell TL. Oleic acid stimulation of amino acid uptake in primary human trophoblast cells is mediated by phosphatidic acid and mTOR signaling. FASEB Bioadv 2024; 6:1-11. [PMID: 38223199 PMCID: PMC10782470 DOI: 10.1096/fba.2023-00113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 10/19/2023] [Accepted: 10/30/2023] [Indexed: 01/16/2024] Open
Abstract
Normal fetal development is critically dependent on optimal nutrient supply by the placenta, and placental amino acid transport has been demonstrated to be positively associated with fetal growth. Mechanistic target of rapamycin (mTOR) is a positive regulator of placental amino acid transporters, such as System A. Oleic acid (OA) has been previously shown to have a stimulatory role on placental mTOR signaling and System A amino acid uptake in primary human trophoblast (PHT) cells. We investigated the mechanistic link between OA and System A activity in PHT. We found that inhibition of mTOR complex 1 or 2, using small interfering RNA to knock down raptor or rictor, prevented OA-stimulated System A amino acid transport indicating the interaction of OA with mTOR. Phosphatidic acid (PA) is a key intermediary for phospholipid biosynthesis and a known regulator of the mTOR pathway; however, phospholipid biosynthetic pathways have not been extensively studied in placenta. We identified placental isoforms of acyl transferase enzymes involved in de novo phospholipid synthesis. Silencing of 1-acylglycerol-3-phosphate-O-acyltransferase-4, an enzyme in this pathway, prevented OA mediated stimulation of mTOR and System A amino acid transport. These data indicate that OA stimulates mTOR and amino acid transport in PHT cells mediated through de novo synthesis of PA. We speculate that fatty acids in the maternal circulation, such as OA, regulate placental functions critical for fetal growth by interaction with mTOR and that late pregnancy hyperlipidemia may be critical for increasing nutrient transfer to the fetus.
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Affiliation(s)
- Elena Silva
- Department of Obstetrics & GynecologyUniversity of Colorado Anschutz Medical CampusAuroraColoradoUSA
| | | | - Anita Kramer
- Department of Obstetrics & GynecologyUniversity of Colorado Anschutz Medical CampusAuroraColoradoUSA
| | - Lana Madi
- Department of Obstetrics & GynecologyUniversity of Colorado Anschutz Medical CampusAuroraColoradoUSA
| | - Priyadarshini Pantham
- Ob/Gyn & Reproductive SciencesUniversity of California, San DiegoLa JollaCaliforniaUSA
| | - Stephanie Chassen
- Department of Pediatrics, Section of NeonatologyUniversity of Colorado, Anschutz Medical CampusAuroraColoradoUSA
| | - Thomas Jansson
- Department of Obstetrics & GynecologyUniversity of Colorado Anschutz Medical CampusAuroraColoradoUSA
| | - Theresa L. Powell
- Department of Obstetrics & GynecologyUniversity of Colorado Anschutz Medical CampusAuroraColoradoUSA
- Department of Pediatrics, Section of NeonatologyUniversity of Colorado, Anschutz Medical CampusAuroraColoradoUSA
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Gou R, Zhang X. Glycolysis: A fork in the path of normal and pathological pregnancy. FASEB J 2023; 37:e23263. [PMID: 37889786 DOI: 10.1096/fj.202301230r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 09/17/2023] [Accepted: 10/04/2023] [Indexed: 10/29/2023]
Abstract
Glucose metabolism is vital to the survival of living organisms. Since the discovery of the Warburg effect in the 1920s, glycolysis has become a major research area in the field of metabolism. Glycolysis has been extensively studied in the field of cancer and is considered as a promising therapeutic target. However, research on the role of glycolysis in pregnancy is limited. Recent evidence suggests that blastocysts, trophoblasts, decidua, and tumors all acquire metabolic energy at specific stages in a highly similar manner. Glycolysis, carefully controlled throughout pregnancy, maintains a dynamic and coordinated state, so as to maintain the homeostasis of the maternal-fetal interface and ensure normal gestation. In the present review, we investigate metabolic remodeling and the selective propensity of the embryo and placenta for glycolysis. We then address dysregulated glycolysis that occurs in the cellular interactive network at the maternal-fetal interface in miscarriage, preeclampsia, fetal growth restriction, and gestational diabetes mellitus. We provide new insights into the field of maternal-fetal medicine from a metabolic perspective, thus revealing the mystery of human pregnancy.
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Affiliation(s)
- Rui Gou
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, P.R. China
| | - Xiaohong Zhang
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, P.R. China
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Page L, Younge N, Freemark M. Hormonal Determinants of Growth and Weight Gain in the Human Fetus and Preterm Infant. Nutrients 2023; 15:4041. [PMID: 37764824 PMCID: PMC10537367 DOI: 10.3390/nu15184041] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/13/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
The factors controlling linear growth and weight gain in the human fetus and newborn infant are poorly understood. We review here the changes in linear growth, weight gain, lean body mass, and fat mass during mid- and late gestation and the early postnatal period in the context of changes in the secretion and action of maternal, placental, fetal, and neonatal hormones, growth factors, and adipocytokines. We assess the effects of hormonal determinants on placental nutrient delivery and the impact of preterm delivery on hormone expression and postnatal growth and metabolic function. We then discuss the effects of various maternal disorders and nutritional and pharmacologic interventions on fetal and perinatal hormone and growth factor production, growth, and fat deposition and consider important unresolved questions in the field.
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Affiliation(s)
- Laura Page
- Division of Pediatric Endocrinology, Duke University Medical Center, Durham, NC 27710, USA;
| | - Noelle Younge
- Neonatology, Duke University Medical Center, Durham, NC 27710, USA;
| | - Michael Freemark
- Division of Pediatric Endocrinology, Duke University Medical Center, Durham, NC 27710, USA;
- The Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27710, USA
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8
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Aldahmash W, Harrath AH, Aljerian K, Sabr Y, Alwasel S. Expression of Glucose Transporters 1 and 3 in the Placenta of Pregnant Women with Gestational Diabetes Mellitus. Life (Basel) 2023; 13:life13040993. [PMID: 37109521 PMCID: PMC10143906 DOI: 10.3390/life13040993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/29/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND The annual prevalence of gestational diabetes mellitus-characterized by an increase in blood glucose in pregnant women-has been increasing worldwide. The goal of this study was to evaluate the expression of glucose transporter 1 (GLUT1) and glucose transporter 3 (GLUT3) in the placenta of women with gestational diabetes mellitus. METHODS Sixty-five placentas from women admitted to the King Saud University Medical City, Riyadh, Saudi Arabia, were analyzed; 34 and 31 placentas were from healthy pregnant women and women with gestational diabetes, respectively. The expressions of GLUT1 and GLUT3 were assessed using RT-PCR, Western blotting, and immunohistochemical methods. The degree of apoptosis in the placental villi was estimated via a TUNEL assay. RESULTS The results of the protein expression assays and immunohistochemical staining showed that the levels of GLUT1 and GLUT3 were significantly higher in the placentas of pregnant women with gestational diabetes than those in the placentas of healthy pregnant women. In addition, the findings showed an increase in apoptosis in the placenta of pregnant women with gestational diabetes compared to that in the placenta of healthy pregnant women. However, the results of gene expression assays showed no significant difference between the two groups. CONCLUSIONS Based on these results, we conclude that gestational diabetes mellitus leads to an increased incidence of apoptosis in the placental villi and alters the level of GLUT1 and GLUT3 protein expressions in the placenta of women with gestational diabetes. Understanding the conditions in which the fetus develops in the womb of a pregnant woman with gestational diabetes may help researchers understand the underlying causes of the development of chronic diseases later in life.
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Affiliation(s)
- Waleed Aldahmash
- Zoology Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Abdel Halim Harrath
- Zoology Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Khaldoon Aljerian
- Pathology Department, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia
| | - Yasser Sabr
- Obstetrics and Gynaecology Department, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia
| | - Saleh Alwasel
- Zoology Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
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9
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RIP140-Mediated NF-κB Inflammatory Pathway Promotes Metabolic Dysregulation in Retinal Pigment Epithelium Cells. Curr Issues Mol Biol 2022; 44:5788-5801. [DOI: 10.3390/cimb44110393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/09/2022] [Accepted: 11/16/2022] [Indexed: 11/22/2022] Open
Abstract
Metabolic dysregulation of the retinal pigment epithelium (RPE) has been implicated in age-related macular degeneration (AMD). However, the molecular regulation of RPE metabolism remains unclear. RIP140 is known to affect oxidative metabolism and mitochondrial biogenesis by negatively controlling mitochondrial pathways regulated by PPAR-γ co-activator-1 α(PGC-1α). This study aims to disclose the effect of RIP140 on the RPE metabolic program in vitro and in vivo. RIP140 protein levels were assayed by Western blotting. Gene expression was tested using quantitative real-time PCR (qRT-PCR), ATP production, and glycogen concentration assays, and the release of inflammatory factors was analyzed by commercial kits. Mice photoreceptor function was measured by electroretinography (ERG). In ARPE-19 cells, RIP140 overexpression changed the expression of the key metabolic genes and lipid processing genes, inhibited mitochondrial ATP production, and enhanced glycogenesis. Moreover, RIP140 overexpression promoted the translocation of NF-κB and increased the expression and production of IL-1β, IL-6, and TNF-α in ARPE-19 cells. Importantly, we also observed the overexpression of RIP140 through adenovirus delivery in rat retinal cells, which significantly decreased the amplitude of the a-wave and b-wave measured by ERG assay. Therapeutic strategies that modulate the activity of RIP140 could have clinical utility for the treatment of AMD in terms of preventing RPE degeneration.
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Huang CF, Tiao MM, Lin IC, Huang LT, Sheen JM, Tain YL, Hsu CN, Tsai CC, Lin YJ, Yu HR. Maternal Metformin Treatment Reprograms Maternal High-Fat Diet-Induced Hepatic Steatosis in Offspring Associated with Placental Glucose Transporter Modifications. Int J Mol Sci 2022; 23:ijms232214239. [PMID: 36430717 PMCID: PMC9694630 DOI: 10.3390/ijms232214239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/11/2022] [Accepted: 11/12/2022] [Indexed: 11/21/2022] Open
Abstract
Maternal high-fat (HF) diet exposure in utero may affect fetal development and cause metabolic problems throughout life due to lipid dysmetabolism and oxidative damage. Metformin has been suggested as a potential treatment for body weight reduction and nonalcoholic fatty liver disease, but its reprogramming effect on offspring is undetermined. This study assesses the effects of maternal metformin treatment on hepatic steatosis in offspring caused by maternal HF diet. Female rats were fed either a control or an HF diet before conception, with or without metformin treatment during gestation, and placenta and fetal liver tissues were collected. In another experiment, the offspring were fed a control diet until 120 d (adult stage). Metformin treatment during pregnancy ameliorates placental oxidative stress and enhances placental glucose transporter 1 (GLUT1), GLUT3, and GLUT4 expression levels through 5' adenosine monophosphate-activated protein kinase (AMPK) activation. Maternal metformin treatment was shown to reprogram maternal HF diet-induced changes in offspring fatty liver with the effects observed in adulthood as well. Further validation is required to develop maternal metformin therapy for clinical applications.
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Affiliation(s)
- Chien-Fu Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Mao-Meng Tiao
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
- Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - I-Chun Lin
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
- Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Li-Tung Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
- Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Jiunn-Ming Sheen
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
- Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - You-Lin Tain
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
- Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
| | - Chien-Ning Hsu
- Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Ching-Chou Tsai
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Yu-Ju Lin
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Hong-Ren Yu
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
- Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- Correspondence: ; Tel.: +886-7-731-7123 (ext. 8713)
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Sibiak R, Ozegowska K, Wender-Ozegowska E, Gutaj P, Mozdziak P, Kempisty B. Fetomaternal Expression of Glucose Transporters (GLUTs)-Biochemical, Cellular and Clinical Aspects. Nutrients 2022; 14:2025. [PMID: 35631166 PMCID: PMC9146575 DOI: 10.3390/nu14102025] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/28/2022] [Accepted: 05/11/2022] [Indexed: 12/10/2022] Open
Abstract
Several types of specialized glucose transporters (GLUTs) provide constant glucose transport from the maternal circulation to the developing fetus through the placental barrier from the early stages of pregnancy. GLUT1 is a prominent protein isoform that regulates placental glucose transfer via glucose-facilitated diffusion. The GLUT1 membrane protein density and permeability of the syncytial basal membrane (BM) are the main factors limiting the rate of glucose diffusion in the fetomaternal compartment in physiological conditions. Besides GLUT1, the GLUT3 and GLUT4 isoforms are widely expressed across the human placenta. Numerous medical conditions and molecules, such as hormones, adipokines, and xenobiotics, alter the GLUT's mRNA and protein expression. Diabetes upregulates the BM GLUT's density and promotes fetomaternal glucose transport, leading to excessive fetal growth. However, most studies have found no between-group differences in GLUTs' placental expression in macrosomic and normal control pregnancies. The fetomaternal GLUTs expression may also be influenced by several other conditions, such as chronic hypoxia, preeclampsia, and intrahepatic cholestasis of pregnancy.
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Affiliation(s)
- Rafal Sibiak
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-701 Poznan, Poland;
- Doctoral School, Poznan University of Medical Sciences, 60-701 Poznan, Poland
| | - Katarzyna Ozegowska
- Department of Infertility and Reproductive Endocrinology, Poznan University of Medical Sciences, 61-701 Poznan, Poland;
| | - Ewa Wender-Ozegowska
- Department of Reproduction, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (E.W.-O.); (P.G.)
| | - Pawel Gutaj
- Department of Reproduction, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (E.W.-O.); (P.G.)
| | - Paul Mozdziak
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
| | - Bartosz Kempisty
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-701 Poznan, Poland;
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
- Department of Anatomy, Poznan University of Medical Sciences, 60-701 Poznan, Poland
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
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12
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Hufnagel A, Dearden L, Fernandez-Twinn DS, Ozanne SE. Programming of cardiometabolic health: the role of maternal and fetal hyperinsulinaemia. J Endocrinol 2022; 253:R47-R63. [PMID: 35258482 PMCID: PMC9066586 DOI: 10.1530/joe-21-0332] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 03/08/2022] [Indexed: 11/13/2022]
Abstract
Obesity and gestational diabetes during pregnancy have multiple short- and long-term consequences for both mother and child. One common feature of pregnancies complicated by maternal obesity and gestational diabetes is maternal hyperinsulinaemia, which has effects on the mother and her adaptation to pregnancy. Even though insulin does not cross the placenta insulin can act on the placenta as well affecting placental growth, angiogenesis and lipid metabolism. Obese and gestational diabetic pregnancies are often characterised by maternal hyperglycaemia resulting in exposure of the fetus to high levels of glucose, which freely crosses the placenta. This leads to stimulation of fetal ß-cells and insulin secretion in the fetus. Fetal hyperglycaemia/hyperinsulinaemia has been shown to cause multiple complications in fetal development, such as altered growth trajectories, impaired neuronal and cardiac development and early exhaustion of the pancreas. These changes could increase the susceptibility of the offspring to develop cardiometabolic diseases later in life. In this review, we aim to summarize and review the mechanisms by which maternal and fetal hyperinsulinaemia impact on (i) maternal health during pregnancy; (ii) placental and fetal development; (iii) offspring energy homeostasis and long-term cardiometabolic health; (iv) how interventions can alleviate these effects.
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Affiliation(s)
- Antonia Hufnagel
- University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Addenbrooke’s Hospital, Cambridge, Cambridgeshire, UK
| | - Laura Dearden
- University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Addenbrooke’s Hospital, Cambridge, Cambridgeshire, UK
| | - Denise S Fernandez-Twinn
- University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Addenbrooke’s Hospital, Cambridge, Cambridgeshire, UK
| | - Susan E Ozanne
- University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Addenbrooke’s Hospital, Cambridge, Cambridgeshire, UK
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13
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Zhang L, Yu X, Wu Y, Fu H, Xu P, Zheng Y, Wen L, Yang X, Zhang F, Hu M, Wang H, Liu X, Qiao J, Peng C, Gao R, Saffery R, Fu Y, Qi H, Tong C, Kilby MD, Baker PN. Gestational Diabetes Mellitus-Associated Hyperglycemia Impairs Glucose Transporter 3 Trafficking in Trophoblasts Through the Downregulation of AMP-Activated Protein Kinase. Front Cell Dev Biol 2021; 9:722024. [PMID: 34796169 PMCID: PMC8593042 DOI: 10.3389/fcell.2021.722024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 10/08/2021] [Indexed: 12/25/2022] Open
Abstract
AMP-activated protein kinase (AMPK) is an important regulator of glucose metabolism, and glucose transporter 3 (GLUT3) is an efficient glucose transporter in trophoblasts. Whether placental AMPK and GLUT3 respond accordingly to gestational diabetes mellitus (GDM) remains uncertain. Here, we explored the regulatory role of AMPK in the GLUT3-dependent uptake of glucose by placental trophoblasts and the viability of the cells. In this study, the level of glycolysis in normal and GDM-complicated placentas was assessed by LC-MS/MS. The trophoblast hyperglycemia model was induced by the incubation of HTR8/SVneo cells with a high glucose concentration. GDM animal models were generated with db/ + mice and C57BL/6J mice fed a high-fat diet, and AMPK was manipulated by the oral administration of metformin. The uptake of glucose by trophoblasts was assessed using 2-NBDG or 2-deoxy-D-[3H] glucose. The results showed that GDM is associated with impaired glycolysis, AMPK activity, GLUT3 expression in the plasma membrane (PM) and cell survival in the placenta. Hyperglycemia induced similar changes in trophoblasts, and these changes were rescued by AMPK activation. Both hyperglycemic db/ + and high-fat diet-induced GDM mice exhibited a compromised AMPK–GLUT3 axis and suppressed cell viability in the placenta as well as excessive fetal growth, and all of these effects were partially alleviated by metformin. Taken together, our findings support the notion that AMPK activation upregulates trophoblast glucose uptake by stimulating GLUT3 translocation, which is beneficial for viability. Thus, the modulation of glucose metabolism in trophoblasts by targeting AMPK might ameliorate the adverse intrauterine environment caused by GDM.
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Affiliation(s)
- Li Zhang
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China.,International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Xinyang Yu
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China.,International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Yue Wu
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China.,International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Huijia Fu
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China.,International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Ping Xu
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Biochemistry and Molecular Biology, University of Texas McGovern Medical School, Houston, TX, United States
| | - Yangxi Zheng
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Biochemistry and Molecular Biology, University of Texas McGovern Medical School, Houston, TX, United States.,Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, TX, United States
| | - Li Wen
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China.,International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Xiaotao Yang
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China.,International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Fumei Zhang
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China.,International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Mingyu Hu
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China.,International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Hao Wang
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China.,International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Xiyao Liu
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China.,International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Juan Qiao
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China.,International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Chuan Peng
- State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China
| | - Rufei Gao
- International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.,Laboratory of Reproductive Biology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Richard Saffery
- International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.,Department of Paediatrics, Cancer, Disease and Developmental Epigenetics, Murdoch Children's Research Institute, University of Melbourne, Parkville, VIC, Australia
| | - Yong Fu
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China.,International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Hongbo Qi
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China.,International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Chao Tong
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China.,International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Mark D Kilby
- International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.,Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom
| | - Philip N Baker
- International Collaborative Laboratory of Reproduction and Development of the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.,College of Life Sciences, University of Leicester, Leicester, United Kingdom
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14
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Espinoza C, Fuenzalida B, Leiva A. Increased Fetal Cardiovascular Disease Risk: Potential Synergy Between Gestational Diabetes Mellitus and Maternal Hypercholesterolemia. Curr Vasc Pharmacol 2021; 19:601-623. [PMID: 33902412 DOI: 10.2174/1570161119666210423085407] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/27/2021] [Accepted: 03/16/2021] [Indexed: 01/25/2023]
Abstract
Cardiovascular diseases (CVD) remain a major cause of death worldwide. Evidence suggests that the risk for CVD can increase at the fetal stages due to maternal metabolic diseases, such as gestational diabetes mellitus (GDM) and maternal supraphysiological hypercholesterolemia (MSPH). GDM is a hyperglycemic, inflammatory, and insulin-resistant state that increases plasma levels of free fatty acids and triglycerides, impairs endothelial vascular tone regulation, and due to the increased nutrient transport, exposes the fetus to the altered metabolic conditions of the mother. MSPH involves increased levels of cholesterol (mainly as low-density lipoprotein cholesterol) which also causes endothelial dysfunction and alters nutrient transport to the fetus. Despite that an association has already been established between MSPH and increased CVD risk, however, little is known about the cellular processes underlying this relationship. Our knowledge is further obscured when the simultaneous presentation of MSPH and GDM takes place. In this context, GDM and MSPH may substantially increase fetal CVD risk due to synergistic impairment of placental nutrient transport and endothelial dysfunction. More studies on the separate and/or cumulative role of both processes are warranted to suggest specific treatment options.
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Affiliation(s)
- Cristian Espinoza
- Faculty of Biological Sciences, Pontificia Universidad Catolica de Chile, Santiago 8330024, Chile
| | - Barbara Fuenzalida
- Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012 Bern, Switzerland
| | - Andrea Leiva
- School of Medical Technology, Health Sciences Faculty, Universidad San Sebastian, Providencia 7510157, Chile
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15
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Chae SA, Son JS, Du M. Prenatal exercise in fetal development: a placental perspective. FEBS J 2021; 289:3058-3071. [PMID: 34449982 DOI: 10.1111/febs.16173] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 08/09/2021] [Accepted: 08/26/2021] [Indexed: 02/06/2023]
Abstract
Maternal obesity (MO) and gestational diabetes mellitus (GDM) are common in Western societies, which impair fetal development and predispose offspring to metabolic dysfunction. Placenta is the organ linking the mother to her fetus, and MO suppresses the development of vascular system and expression of nutrient transporters in placenta, thereby affecting fetal development. For maintaining its proper physiological function, placenta is energy demanding, which is met through extensive oxidative phosphorylation. However, the oxidative capacity of placenta is suppressed due to MO and GDM. Recently, several studies showed that physical activity during pregnancy enhances oxidative metabolism and improves placental function, which might be partially mediated by exerkines, referring to cytokines elicited by exercise. In addition, as an endocrine organ, placenta secretes cytokines, termed placentokines, including apelin, superoxide dismutase 3, irisin, and adiponectin, which mediate fetal development and maternal metabolism. Possible molecular mechanisms linking maternal exercise and placentokines to placental and fetal development are further discussed. As an emerging field, up to now, available studies are limited, mostly conducted in rodents. Given the epidemics of obesity and metabolic disorders, as well as the prevalence of maternal sedentary lifestyle, the effects of exercise of pregnant women on placental function and placentokine secretion, as well as their impacts on fetal development, need to be further examined.
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Affiliation(s)
- Song Ah Chae
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA, USA
| | - Jun Seok Son
- Laboratory of Perinatal Kinesioepigenetics, Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Min Du
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA, USA
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16
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Joshi NP, Mane AR, Sahay AS, Sundrani DP, Joshi SR, Yajnik CS. Role of Placental Glucose Transporters in Determining Fetal Growth. Reprod Sci 2021; 29:2744-2759. [PMID: 34339038 DOI: 10.1007/s43032-021-00699-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 07/16/2021] [Indexed: 11/29/2022]
Abstract
Maternal nutrient availability and its transport through the placenta are crucial for fetal development. Nutrients are transported to the fetus via specific transporters present on the microvillous (MVM) and basal membrane (BM) of the placenta. Glucose is the most abundant nutrient transferred to the fetus and plays a key role in the fetal growth and development. The transfer of glucose across the human placenta is directly proportional to maternal glucose concentrations, and is mediated by glucose transporter family proteins (GLUTs). Maternal glucose concentration influences expression and activity of GLUTs in the MVM (glucose uptake) and BM (glucose delivery). Alteration in the number and function of these transporters may affect the growth and body composition of the fetus. The thin-fat phenotype of the Indian baby (low ponderal index, high adiposity) is proposed as a harbinger of future metabolic risk. We propose that placental function mediated through nutrient transporters contributes to the phenotype of the baby, specifically that glucose transporters will influence neonatal fat. This review discusses the role of various glucose transporters in the placenta in determining fetal growth and body composition, in light of the above hypothesis.
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Affiliation(s)
- Nikita P Joshi
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune-Satara Road, Pune, 411043, India
| | - Aditi R Mane
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune-Satara Road, Pune, 411043, India
| | - Akriti S Sahay
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune-Satara Road, Pune, 411043, India
| | - Deepali P Sundrani
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune-Satara Road, Pune, 411043, India
| | - Sadhana R Joshi
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune-Satara Road, Pune, 411043, India.
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17
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Irvin-Choy NS, Nelson KM, Dang MN, Gleghorn JP, Day ES. Gold nanoparticle biodistribution in pregnant mice following intravenous administration varies with gestational age. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2021; 36:102412. [PMID: 34147664 DOI: 10.1016/j.nano.2021.102412] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/20/2021] [Accepted: 05/10/2021] [Indexed: 01/03/2023]
Abstract
The use of nanoparticles (NPs) to deliver therapeutics to reproductive organs is an emerging approach to safely and effectively treat mothers and babies facing pregnancy complications. This study investigates the biodistribution of two different sized gold-based NPs in pregnant mice following systemic delivery as a function of gestational age. Poly(ethylene glycol)-coated 15 nm gold nanoparticles or 150 nm diameter silica core/gold nanoshells were intravenously administered to pregnant mice at gestational days (E)9.5 or 14.5. NP distribution was analyzed twenty-four hours later by inductively coupled plasma-mass spectrometry and silver staining of histological specimens. More NPs accumulated in placentas than embryos and delivery to these tissues was greater at E9.5 than E14.5. Neither NP type affected fetal weight or placental weight, indicating minimal short-term toxicity in early to mid-stage pregnancy. These findings warrant continued development of NPs as tools to deliver therapeutics to reproductive tissues safely.
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Affiliation(s)
- N'Dea S Irvin-Choy
- Department of Biomedical Engineering, University of Delaware, Newark, USA
| | - Katherine M Nelson
- Department of Chemical and Biomolecular Engineering, University of Delaware, DE, USA
| | - Megan N Dang
- Department of Biomedical Engineering, University of Delaware, Newark, USA
| | - Jason P Gleghorn
- Department of Biomedical Engineering, University of Delaware, Newark, USA; Department of Biological Sciences, University of Delaware, Newark, USA.
| | - Emily S Day
- Department of Biomedical Engineering, University of Delaware, Newark, USA; Department of Materials Science and Engineering, University of Delaware, Newark, USA; Helen F. Cancer Research & Research Institute, University of Delaware, Newark, USA.
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18
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Chang YL, Chao AS, Chang SD, Cheng PJ. Placental glucose transporter 1 and 3 gene expression in Monochorionic twin pregnancies with selective fetal growth restriction. BMC Pregnancy Childbirth 2021; 21:260. [PMID: 33773574 PMCID: PMC8005242 DOI: 10.1186/s12884-021-03744-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 03/22/2021] [Indexed: 11/10/2022] Open
Abstract
Background In monochorionic twin (MC) gestations with selective fetal growth restriction (FGR), the discordant fetal growth usually is due to unequal placental sharing. Glucose, which is essential for oxidative metabolism in the growing placenta and fetus, is transferred from maternal blood by facilitated carrier-mediated diffusion via glucose transporters (GLUTs). How the GLUTs expression varies in the two placenta territories manifests discordant perfusion in MC twin pregnancy with selective FGR is unknown. This study evaluates the human placental GLUT1 and GLUT3 gene expression in MC twin gestations with selective FGR. Methods MC twin pregnancy with selective FGR was defined as the presence of inter-twin birth weight discordance of > 25% and the smaller twin with a birth weight less than the 10th percentile in third trimester. Fetal umbilical artery Doppler was checked within 1 week before delivery in the two fetuses. An abnormal umbilical artery Doppler was defined as persistently absent or reverse end-diastolic flow (UA-AREDF). GLUT1, GLUT3 and HIF-1α gene expression were assayed in each twin’s placental territories. The inter-twin placental gene expression ratio was calculated as the placenta GLUTs or HIF-1α expression level of the selective FGR twin divided by expression level of the appropriate-for-gestational-age (AGA) cotwin. Higher gene expression ratio means elevated gene expression in the selective FGR twin’s placenta territory compared to AGA twin’s placenta territory. Results 15 MC twin gestations with selective FGR including nine with normal (group 1) and six with abnormal selective FGR twin UA Doppler (group 2) were included into this study. The GLUT3 and HIF-1α gene expression are significantly elevated in selective FGR twin’s placenta territory in group 2 twin pregnancies (mean gene expression ratio as 2.23 and 1.65, p values as 0.015 and 0.045, respectively), but not in in group 1 twin pregnancies. Conclusion The upregulation of placental GLUT3 gene expression in selective FGR fetus with abnormal UA Doppler may be due to hypo-perfusion which is mediated by up -regulation of HIF-1α gene expression.
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Affiliation(s)
- Yao-Lung Chang
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou medical center and College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| | - An-Shine Chao
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou medical center and College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shuenn-Dyh Chang
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou medical center and College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Po-Jen Cheng
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou medical center and College of Medicine, Chang Gung University, Taoyuan, Taiwan
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19
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Hu M, Li J, Baker PN, Tong C. Revisiting preeclampsia: a metabolic disorder of the placenta. FEBS J 2021; 289:336-354. [PMID: 33529475 DOI: 10.1111/febs.15745] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 01/13/2021] [Accepted: 01/29/2021] [Indexed: 12/31/2022]
Abstract
Preeclampsia (PE) is a leading cause of maternal and neonatal mortality and morbidity worldwide, impacting the long-term health of both mother and offspring. PE has long been characterized by deficient trophoblast invasion into the uterus and consequent placental hypoperfusion, yet the upstream causative factors and effective interventional targets for PE remain unknown. Alterations in the metabolism of preeclamptic placentas are thought to result from placental ischemia, while disturbances of the metabolism and of metabolites in PE pathogenesis are largely ignored. In fact, as one of the largest fetal organs at birth, the placenta consumes a considerable amount of glucose and fatty acid. Increasing evidence suggests glucose and fatty acid exist as energy substrates and regulate placental development through bioactive derivates. Moreover, recent findings have revealed that the placental metabolism adapts readily to environmental changes, altering its response to nutrients and endocrine signals; this adaptability optimizes pregnancy outcomes by diversifying available carbon sources for energy production, hormone synthesis, angiogenesis, immune activation, and tolerance, and fetoplacental growth. These observations raise the possibility that carbohydrate and lipid metabolism abnormalities play a role in both the etiology and clinical progression of PE, sparking a renewed interest in the interrelationship between PE and metabolic dysregulation. This review will focus on key metabolic substrates and regulatory molecules in the placenta and aim to provide novel insights with respect to the metabolism's role in modulating placental development and functions. Further investigations from this perspective are poised to decipher the etiology of PE and suggest potential therapies.
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Affiliation(s)
- Mingyu Hu
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, China
| | - Ji Li
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | | | - Chao Tong
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, China
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20
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Song TR, Su GD, Chi YL, Wu T, Xu Y, Chen CC. Dysregulated miRNAs contribute to altered placental glucose metabolism in patients with gestational diabetes via targeting GLUT1 and HK2. Placenta 2021; 105:14-22. [PMID: 33517149 DOI: 10.1016/j.placenta.2021.01.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 01/05/2021] [Accepted: 01/14/2021] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Dysregulated genes in glucose transport and metabolize pathways have been found in patients with Gestational diabetes (GDM), but the underlying mechanisms were still unclear. MATERIALS AND METHODS Placental villous samples were collected from 31 patients with GDM and 20 healthy controls. The expression of GLUT1, GLUT4, GLUT9 and HK2 was examined by immunoblotting and qRT-PCR. The miRNAs have the potential targeting GLUT1 and HK2 were predicted using online bioinformatics tool: TargetScan. The interaction between miRNAs and target genes were confirmed by dual luciferase assay and immunoblotting. The function of miR-9 and miR-22 on glucose metabolism was examined by glucose uptake assay and lactate secretion assay. RESULTS GLUT1 and HK2 proteins level was found upregulated in patients with GDM, but the mRNA level was not significantly changed. Predicted by using bioinformatics tools and confirmed by dual luciferase assay and immunoblotting, GLUT1 was identified as a target of miR-9 and miR-22, whereas HK2 was identified as a target of miR-9. MiR-9 and miR-22 level was found reduced in the placenta villous and negatively correlated with the expression of GLUT1 and HK2. Functional studies indicated that miR-9 and miR-22 inhibitors upregulated the expression of GLUT1 and HK2, and then increased the glucose uptake, lactate secretion, cell viability and repressed apoptosis in primary syncytiotrophoblasts (STBs) and HTR8/SVneo cells. DISCUSSION The upregulation of GLUT1 and HK2 in the placenta, which is induced by miR-9 and miR-22 reduction, contributes to the disordered glucose metabolism in patients with GDM.
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Affiliation(s)
- Tian-Rong Song
- Obstetrics and Gynecology Department, University of Hong Kong Shenzhen Hospital, 518000, Shenzhen, Guangdong, China.
| | - Gui-Dong Su
- Obstetrics and Gynecology Department, Nanfang Hospital Affiliated to Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Ya-Li Chi
- Obstetrics and Gynecology Department, Nanfang Hospital Affiliated to Southern Medical University, 510515, Guangzhou, Guangdong, China
| | - Ting Wu
- Obstetrics and Gynecology Department, University of Hong Kong Shenzhen Hospital, 518000, Shenzhen, Guangdong, China
| | - Yue Xu
- Obstetrics and Gynecology Department, University of Hong Kong Shenzhen Hospital, 518000, Shenzhen, Guangdong, China
| | - Chun-Chun Chen
- Obstetrics and Gynecology Department, University of Hong Kong Shenzhen Hospital, 518000, Shenzhen, Guangdong, China
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21
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Hebert JF, Myatt L. Placental mitochondrial dysfunction with metabolic diseases: Therapeutic approaches. Biochim Biophys Acta Mol Basis Dis 2021; 1867:165967. [PMID: 32920120 PMCID: PMC8043619 DOI: 10.1016/j.bbadis.2020.165967] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 09/03/2020] [Accepted: 09/04/2020] [Indexed: 12/25/2022]
Abstract
Both obesity and gestational diabetes mellitus (GDM) lead to poor maternal and fetal outcomes, including pregnancy complications, fetal growth issues, stillbirth, and developmental programming of adult-onset disease in the offspring. Increased placental oxidative/nitrative stress and reduced placental (trophoblast) mitochondrial respiration occur in association with the altered maternal metabolic milieu of obesity and GDM. The effect is particularly evident when the fetus is male, suggesting a sexually dimorphic influence on the placenta. In addition, obesity and GDM are associated with inflexibility in trophoblast, limiting the ability to switch between usage of glucose, fatty acids, and glutamine as substrates for oxidative phosphorylation, again in a sexually dimorphic manner. Here we review mechanisms underlying placental mitochondrial dysfunction: its relationship to maternal and fetal outcomes and the influence of fetal sex. Prevention of placental oxidative stress and mitochondrial dysfunction may improve pregnancy outcomes. We outline pathways to ameliorate deficient mitochondrial respiration, particularly the benefits and pitfalls of mitochondria-targeted antioxidants.
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Affiliation(s)
- Jessica F Hebert
- Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, United States of America
| | - Leslie Myatt
- Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, United States of America.
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22
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Meng X, Lian X, Li X, Ya Q, Li T, Zhang Y, Yang Y, Zhang Y. Synthesis of 2'-paclitaxel 2-deoxy-2-fluoro-glucopyranosyl carbonate for specific targeted delivery to cancer cells. Carbohydr Res 2020; 493:108034. [PMID: 32485481 DOI: 10.1016/j.carres.2020.108034] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 04/28/2020] [Accepted: 05/14/2020] [Indexed: 12/17/2022]
Abstract
A novel 2-fluorodeoxyglucose conjugated derivative of paclitaxel was efficiently synthesized using a linker between 2'-OH of paclitaxel and C1-hydroxyl group of 2-fluorodeoxyglucose. In preparation of the prodrug, allyl carbonates were selected as the protective group and the efficient one-step removal of allyloxycarbonyl groups at the end of the synthesis using palladium chemistry gave the target molecule in good yield. The prodrug not only improved the pharmaceutical properties of paclitaxel, such as solubility and stability, but also demonstrated enhanced cytotoxicity and selectivity for cancer cells and less toxicity toward normal HUVEC cells.
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Affiliation(s)
- Xin Meng
- Key Laboratory of Industrial Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin, 300457, PR China.
| | - Xujing Lian
- Key Laboratory of Industrial Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin, 300457, PR China
| | - Xiao Li
- Key Laboratory of Industrial Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin, 300457, PR China
| | - Qiang Ya
- Key Laboratory of Industrial Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin, 300457, PR China
| | - Tingshen Li
- Key Laboratory of Industrial Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin, 300457, PR China
| | - Yongmin Zhang
- Université Pierre et Marie Curie-Paris 6, Institut Parisien de Chimie Moléculaire, UMR, CNRS, 8232, 4 Place Jussieu, 75005, Paris, France
| | - Yang Yang
- Key Laboratory of Industrial Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin, 300457, PR China.
| | - Yan Zhang
- Department of Pharmacy, Qilu Hospital of Shandong University, Jinan, 250012, Shandong Province, PR China
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James-Allan LB, Teal S, Powell TL, Jansson T. Changes in Placental Nutrient Transporter Protein Expression and Activity Across Gestation in Normal and Obese Women. Reprod Sci 2020; 27:1758-1769. [PMID: 32072607 DOI: 10.1007/s43032-020-00173-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 02/03/2020] [Indexed: 11/26/2022]
Abstract
Fetal growth and development are dependent on placental nutrient transport. The syncytiotrophoblast (ST) and its two polarized plasma membranes, the maternal-facing microvillous membrane (MVM) and fetal-facing basal membrane (BM), represent the primary barrier in the human placenta, controlling transplacental transfer of small solutes. MVM and BM nutrient transporter expression and activity are increased in obese mothers delivering large babies. However, placental nutrient transporter expression and activity in early gestation in normal and obese women are largely unknown. Placentas from normal BMI and obese women at 6-24 weeks of gestation, and term placentas from normal BMI women, were collected and ST plasma membranes isolated. The activity and protein expression of amino acid, glucose, and fatty acid transporters was assessed. No significant differences were observed in placental nutrient transporter protein expression between normal BMI and obese women in early pregnancy. In the MVM, system A amino acid activity (p = 0.02), SNAT2 (p < 0.0001), SNAT4 (p < 0.001), and GLUT1 (p = 0.01) protein expression were higher at term compared with early gestation. In contrast, MVM system L activity (p = 0.001), FATP4 (p = 0.03), and FATP6 (p = 0.009) protein expression were lower at term compared with early pregnancy. In the BM, there was no change in system L activity across gestation; however, BM FATP6 (p = 0.002) protein expression was lower at term compared with early pregnancy. These results suggest that placental transport of amino acids, glucose, and fatty acids are subjected to coordinated regulation across gestation to meet a fetal nutrient demand that changes with advancing pregnancy.
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Affiliation(s)
- Laura B James-Allan
- Department of Obstetrics/Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
| | - Stephanie Teal
- Department of Obstetrics/Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Theresa L Powell
- Department of Obstetrics/Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Thomas Jansson
- Department of Obstetrics/Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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24
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Chassen S, Jansson T. Complex, coordinated and highly regulated changes in placental signaling and nutrient transport capacity in IUGR. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165373. [PMID: 30684642 PMCID: PMC6650384 DOI: 10.1016/j.bbadis.2018.12.024] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 12/20/2018] [Accepted: 12/26/2018] [Indexed: 01/01/2023]
Abstract
The most common cause of intrauterine growth restriction (IUGR) in the developed world is placental insufficiency, a concept often used synonymously with reduced utero-placental and umbilical blood flows. However, placental insufficiency and IUGR are associated with complex, coordinated and highly regulated changes in placental signaling and nutrient transport including inhibition of insulin and mTOR signaling and down-regulation of specific amino acid transporters, Na+/K+-ATPase, the Na+/H+-exchanger, folate and lactate transporters. In contrast, placental glucose transport capacity is unaltered and Ca2+-ATPase activity and the expression of proteins involved in placental lipid transport are increased in IUGR. These findings are not entirely consistent with the traditional view that the placenta is dysfunctional in IUGR, but rather suggest that the placenta adapts to reduce fetal growth in response to an inability of the mother to allocate resources to the fetus. This new model has implications for the understanding of the mechanisms underpinning IUGR and for the development of intervention strategies.
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Affiliation(s)
- Stephanie Chassen
- Department of Pediatrics, Division of Neonatology, University of Colorado, Anschutz Medical Campus, Aurora, USA
| | - Thomas Jansson
- Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado, Anschutz Medical Campus, Aurora, USA.
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25
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Johns EC, Denison FC, Reynolds RM. The impact of maternal obesity in pregnancy on placental glucocorticoid and macronutrient transport and metabolism. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165374. [PMID: 30684643 DOI: 10.1016/j.bbadis.2018.12.025] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 12/12/2018] [Accepted: 12/26/2018] [Indexed: 12/15/2022]
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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Affiliation(s)
- Emma C Johns
- Tommy's Centre for Maternal and Fetal Health, MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom
| | - Fiona C Denison
- Tommy's Centre for Maternal and Fetal Health, MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom
| | - Rebecca M Reynolds
- Tommy's Centre for Maternal and Fetal Health, MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom; BHF/University Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
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26
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Stanirowski PJ, Lipa M, Bomba-Opoń D, Wielgoś M. Expression of placental glucose transporter proteins in pregnancies complicated by fetal growth disorders. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2020; 123:95-131. [PMID: 33485490 DOI: 10.1016/bs.apcsb.2019.12.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
During pregnancy fetal growth disorders, including fetal macrosomia and fetal growth restriction (FGR) are associated with numerous maternal-fetal complications, as well as due to the adverse effect of the intrauterine environment lead to an increased morbidity in adult life. Accumulating evidence suggests that occurrence of fetal macrosomia or FGR, may be associated with alterations in the transfer of nutrients across the placenta, in particular of glucose. The placental expression and activity of specific GLUT transporters are the main regulatory factors in the process of maternal-fetal glucose exchange. This review article summarizes the results of previous studies on the expression of GLUT transporters in the placenta, concentrating on human pregnancies complicated by intrauterine fetal growth disorders. Characteristics of each transporter protein found in the placenta is presented, alterations in the location and expression of GLUT isoforms observed in individual placental compartments are described, and the factors regulating the expression of selected GLUT proteins are examined. Based on the above data, the potential function of each GLUT isoform in the maternal-fetal glucose transfer is determined. Further on, a detailed analysis of changes in the expression of glucose transporters in pregnancies complicated by fetal growth disorders is given, and significance of these modifications for the pathogenesis of fetal macrosomia and FGR is discussed. In the final part novel interventional approaches that might reduce the risk associated with abnormalities of intrauterine fetal growth through modifications of placental GLUT-mediated glucose transfer are explored.
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Affiliation(s)
- Paweł Jan Stanirowski
- 1(st) Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland; Club 35. Polish Society of Gynecologists and Obstetricians, Warsaw, Poland
| | - Michał Lipa
- 1(st) Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland; Club 35. Polish Society of Gynecologists and Obstetricians, Warsaw, Poland
| | - Dorota Bomba-Opoń
- 1(st) Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland
| | - Mirosław Wielgoś
- 1(st) Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland
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27
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Castillo-Castrejon M, Jansson T, Powell TL. No evidence of attenuation of placental insulin-stimulated Akt phosphorylation and amino acid transport in maternal obesity and gestational diabetes mellitus. Am J Physiol Endocrinol Metab 2019; 317:E1037-E1049. [PMID: 31573844 PMCID: PMC6962503 DOI: 10.1152/ajpendo.00196.2019] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Pregnancies complicated by obesity and/or gestational diabetes (GDM) are associated with peripheral insulin resistance; however, the insulin responsiveness of the placenta in these pregnancy complications remains largely unknown. We tested the hypothesis that primary human trophoblast cells and placental villous explants will be insulin responsive, characterized by amino acid transport, Akt and Erk activity with maternal obesity, and/or GDM. We evaluated term placentas from women with normal body mass index (BMI) (normal; n = 15), obesity (OB; n = 11), normal BMI with GDM (N-GDM; n = 11), and obesity with GDM (OB-GDM; n = 11). In a subgroup, primary human trophoblast cells (PHT) were isolated, and in an independent subgroup placental villous explants were exposed to varying concentrations of insulin. Amino acid transport capacity and insulin signaling activity were determined. Insulin significantly increased amino acid transport activity to a similar degree in PHT cells isolated from normal (+21%), N-GDM (+38%), OB (+37%), and OB-GDM (+35%) pregnancies. Insulin increased Akt and Erk phosphorylation in PHT cells (3-fold) and in villous explants (2-fold) in all groups to a similar degree. In contrast to the peripheral maternal insulin resistance commonly associated with obesity and/or GDM, we found that the placenta is insulin sensitive in these pregnancy complications. We suggest that elevated maternal insulin levels in pregnancies complicated by obesity and/or GDM promote critical placental functions, including amino acid transport. Insulin-stimulated placental nutrient delivery may contribute to the increased risk of fetal overgrowth and adiposity in these pregnancies. Moreover, our findings may inform efforts to optimize insulin regimens for women with GDM.
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Affiliation(s)
- Marisol Castillo-Castrejon
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Thomas Jansson
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Theresa L Powell
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Department of Pediatrics, Section of Neonatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
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28
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Kappen C, Kruger C, Jones S, Herion NJ, Salbaum JM. Maternal diet modulates placental nutrient transporter gene expression in a mouse model of diabetic pregnancy. PLoS One 2019; 14:e0224754. [PMID: 31774824 PMCID: PMC6881028 DOI: 10.1371/journal.pone.0224754] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Accepted: 10/21/2019] [Indexed: 12/30/2022] Open
Abstract
Diabetes in the mother during pregnancy is a risk factor for birth defects and perinatal complications and can affect long-term health of the offspring through developmental programming of susceptibility to metabolic disease. We previously showed that Streptozotocin-induced maternal diabetes in mice is associated with altered cell differentiation and with smaller size of the placenta. Placental size and fetal size were affected by maternal diet in this model, and maternal diet also modulated the risk for neural tube defects. In the present study, we sought to determine the extent to which these effects might be mediated through altered expression of nutrient transporters, specifically glucose and fatty acid transporters in the placenta. Our results demonstrate that expression of several transporters is modulated by both maternal diet and maternal diabetes. Diet was revealed as the more prominent determinant of nutrient transporter expression levels, even in pregnancies with uncontrolled diabetes, consistent with the role of diet in placental and fetal growth. Notably, the largest changes in nutrient transporter expression levels were detected around midgestation time points when the placenta is being formed. These findings place the critical time period for susceptibility to diet exposures earlier than previously appreciated, implying that mechanisms underlying developmental programming can act on placenta formation.
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Affiliation(s)
- Claudia Kappen
- Department of Developmental Biology, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, United States of America
- * E-mail:
| | - Claudia Kruger
- Department of Developmental Biology, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, United States of America
| | - Sydney Jones
- Baton Rouge, Louisiana, United States of America Regulation of Gene Expression Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, United States of America
| | - Nils J. Herion
- Department of Developmental Biology, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, United States of America
- Baton Rouge, Louisiana, United States of America Regulation of Gene Expression Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, United States of America
| | - J. Michael Salbaum
- Baton Rouge, Louisiana, United States of America Regulation of Gene Expression Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, United States of America
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29
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James-Allan LB, Arbet J, Teal SB, Powell TL, Jansson T. Insulin stimulates GLUT4 trafficking to the syncytiotrophoblast basal plasma membrane in the human placenta. J Clin Endocrinol Metab 2019; 104:4225-4238. [PMID: 31112275 PMCID: PMC6688457 DOI: 10.1210/jc.2018-02778] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 05/15/2019] [Indexed: 01/30/2023]
Abstract
CONTEXT Placental transport capacity influences fetal glucose supply. The syncytiotrophoblast is the transporting epithelium in the human placenta, expressing glucose transporters (GLUT) and insulin receptors (IR) in its maternal-facing microvillous (MVM) and fetal-facing basal plasma membrane (BM). OBJECTIVE The objectives of this study were to (1) determine the expression of the insulin-sensitive GLUT4 glucose transporter and IR in the syncytiotrophoblast plasma membranes across gestation in normal pregnancy and in pregnancies complicated by maternal obesity and (2) assess the effect of insulin on GLUT4 plasma membrane trafficking in human placental explants. DESIGN, SETTING, PARTICIPANTS Placental tissue was collected across gestation from women with normal body mass index (BMI) and obese mothers with appropriate for gestational age (AGA) and macrosomic infants. MVM and BM were isolated. MAIN OUTCOME MEASURES Protein expression of GLUT4, GLUT1 and IR were determined by western blot. RESULTS GLUT4 was exclusively expressed in the BM and IR was predominantly expressed in the MVM, with increasing expression across gestation. BM GLUT1 expression was increased and BM GLUT4 expression was decreased in obese women delivering macrosomic babies. In placental villous explants incubation with insulin stimulated Akt (S473) phosphorylation (+76%, p=0.0003, n=13) independent of maternal BMI and increased BM GLUT4 protein expression (+77%, p=0.0013, n=7) in placentas from lean but not obese women. CONCLUSION We propose that maternal insulin stimulates placental glucose transport by promoting GLUT4 trafficking to the BM, which may enhance glucose transfer to the fetus in response to postprandial hyperinsulinemia in women with normal BMI.
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Affiliation(s)
- Laura B James-Allan
- Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Correspondence and Reprint Requests: Laura B. James-Allan, PhD, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, Colorado 80045. E-mail:
| | - Jaron Arbet
- Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Stephanie B Teal
- Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Theresa L Powell
- Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Thomas Jansson
- Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
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30
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Hoch D, Gauster M, Hauguel-de Mouzon S, Desoye G. Diabesity-associated oxidative and inflammatory stress signalling in the early human placenta. Mol Aspects Med 2019; 66:21-30. [DOI: 10.1016/j.mam.2018.11.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 11/08/2018] [Accepted: 11/30/2018] [Indexed: 12/17/2022]
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31
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Walker N, Filis P, O'Shaughnessy PJ, Bellingham M, Fowler PA. Nutrient transporter expression in both the placenta and fetal liver are affected by maternal smoking. Placenta 2019; 78:10-17. [PMID: 30955705 PMCID: PMC6461130 DOI: 10.1016/j.placenta.2019.02.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 02/18/2019] [Accepted: 02/19/2019] [Indexed: 01/17/2023]
Abstract
Introduction The placenta controls nutrient transfer between mother and fetus via membrane transporters. Appropriate transplacental passage of nutrients is essential for fetal growth and development. We investigated whether transporter transcript levels in human placenta-liver pairs from first and early second trimester pregnancies exhibit gestational age- or fetal sex-specific profiles and whether these are dysregulated by maternal smoking. Methods In a step-change for the field, paired placenta and fetal livers from 54 electively terminated, normally-progressing pregnancies (7–20 weeks of gestation, Scottish Advanced Fetal Research Study, REC 15/NS/0123) were sexed and cigarette smoking-exposure confirmed. Thirty-six nutrient transporter transcripts were quantified using RT-qPCR. Results While fetal, liver and placenta weights were not altered by maternal smoking, levels of transporter transcripts changed with fetal age and sex in the placenta and fetal liver and their trajectories were altered if the mother smoked. Placental levels of glucose uptake transporters SLC2A1 and SLC2A3 increased in smoking-exposed fetuses while smoking was associated with altered levels of amino acid and fatty acid transporter genes in both tissues. SLC7A8, which exchanges non-essential amino acids in the fetus for essential amino acids from the placenta, was reduced in smoking-exposed placentas while transcript levels of four hepatic fatty acid uptake transporters were also reduced by smoking. Discussion This data shows that fetal sex and age and maternal smoking are associated with altered transporter transcript levels. This could influence nutrient transport across the placenta and subsequent uptake by the fetal liver, altering trophic delivery to the growing fetus.
Nutrient transporters show differential expression in first/second trimesters. Maternal smoking alters transporter expression of three essential nutrient groups. Fatty acid transporter expression is reduced in smoke-exposed fetal livers.
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Affiliation(s)
- Natasha Walker
- Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
| | - Panagiotis Filis
- Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
| | - Peter J O'Shaughnessy
- Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Michelle Bellingham
- Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G61 1QH, UK
| | - Paul A Fowler
- Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
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32
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Illsley NP, Baumann MU. Human placental glucose transport in fetoplacental growth and metabolism. Biochim Biophys Acta Mol Basis Dis 2018; 1866:165359. [PMID: 30593896 DOI: 10.1016/j.bbadis.2018.12.010] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 11/13/2018] [Accepted: 12/06/2018] [Indexed: 02/07/2023]
Abstract
While efficient glucose transport is essential for all cells, in the case of the human placenta, glucose transport requirements are two-fold; provision of glucose for the growing fetus in addition to the supply of glucose required the changing metabolic needs of the placenta itself. The rapidly evolving environment of placental cells over gestation has significant consequences for the development of glucose transport systems. The two-fold transport requirement of the placenta means also that changes in expression will have effects not only for the placenta but also for fetal growth and metabolism. This review will examine the localization, function and evolution of placental glucose transport systems as they are altered with fetal development and the transport and metabolic changes observed in pregnancy pathologies.
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Affiliation(s)
- Nicholas P Illsley
- Center for Abnormal Placentation, Department of Obstetrics and Gynecology, Hackensack University Medical Center, Hackensack, NJ, USA.
| | - Marc U Baumann
- Department of Obstetrics and Gynaecology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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Natural disaster-related prenatal maternal stress is associated with alterations in placental glucocorticoid system: The QF2011 Queensland Flood Study. Psychoneuroendocrinology 2018; 94:38-48. [PMID: 29754004 DOI: 10.1016/j.psyneuen.2018.04.027] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 02/25/2018] [Accepted: 04/24/2018] [Indexed: 12/19/2022]
Abstract
We investigated the effects of a natural disaster (a sudden flood) as a source of prenatal maternal stress (PNMS) on the placental glucocorticoid system and glucose transporters. Whether the gestational age at the time of the flood moderated these effects was also evaluated. Placental samples were collected from participants in the 2011 Queensland Flood Study (QF2011) who were pregnant in the first or second trimester at the onset of the flood. Detailed questionnaire results for objective hardship and composite subjective distress were obtained to assess stress levels. Subjective distress was significantly associated with a reduction in placental NR3C1-β mRNA levels for males only (β = -0.491, p = 0.005). In female placentas, objective hardship was marginally linked with lower SLC2A1 mRNA levels while subjective distress was a marginally significant predictor of higher placental SLC2A4 mRNA levels. Gestational age at the time of the flood was a significant moderator of the effect of subjective distress on placental mRNA levels for NR3C1-α (p = 0.046) and HSD11B1 (p = 0.049) in male placentas: if the flood occurred in mid-pregnancy, lower subjective distress predicted higher HSD11B1 while higher subjective distress predicted lower NR3C1-α placental mRNA level. While results did not show any PNMS effects on placental HSD11B2 mRNA and protein levels, and activity, we showed a reduction in placental NR3C1-β mRNA level in male placentas. Our results show evidence of distinct placental glucocorticoid and glucose systems adaptations to PNMS as a function of fetal sex and gestational timing of exposure, with high subjective PNMS in mid-pregnancy associated with lower levels of expression of glucocorticoid-promoting gene in males, leaving the fetus less protected against maternal stress. The exact mechanism by which natural disaster-related PNMS acts on the placenta and the impact on fetal programming requires further investigation.
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34
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Basak S, Vilasagaram S, Naidu K, Duttaroy AK. Insulin-dependent, glucose transporter 1 mediated glucose uptake and tube formation in the human placental first trimester trophoblast cells. Mol Cell Biochem 2018; 451:91-106. [DOI: 10.1007/s11010-018-3396-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 06/26/2018] [Indexed: 12/20/2022]
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35
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Placental Expression of Glucose Transporter Proteins in Pregnancies Complicated by Gestational and Pregestational Diabetes Mellitus. Can J Diabetes 2018; 42:209-217. [DOI: 10.1016/j.jcjd.2017.04.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 04/18/2017] [Accepted: 04/24/2017] [Indexed: 12/31/2022]
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Janzen C, Lei MYY, Jeong ISD, Ganguly A, Sullivan P, Paharkova V, Capodanno G, Nakamura H, Perry A, Shin BC, Lee KW, Devaskar SU. Humanin (HN) and glucose transporter 8 (GLUT8) in pregnancies complicated by intrauterine growth restriction. PLoS One 2018; 13:e0193583. [PMID: 29590129 PMCID: PMC5873989 DOI: 10.1371/journal.pone.0193583] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 02/14/2018] [Indexed: 12/20/2022] Open
Abstract
Background Intrauterine growth restriction (IUGR) results from a lack of nutrients transferred to the developing fetus, particularly oxygen and glucose. Increased expression of the cytoprotective mitochondrial peptide, humanin (HN), and the glucose transporter 8, GLUT8, has been reported under conditions of hypoxic stress. However, the presence and cellular localization of HN and GLUT8 in IUGR-related placental pathology remain unexplored. Thus, we undertook this study to investigate placental expression of HN and GLUT8 in IUGR-affected versus normal pregnancies. Results We found 1) increased HN expression in human IUGR-affected pregnancies on the maternal aspect of the placenta (extravillous trophoblastic (EVT) cytoplasm) compared to control (i.e. appropriate for gestational age) pregnancies, and a concomitant increase in GLUT8 expression in the same compartment, 2) HN and GLUT8 showed a protein-protein interaction by co-immunoprecipitation, 3) elevated HN and GLUT8 levels in vitro under simulated hypoxia in human EVT cells, HTR8/SVneo, and 4) increased HN expression but attenuated GLUT8 expression in vitro under serum deprivation in HTR8/SVneo cells. Conclusions There was elevated HN expression with cytoplasmic localization to EVTs on the maternal aspect of the human placenta affected by IUGR, also associated with increased GLUT8 expression. We found that while hypoxia increased both HN and GLUT8, serum deprivation increased HN expression alone. Also, a protein-protein interaction between HN and GLUT8 suggests that their interaction may fulfill a biologic role that requires interdependency. Future investigations delineating molecular interactions between these proteins are required to fully uncover their role in IUGR-affected pregnancies.
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Affiliation(s)
- Carla Janzen
- Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- * E-mail:
| | - Margarida Y. Y. Lei
- Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
| | - Il Seok D. Jeong
- Department of Pediatrics, Division of Endocrinology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Neonatal Research Center of the UCLA Children’s Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
| | - Amit Ganguly
- Neonatal Research Center of the UCLA Children’s Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Department of Pediatrics, Division of Neonatology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
| | - Peggy Sullivan
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
| | - Vladislava Paharkova
- Department of Pediatrics, Division of Endocrinology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Neonatal Research Center of the UCLA Children’s Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
| | - Gina Capodanno
- Department of Pediatrics, Division of Endocrinology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Neonatal Research Center of the UCLA Children’s Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
| | - Hiromi Nakamura
- Department of Pediatrics, Division of Endocrinology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Neonatal Research Center of the UCLA Children’s Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
| | - Alix Perry
- Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
| | - Bo-Chul Shin
- Neonatal Research Center of the UCLA Children’s Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Department of Pediatrics, Division of Neonatology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
| | - Kuk-Wha Lee
- Department of Pediatrics, Division of Endocrinology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Neonatal Research Center of the UCLA Children’s Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
| | - Sherin U. Devaskar
- Neonatal Research Center of the UCLA Children’s Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Department of Pediatrics, Division of Neonatology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
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Offspring sex impacts DNA methylation and gene expression in placentae from women with diabetes during pregnancy. PLoS One 2018; 13:e0190698. [PMID: 29470513 PMCID: PMC5823368 DOI: 10.1371/journal.pone.0190698] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 12/19/2017] [Indexed: 12/21/2022] Open
Abstract
Aims/Hypothesis We hypothesized that diabetes during pregnancy (DDP) alters genome-wide DNA methylation in placenta resulting in differentially methylated loci of metabolically relevant genes and downstream changes in RNA and protein expression. Methods We mapped genome-wide DNA methylation with the Infinium 450K Human Methylation Bead Chip in term fetal placentae from Native American and Hispanic women with DDP using a nested case-control design (n = 17 pairs). RNA expression and protein levels were assayed via RNA-Seq and Western Blot. Results Genome-wide DNA methylation analysis revealed 465 CpG sites with significant changes for male offspring, 247 for female offspring, and 277 for offspring of both sexes (p<0.001). Placentae from female offspring were 40% more likely to have significant gains in DNA methylation compared with placentae from male offspring exposed to DDP (p<0.001). Changes in DNA methylation corresponded to changes in RNA and protein levels for 6 genes: PIWIL3, CYBA, GSTM1, GSTM5, KCNE1 and NXN. Differential DNA methylation was detected at loci related to mitochondrial function, DNA repair, inflammation, oxidative stress. Conclusions/Interpretation These findings begin to explain mechanisms responsible for the increased risk for obesity and type 2 diabetes in offspring of mothers with DDP.
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Kondo T, Nakamura M, Kitano S, Kawashima J, Matsumura T, Ohba T, Yamaguchi M, Katabuchi H, Araki E. The clinical course and pathophysiological investigation of adolescent gestational diabetes insipidus: a case report. BMC Endocr Disord 2018; 18:4. [PMID: 29378555 PMCID: PMC5789627 DOI: 10.1186/s12902-018-0234-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 01/23/2018] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Gestational diabetes insipidus (GDI) is a rare endocrine complication during pregnancy that is associated with vasopressinase overproduction from the placenta. Although increased vasopressinase is associated with placental volume, the regulation of placental growth in the later stage of pregnancy is not well known. CASE PRESENTATION A 16-year-old pregnant woman was urgently transferred to our hospital because of threatened premature labor when the Kumamoto earthquakes hit the area where she lived. During her hospitalization, she complained of gradually increasing symptoms of polyuria and polydipsia. The serum level of arginine vasopressin (AVP) was 1.7 pg/mL, which is inconsistent with central DI. The challenge of diagnostic treatment using oral 1-deamino-8-D-AVP (DDAVP) successfully controlled her urine and allowed for normal delivery. DDAVP tablets were not necessary to control her polyuria thereafter. Based on these observations, clinical diagnosis of GDI was confirmed. Pathophysiological analyses revealed that vasopressinase expression was more abundant in the GDI patient's syncytiotrophoblast in placenta compared with that in a control subject. Serum vasopressinase was also observed during gestation and disappeared soon after delivery. Vasopressinase is reportedly identical to oxytocinase or insulin regulated aminopeptidase (IRAP), which is an abundant cargo protein associated with the glucose transporter 4 (GLUT4) storage vesicle. Interestingly, the expression and subcellular localization of GLUT4 appeared to occur in a vasopressinase (IRAP)-dependent manner. CONCLUSION Because placental volume may be associated with vasopressinase overproduction in GDI, vasopressinase (IRAP)/GLUT4 association appears to contribute to the growth of placenta in this case.
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Affiliation(s)
- Tatsuya Kondo
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Chuo-Ward, Honjo, Kumamoto, 860-8556 Japan
| | - Miwa Nakamura
- Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Chuo-Ward, Honjo, Kumamoto, 860-8556 Japan
| | - Sayaka Kitano
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Chuo-Ward, Honjo, Kumamoto, 860-8556 Japan
| | - Junji Kawashima
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Chuo-Ward, Honjo, Kumamoto, 860-8556 Japan
| | - Takeshi Matsumura
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Chuo-Ward, Honjo, Kumamoto, 860-8556 Japan
| | - Takashi Ohba
- Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Chuo-Ward, Honjo, Kumamoto, 860-8556 Japan
| | - Munekage Yamaguchi
- Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Chuo-Ward, Honjo, Kumamoto, 860-8556 Japan
| | - Hidetaka Katabuchi
- Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Chuo-Ward, Honjo, Kumamoto, 860-8556 Japan
| | - Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Chuo-Ward, Honjo, Kumamoto, 860-8556 Japan
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Stanirowski PJ, Szukiewicz D, Pyzlak M, Abdalla N, Sawicki W, Cendrowski K. 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. J Matern Fetal Neonatal Med 2017; 32:650-659. [PMID: 28969476 DOI: 10.1080/14767058.2017.1387897] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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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Affiliation(s)
- Paweł Jan Stanirowski
- a Department of Obstetrics, Gynecology and Oncology, II Faculty of Medicine , Medical University of Warsaw, Mazovian Bródno Hospital , Warsaw , Poland
| | - Dariusz Szukiewicz
- b Department of General and Experimental Pathology with Centre for Preclinical Research and Technology (CEPT), II Faculty of Medicine , Medical University of Warsaw , Warsaw , Poland
| | - Michał Pyzlak
- b Department of General and Experimental Pathology with Centre for Preclinical Research and Technology (CEPT), II Faculty of Medicine , Medical University of Warsaw , Warsaw , Poland
| | - Nabil Abdalla
- a Department of Obstetrics, Gynecology and Oncology, II Faculty of Medicine , Medical University of Warsaw, Mazovian Bródno Hospital , Warsaw , Poland
| | - Włodzimierz Sawicki
- a Department of Obstetrics, Gynecology and Oncology, II Faculty of Medicine , Medical University of Warsaw, Mazovian Bródno Hospital , Warsaw , Poland
| | - Krzysztof Cendrowski
- a Department of Obstetrics, Gynecology and Oncology, II Faculty of Medicine , Medical University of Warsaw, Mazovian Bródno Hospital , Warsaw , Poland
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Abstract
Intrauterine growth restriction (IUGR) has been defined in several ways, but in general describes a condition in which the fetus exhibits poor growth in utero. This complication of pregnancy poses a significant public health burden as well as increased morbidity and mortality for the offspring. In human IUGR, alteration in fetal glucose and insulin homeostasis occurs in an effort to conserve energy and survive at the expense of fetal growth in an environment of inadequate nutrient provision. Several animal models of IUGR have been utilized to study the effects of IUGR on fetal glucose handling, as well as the postnatal reprogramming of energy metabolite handling, which may be unmasked in adulthood as a maladaptive propensity for cardiometabolic disease. This developmental programming may be mediated in part by epigenetic modification of essential regulators of glucose homeostasis. Several pharmacological therapies and nonpharmacological lifestyle modifications have shown early promise in mitigating the risk for or severity of adult metabolic phenotypes but still require further study of unanticipated and/or untoward side effects.
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Affiliation(s)
- Sherin U Devaskar
- Department of Pediatrics, Division of Neonatology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Alison Chu
- Department of Pediatrics, Division of Neonatology, David Geffen School of Medicine at UCLA, Los Angeles, California
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Stanirowski PJ, Szukiewicz D, Pyzlak M, Abdalla N, Sawicki W, Cendrowski K. Impact of pre-gestational and gestational diabetes mellitus on the expression of glucose transporters GLUT-1, GLUT-4 and GLUT-9 in human term placenta. Endocrine 2017; 55:799-808. [PMID: 27981520 PMCID: PMC5316392 DOI: 10.1007/s12020-016-1202-4] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 12/08/2016] [Indexed: 12/21/2022]
Abstract
PURPOSE Various studies in placental tissue suggest that diabetes mellitus alters the expression of glucose transporter (GLUT) proteins, with insulin therapy being a possible modulatory factor. The aim of the present study was quantitative evaluation of the expression of glucose transporters (GLUT-1, GLUT-4, GLUT-9) in the placenta of women in both, uncomplicated and diabetic pregnancy. Additionally, the effect of insulin therapy on the expression of selected glucose transporter isoforms was analyzed. METHODS Term 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 pre-gestational diabetes mellitus (PGDM) (n = 6). Computer-assisted quantitative morphometry of stained placental sections was performed to determine the expression of selected glucose transporter proteins. RESULTS Morphometric analysis revealed a significant increase in the expression of GLUT-4 and GLUT-9 in insulin-dependent diabetic women (GDMG2 + PGDM) as compared to both, control and GDMG1 groups (p < .05). Significantly increased GLUT-1 expression was observed only in placental specimens from patients with PGDM (p < .05). No statistically significant differences in GLUT expression were found between GDMG1 patients and healthy controls. CONCLUSIONS The results of the study confirmed the presence of GLUT-1, GLUT-4 and GLUT-9 proteins in the trophoblast from both, uncomplicated and diabetic pregnancies. In addition, insulin therapy may increase placental expression of GLUT-4 and GLUT-9, and partially GLUT-1, in women with GDMG2/PGDM.
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Affiliation(s)
- Paweł Jan Stanirowski
- Department of Obstetrics, Gynecology and Oncology, II Faculty of Medicine, Medical University of Warsaw, Mazovian Bródno Hospital, Kondratowicza 8, 03-242, Warsaw, Poland.
| | - Dariusz Szukiewicz
- Department of General and Experimental Pathology with Centre for Preclinical Research and Technology (CEPT), II Faculty of Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Michał Pyzlak
- Department of General and Experimental Pathology with Centre for Preclinical Research and Technology (CEPT), II Faculty of Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Nabil Abdalla
- Department of Obstetrics, Gynecology and Oncology, II Faculty of Medicine, Medical University of Warsaw, Mazovian Bródno Hospital, Kondratowicza 8, 03-242, Warsaw, Poland
| | - Włodzimierz Sawicki
- Department of Obstetrics, Gynecology and Oncology, II Faculty of Medicine, Medical University of Warsaw, Mazovian Bródno Hospital, Kondratowicza 8, 03-242, Warsaw, Poland
| | - Krzysztof Cendrowski
- Department of Obstetrics, Gynecology and Oncology, II Faculty of Medicine, Medical University of Warsaw, Mazovian Bródno Hospital, Kondratowicza 8, 03-242, Warsaw, Poland
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Lipopolysaccharide and double stranded viral RNA mediate insulin resistance and increase system a amino acid transport in human trophoblast cells in vitro. Placenta 2017; 51:18-27. [PMID: 28292465 DOI: 10.1016/j.placenta.2017.01.124] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 01/03/2017] [Accepted: 01/19/2017] [Indexed: 01/05/2023]
Abstract
INTRODUCTION Inflammation and underlying low-grade maternal infection can impair insulin signalling and upregulate nutrient transport in the placenta which contribute to fetal overgrowth associated with GDM and/or obese pregnancies. There are, however, no studies on the role of infection on placental nutrient transport in pregnancies complicated by GDM and/or obesity. Thus, the aims of this study were to determine the effect of the bacterial product lipopolysaccharide (LPS) or the viral dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) on the insulin signalling pathway and amino acid transport in primary human trophoblast cells. METHODS Human primary villous trophoblast cells were treated with LPS or poly(I:C). Protein expression of insulin signalling pathway proteins, insulin receptor (IR)-β, insulin receptor substrate (IRS)-1 and protein kinase B (also known as Akt), and phosphatidylinositol-4,5-bisphosphate 3-kinase p85α subunit (PI3K-p85α) protein were assessed by Western blotting. Glucose and amino acid uptake were assessed by radiolabelled assay. Western blotting and qRT-PCR were used to determine amino acid transporter protein and mRNA expression, respectively. RESULTS LPS and poly(I:C) significantly decreased phosphorylation of IR-β, IRS-1, Akt, total PI3K-p85α protein expression and glucose uptake. LPS and poly(I:C) also significantly increased expression of System A amino acid transporters SNAT1 and SNAT2, and System A-mediated uptake of amino acids. DISCUSSION LPS and poly(I:C) induces insulin resistance and increases amino acid uptake in human primary trophoblast cells. This suggests that the presence of low-grade maternal infection can contribute to excess placental nutrient availability and promote fetal overgrowth in pregnancies complicated by GDM and/or obesity.
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Castillo-Castrejon M, Powell TL. Placental Nutrient Transport in Gestational Diabetic Pregnancies. Front Endocrinol (Lausanne) 2017; 8:306. [PMID: 29163373 PMCID: PMC5682011 DOI: 10.3389/fendo.2017.00306] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 10/20/2017] [Indexed: 12/20/2022] Open
Abstract
Maternal obesity during pregnancy is rising and is associated with increased risk of developing gestational diabetes mellitus (GDM), defined as glucose intolerance first diagnosed in pregnancy (1). Fetal growth is determined by the maternal nutrient supply and placental nutrient transfer capacity. GDM-complicated pregnancies are more likely to be complicated by fetal overgrowth or excess adipose deposition in utero. Infants born from GDM mothers have an increased risk of developing cardiovascular and metabolic disorders later in life. Diverse factors, such as ethnicity, age, fetal sex, clinical treatment for glycemic control, gestational weight gain, and body mass index among others, represent a challenge for studying underlying mechanisms in GDM subjects. Determining the individual roles of glucose intolerance, obesity, and other factors on placental function and fetal growth remains a challenge. This review provides an overview of changes in placental macronutrient transport observed in human pregnancies complicated by GDM. Improved knowledge and understanding of the alterations in placenta function that lead to pathological fetal growth will allow for development of new therapeutic interventions and treatments to improve pregnancy outcomes and lifelong health for the mother and her children.
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Affiliation(s)
- Marisol Castillo-Castrejon
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Theresa L. Powell
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of Pediatrics, Section of Neonatology, University of Colorado, Aurora, CO, United States
- *Correspondence: Theresa L. Powell,
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Selesniemi K, Albers RE, Brown TL. Id2 Mediates Differentiation of Labyrinthine Placental Progenitor Cell Line, SM10. Stem Cells Dev 2016; 25:959-74. [PMID: 27168216 PMCID: PMC4931356 DOI: 10.1089/scd.2016.0010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 04/17/2016] [Indexed: 11/12/2022] Open
Abstract
The placenta is an organ that is formed transiently during pregnancy, and appropriate placental development is necessary for fetal survival and growth. Proper differentiation of the labyrinthine layer of the placenta is especially crucial, as it establishes the fetal-maternal interface that is involved in physiological exchange processes. Although previous studies have indicated the importance of inhibitor of differentiation/inhibitor of DNA binding-2 (Id2) helix-loop-helix transcriptional regulator in mediating cell differentiation, the ability of Id2 to regulate differentiation toward the labyrinthine (transport) lineage of the placenta has yet to be determined. In the current study, we have generated labyrinthine trophoblast progenitor cells with increased (SM10-Id2) or decreased (SM10-Id2-shRNA) Id2 expression and determined the effect on TGF-β-induced differentiation. Our Id2 overexpression and knockdown analyses indicate that Id2 mediates TGF-β-induced morphological differentiation of labyrinthine trophoblast cells, as Id2 overexpression prevents differentiation and Id2 knockdown results in differentiation. Thus, our data indicate that Id2 is an important molecular mediator of labyrinthine trophoblast differentiation. An understanding of the regulators of trophoblast progenitor differentiation toward the labyrinthine lineage may offer insights into events governing pregnancy-associated disorders, such as placental insufficiency, fetal growth restriction, and preeclampsia.
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Affiliation(s)
- Kaisa Selesniemi
- Department of Neuroscience, Cell Biology, and Physiology, Wright State University Boonshoft School of Medicine , Dayton, Ohio
| | - Renee E Albers
- Department of Neuroscience, Cell Biology, and Physiology, Wright State University Boonshoft School of Medicine , Dayton, Ohio
| | - Thomas L Brown
- Department of Neuroscience, Cell Biology, and Physiology, Wright State University Boonshoft School of Medicine , Dayton, Ohio
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Huang X, Lüthi M, Ontsouka EC, Kallol S, Baumann MU, Surbek DV, Albrecht C. Establishment of a confluent monolayer model with human primary trophoblast cells: novel insights into placental glucose transport. Mol Hum Reprod 2016; 22:442-56. [PMID: 26931579 DOI: 10.1093/molehr/gaw018] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Accepted: 02/24/2016] [Indexed: 11/14/2022] Open
Abstract
STUDY HYPOTHESIS Using optimized conditions, primary trophoblast cells isolated from human term placenta can develop a confluent monolayer in vitro, which morphologically and functionally resembles the microvilli structure found in vivo. STUDY FINDING We report the successful establishment of a confluent human primary trophoblast monolayer using pre-coated polycarbonate inserts, where the integrity and functionality was validated by cell morphology, biophysical features, cellular marker expression and secretion, and asymmetric glucose transport. WHAT IS KNOWN ALREADY Human trophoblast cells form the initial barrier between maternal and fetal blood to regulate materno-fetal exchange processes. Although the method for isolating pure human cytotrophoblast cells was developed almost 30 years ago, a functional in vitro model with primary trophoblasts forming a confluent monolayer is still lacking. STUDY DESIGN, SAMPLES/MATERIALS, METHODS Human term cytotrophoblasts were isolated by enzymatic digestion and density gradient separation. The purity of the primary cells was evaluated by flow cytometry using the trophoblast-specific marker cytokeratin 7, and vimentin as an indicator for potentially contaminating cells. We screened different coating matrices for high cell viability to optimize the growth conditions for primary trophoblasts on polycarbonate inserts. During culture, cell confluency and polarity were monitored daily by determining transepithelial electrical resistance (TEER) and permeability properties of florescent dyes. The time course of syncytia-related gene expression and hCG secretion during syncytialization were assessed by quantitative RT-PCR and enzyme-linked immunosorbent assay, respectively. The morphology of cultured trophoblasts after 5 days was determined by light microscopy, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Membrane makers were visualized using confocal microscopy. Additionally, glucose transport studies were performed on the polarized trophoblasts in the same system. MAIN RESULTS AND THE ROLE OF CHANCE During 5-day culture, the highly pure trophoblasts were cultured on inserts coated with reconstituted basement membrane matrix . They exhibited a confluent polarized monolayer, with a modest TEER and a size-dependent apparent permeability coefficient (Papp) to fluorescently labeled compounds (MW ∼400-70 000 Da). The syncytialization progress was characterized by gradually increasing mRNA levels of fusogen genes and elevating hCG secretion. SEM analyses confirmed a confluent trophoblast layer with numerous microvilli, and TEM revealed a monolayer with tight junctions. Immunocytochemistry on the confluent trophoblasts showed positivity for the cell-cell adhesion molecule E-cadherin, the tight junction protein 1 (ZO-1) and the membrane proteins ATP-binding cassette transporter A1 (ABCA1) and glucose transporter 1 (GLUT1). Applying this model to study the bidirectional transport of a non-metabolizable glucose derivative indicated a carrier-mediated placental glucose transport mechanism with asymmetric kinetics. LIMITATIONS, REASONS FOR CAUTION The current study is only focused on primary trophoblast cells isolated from healthy placentas delivered at term. It remains to be evaluated whether this system can be extended to pathological trophoblasts isolated from diverse gestational diseases. WIDER IMPLICATIONS OF THE FINDINGS These findings confirmed the physiological properties of the newly developed human trophoblast barrier, which can be applied to study the exchange of endobiotics and xenobiotics between the maternal and fetal compartment, as well as intracellular metabolism, paracellular contributions and regulatory mechanisms influencing the vectorial transport of molecules. LARGE-SCALE DATA Not applicable. STUDY FUNDING AND COMPETING INTERESTS This study was supported by the Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Switzerland, and the Swiss National Science Foundation (grant no. 310030_149958, C.A.). All authors declare that their participation in the study did not involve factual or potential conflicts of interests.
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Affiliation(s)
- Xiao Huang
- Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Bern, Buehlstrasse 28, CH-3012 Bern, Switzerland
| | - Michael Lüthi
- Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Bern, Buehlstrasse 28, CH-3012 Bern, Switzerland
| | - Edgar C Ontsouka
- Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Bern, Buehlstrasse 28, CH-3012 Bern, Switzerland
| | - Sampada Kallol
- Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Bern, Buehlstrasse 28, CH-3012 Bern, Switzerland
| | - Marc U Baumann
- Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland
| | - Daniel V Surbek
- Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland Department of Obstetrics and Gynecology, University Hospital, University of Bern, Bern, Switzerland
| | - Christiane Albrecht
- Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Bern, Switzerland Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Bern, Buehlstrasse 28, CH-3012 Bern, Switzerland
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Protein expression of fatty acid transporter 2 is polarized to the trophoblast basal plasma membrane and increased in placentas from overweight/obese women. Placenta 2016; 40:60-6. [PMID: 27016784 DOI: 10.1016/j.placenta.2016.02.010] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 02/12/2016] [Accepted: 02/18/2016] [Indexed: 11/20/2022]
Abstract
BACKGROUND Obese and overweight women are more likely to deliver a large infant or an infant with increased adiposity, however the underlying mechanisms are not well established. We tested the hypothesis that placental capacity to transport fatty acid is increased in overweight/obese women. METHODS Pregnant women with body mass index (BMI) ranging from 18.4 to 54.3 kg/m(2) and with uncomplicated term pregnancies were recruited for collection of blood samples and placental tissue. Maternal and fetal levels of non-esterified fatty acids (NEFAs) were measured in plasma. The expression and localization of CD36/fatty acid translocase (FAT), fatty acid transport protein (FATP)2, and FATP4 was determined in fixed placental tissue and in isolated syncytiotrophoblast plasma membranes from normal and high BMI mothers. RESULTS Maternal and fetal plasma NEFA levels did not correlate (n = 42). FATP2 and FATP4 expressions were higher in the basal plasma membrane (BPM) compared to the microvillous membrane (P < 0.001; n = 7) per unit membrane protein. BPM expression of FATP2 correlated with maternal BMI (P < 0.01; n = 30); there was no association between CD36/FAT or FATP4 expression and maternal BMI. CONCLUSION The polarization of FATPs to the BPM will facilitate fatty acid transfer across the placenta. In overweight/obese pregnancies, the increased FATP2 expression could contribute to increased fatty acid delivery to the fetus and while we have no direct data we speculate that this could lead accelerated fetal growth or increased fat deposition.
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Bloise E, Ortiga-Carvalho TM, Reis FM, Lye SJ, Gibb W, Matthews SG. ATP-binding cassette transporters in reproduction: a new frontier. Hum Reprod Update 2015; 22:164-81. [PMID: 26545808 DOI: 10.1093/humupd/dmv049] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 10/19/2015] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The transmembrane ATP-binding cassette (ABC) transporters actively efflux an array of clinically relevant compounds across biological barriers, and modulate biodistribution of many physiological and pharmacological factors. To date, over 48 ABC transporters have been identified and shown to be directly and indirectly involved in peri-implantation events and fetal/placental development. They efflux cholesterol, steroid hormones, vitamins, cytokines, chemokines, prostaglandins, diverse xenobiotics and environmental toxins, playing a critical role in regulating drug disposition, immunological responses and lipid trafficking, as well as preventing fetal accumulation of drugs and environmental toxins. METHODS This review examines ABC transporters as important mediators of placental barrier functions and key reproductive processes. Expression, localization and function of all identified ABC transporters were systematically reviewed using PubMed and Google Scholar websites to identify relevant studies examining ABC transporters in reproductive tissues in physiological and pathophysiological states. Only reports written in English were incorporated with no restriction on year of publication. While a major focus has been placed on the human, extensive evidence from animal studies is utilized to describe current understanding of the regulation and function of ABC transporters relevant to human reproduction. RESULTS ABC transporters are modulators of steroidogenesis, fertilization, implantation, nutrient transport and immunological responses, and function as 'gatekeepers' at various barrier sites (i.e. blood-testes barrier and placenta) against potentially harmful xenobiotic factors, including drugs and environmental toxins. These roles appear to be species dependent and change as a function of gestation and development. The best-described ABC transporters in reproductive tissues (primarily in the placenta) are the multidrug transporters p-glycoprotein and breast cancer-related protein, the multidrug resistance proteins 1 through 5 and the cholesterol transporters ABCA1 and ABCG1. CONCLUSIONS The ABC transporters have various roles across multiple reproductive tissues. Knowledge of efflux direction, tissue distribution, substrate specificity and regulation of the ABC transporters in the placenta and other reproductive tissues is rapidly expanding. This will allow better understanding of the disposition of specific substrates within reproductive tissues, and facilitate development of novel treatments for reproductive disorders as well as improved approaches to protecting the developing fetus.
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Affiliation(s)
- E Bloise
- Laboratory of Translational Endocrinology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - T M Ortiga-Carvalho
- Laboratory of Translational Endocrinology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - F M Reis
- Division of Human Reproduction, Department of Obstetrics and Gynecology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - S J Lye
- Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, Canada M5S 1A8 Department Obstetrics & Gynecology, University of Toronto, Toronto, ON, Canada Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - W Gibb
- Department of Obstetrics & Gynecology, University of Ottawa, Ottawa, ON, Canada Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - S G Matthews
- Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, Canada M5S 1A8 Department Obstetrics & Gynecology, University of Toronto, Toronto, ON, Canada Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
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Brett KE, Ferraro ZM, Holcik M, Adamo KB. Placenta nutrient transport-related gene expression: the impact of maternal obesity and excessive gestational weight gain. J Matern Fetal Neonatal Med 2015; 29:1399-405. [DOI: 10.3109/14767058.2015.1049522] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Gaccioli F, Aye ILMH, Roos S, Lager S, Ramirez VI, Kanai Y, Powell TL, Jansson T. Expression and functional characterisation of System L amino acid transporters in the human term placenta. Reprod Biol Endocrinol 2015; 13:57. [PMID: 26050671 PMCID: PMC4462079 DOI: 10.1186/s12958-015-0054-8] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Accepted: 05/28/2015] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND System L transporters LAT1 (SLC7A5) and LAT2 (SLC7A8) mediate the uptake of large, neutral amino acids in the human placenta. Many System L substrates are essential amino acids, thus representing crucial nutrients for the growing fetus. Both LAT isoforms are expressed in the human placenta, but the relative contribution of LAT1 and LAT2 to placental System L transport and their subcellular localisation are not well established. Moreover, the influence of maternal body mass index (BMI) on placental System L amino acid transport is poorly understood. Therefore the aims of this study were to determine: i) the relative contribution of the LAT isoforms to System L transport activity in primary human trophoblast (PHT) cells isolated from term placenta; ii) the subcellular localisation of LAT transporters in human placenta; and iii) placental expression and activity of System L transporters in response to maternal overweight/obesity. METHODS System L mediated leucine uptake was measured in PHT cells after treatment with si-RNA targeting LAT1 and/or LAT2. The localisation of LAT isoforms was studied in isolated microvillous plasma membranes (MVM) and basal membranes (BM) by Western blot analysis. Results were confirmed by immunohistochemistry in sections of human term placenta. Expression and activity System L transporters was measured in isolated MVM from women with varying pre-pregnancy BMI. RESULTS Both LAT1 and LAT2 isoforms contribute to System L transport activity in primary trophoblast cells from human term placenta. LAT1 and LAT2 transporters are highly expressed in the MVM of the syncytiotrophoblast layer at term. LAT2 is also localised in the basal membrane and in endothelial cells lining the fetal capillaries. Measurements in isolated MVM vesicles indicate that System L transporter expression and activity is not influenced by maternal BMI. CONCLUSIONS LAT1 and LAT2 are present and functional in the syncytiotrophoblast MVM, whereas LAT2 is also expressed in the BM and in the fetal capillary endothelium. In contrast to placental System A and beta amino acid transporters, MVM System L activity is unaffected by maternal overweight/obesity.
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Affiliation(s)
- Francesca Gaccioli
- Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK.
| | - Irving L M H Aye
- Division of Basic Reproductive Sciences, Department of Obstetrics and Gynaecology, University of Colorado Denver Anschutz Medical Campus, Aurora, Denver, CO, USA.
| | - Sara Roos
- Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
| | - Susanne Lager
- Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK.
| | - Vanessa I Ramirez
- Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX, USA.
| | - Yoshikatsu Kanai
- Division of Bio-System Pharmacology, Department of Pharmacology, Osaka University Graduate School of Medicine, Osaka, Japan.
| | - Theresa L Powell
- Section of Neonatology, Department of Pediatrics, University of Colorado Denver Anschutz Medical Campus, Aurora, Denver, CO, USA.
| | - Thomas Jansson
- Division of Basic Reproductive Sciences, Department of Obstetrics and Gynaecology, University of Colorado Denver Anschutz Medical Campus, Aurora, Denver, CO, USA.
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Melnik BC, John SM, Schmitz G. Milk consumption during pregnancy increases birth weight, a risk factor for the development of diseases of civilization. J Transl Med 2015; 13:13. [PMID: 25592553 PMCID: PMC4302093 DOI: 10.1186/s12967-014-0377-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 12/29/2014] [Indexed: 02/06/2023] Open
Abstract
Antenatal dietary lifestyle intervention and nutrition during pregnancy and early postnatal life are important for appropriate lifelong metabolic programming. Epidemiological evidence underlines the crucial role of increased birth weight as a risk factor for the development of chronic diseases of civilization such as obesity, diabetes and cancer. Obstetricians and general practitioners usually recommend milk consumption during pregnancy as a nutrient enriched in valuable proteins and calcium for bone growth. However, milk is not just a simple nutrient, but has been recognized to function as an endocrine signaling system promoting anabolism and postnatal growth by activating the nutrient-sensitive kinase mTORC1. Moreover, pasteurized cow’s milk transfers biologically active exosomal microRNAs into the systemic circulation of the milk consumer apparently affecting more than 11 000 human genes including the mTORC1-signaling pathway. This review provides literature evidence and evidence derived from translational research that milk consumption during pregnancy increases gestational, placental, fetal and birth weight. Increased birth weight is a risk factor for the development of diseases of civilization thus involving key disciplines of medicine. With regard to the presented evidence we suggest that dietary recommendations promoting milk consumption during pregnancy have to be re-evaluated.
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Affiliation(s)
- Bodo C Melnik
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Sedanstrasse 115, D-49090, Osnabrück, Germany.
| | - Swen Malte John
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Sedanstrasse 115, D-49090, Osnabrück, Germany.
| | - Gerd Schmitz
- Institute of Clinical Chemistry and Laboratory Medicine, University Clinics of Regensburg, Regensburg, Germany.
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