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1
Shearman, Lauren P., Alison M. McReynolds, Feng C. Zhou, and Jerrold S. Meyer. "Relationship between [125I]RTI-55-labeled cocaine binding sites and the serotonin transporter in rat placenta." American Journal of Physiology-Cell Physiology 275, no. 6 (December 1, 1998): C1621—C1629. http://dx.doi.org/10.1152/ajpcell.1998.275.6.c1621.
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We investigated the characteristics of cocainelike binding sites in rat placenta using [125I]RTI-55. [3H]paroxetine binding and immunocytochemical staining for serotonin [5-hydroxytryptamine (5-HT)] and for the 5-HT transporter were also used to obtain evidence for rat placental 5-HT uptake. [125I]RTI-55 saturation analyses with membranes from normal gestational day 20 placentas yielded curvilinear Scatchard plots that were resolved into high- and low-affinity components (mean dissociation constants of 0.29 and 7.9 nM, respectively). Drug competition studies with various monoamine uptake inhibitors gave rise to complex multiphasic displacement curves, although the results obtained with the selective 5-HT uptake inhibitor citalopram suggest that the 5-HT transporter is an important component of placental high-affinity [125I]RTI-55 binding. The presence of a rat placental 5-HT uptake system was additionally supported by the [3H]paroxetine binding experiments and by the presence throughout the placenta of immunoreactivity for 5-HT and the 5-HT transporter. Immunostaining with both antibodies was most intense in the junctional zone, whereas the density of [125I]RTI-55 binding sites was greater in the placental labyrinth. This discrepancy may be due to the fact that [125I]RTI-55 appears to be labeling additional cellular components besides the 5-HT transporter. The presence of cocaine- and antidepressant-sensitive 5-HT transporters in the placenta has important implications for the possible effects of these compounds on pregnancy and fetal development.
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Granitzer, Sebastian, Isabella Ellinger, Rumsha Khan, Katharina Gelles, Raimund Widhalm, Markus Hengstschläger, Harald Zeisler, et al. "In vitro function and in situ localization of Multidrug Resistance-associated Protein (MRP)1 (ABCC1) suggest a protective role against methyl mercury-induced oxidative stress in the human placenta." Archives of Toxicology 94, no. 11 (September 11, 2020): 3799–817. http://dx.doi.org/10.1007/s00204-020-02900-5.
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Abstract Methyl mercury (MeHg) is an organic highly toxic compound that is transported efficiently via the human placenta. Our previous data suggest that MeHg is taken up into placental cells by amino acid transporters while mercury export from placental cells mainly involves ATP binding cassette (ABC) transporters. We hypothesized that the ABC transporter multidrug resistance-associated protein (MRP)1 (ABCC1) plays an essential role in mercury export from the human placenta. Transwell transport studies with MRP1-overexpressing Madin-Darby Canine Kidney (MDCK)II cells confirmed the function of MRP1 in polarized mercury efflux. Consistent with this, siRNA-mediated MRP1 gene knockdown in the human placental cell line HTR-8/SVneo resulted in intracellular mercury accumulation, which was associated with reduced cell viability, accompanied by increased cytotoxicity, apoptosis, and oxidative stress as determined via the glutathione (GSH) status. In addition, the many sources claiming different localization of MRP1 in the placenta required a re-evaluation of its localization in placental tissue sections by immunofluorescence microscopy using an MRP1-specific antibody that was validated in-house. Taken together, our results show that (1) MRP1 preferentially mediates apical-to-basolateral mercury transport in epithelial cells, (2) MRP1 regulates the GSH status of placental cells, (3) MRP1 function has a decisive influence on the viability of placental cells exposed to low MeHg concentrations, and (4) the in situ localization of MRP1 corresponds to mercury transport from maternal circulation to the placenta and fetus. We conclude that MRP1 protects placental cells from MeHg-induced oxidative stress by exporting the toxic metal and by maintaining the placental cells' GSH status in equilibrium.
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do Imperio, Guinever Eustaquio, Enrrico Bloise, Mohsen Javam, Phetcharawan Lye, Andrea Constantinof, Caroline Dunk, Fernando Marcos dos Reis, et al. "Chorioamnionitis Induces a Specific Signature of Placental ABC Transporters Associated with an Increase of miR-331-5p in the Human Preterm Placenta." Cellular Physiology and Biochemistry 45, no. 2 (2018): 591–604. http://dx.doi.org/10.1159/000487100.
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Background/Aims: The ATP-binding cassette (ABC) transporters mediate drug biodisposition and immunological responses in the placental barrier. In vitro infective challenges alter expression of specific placental ABC transporters. We hypothesized that chorioamnionitis induces a distinct pattern of ABC transporter expression. Methods: Gene expression of 50 ABC transporters was assessed using TaqMan® Human ABC Transporter Array, in preterm human placentas without (PTD; n=6) or with histological chorioamnionitis (PTDC; n=6). Validation was performed using qPCR, immunohistochemistry and Western blot. MicroRNAs known to regulate P-glycoprotein (P-gp) were examined by qPCR. Results: Up-regulation of ABCB9, ABCC2 and ABCF2 mRNA was detected in chorioamnionitis (p<0.05), whereas placental ABCB1 (P-gp; p=0.051) and ABCG2 (breast cancer resistance protein-BCRP) mRNA levels (p=0.055) approached near significant up-regulation. In most cases, the magnitude of the effect significantly correlated to the severity of inflammation. Upon validation, increased placental ABCB1 and ABCG2 mRNA levels (p<0.05) were observed. At the level of immunohistochemistry, while BCRP was increased (p<0.05), P-gp staining intensity was significantly decreased (p<0.05) in PTDC. miR-331-5p, involved in P-gp suppression, was upregulated in PTDC (p<0.01) and correlated to the grade of chorioamnionitis (p<0.01). Conclusions: Alterations in the expression of ABC transporters will likely lead to modified transport of clinically relevant compounds at the inflamed placenta. A better understanding of the potential role of these transporters in the events surrounding PTD may also enable new strategies to be developed for prevention and treatment of PTD.
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Xu, Jie, Jiao Wang, Yang Cao, Xiaotong Jia, Yujia Huang, Minghui Cai, Chunmei Lu, and Hui Zhu. "Downregulation of Placental Amino Acid Transporter Expression and mTORC1 Signaling Activity Contributes to Fetal Growth Retardation in Diabetic Rats." International Journal of Molecular Sciences 21, no. 5 (March 7, 2020): 1849. http://dx.doi.org/10.3390/ijms21051849.
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Alterations in placental transport may contribute to abnormal fetal intrauterine growth in pregnancies complicated by diabetes, but it is not clear whether the placental amino acid transport system is altered in diabetic pregnancies. We therefore studied the changes in the expressions of placental amino acid transporters in a rat model of diabetes induced by streptozotocin, and tested the effects of hyperglycemia on trophoblast amino acid transporter in vitro. Our results showed that the expressions for key isoforms of system L amino acid transporters were significantly reduced in the placentas of streptozotocin-induced diabetic pregnant rats, which was associated with the decreased birthweight in the rats. A decreased placental efficiency and decreased placental mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activity were also found in the rat model. In addition, hyperglycemia in vitro could inhibit amino acid transporter expression and mTORC1 activity in human trophoblast. Inhibition of mTORC1 activity led to reduced amino acid transporter expression in placental trophoblast. We concluded that reduced placental mTORC1 activity during pregnancy resulted in decreased placental amino acid transporter expression and, subsequently, contributed to fetal intrauterine growth restriction in pregnancies complicated with diabetes.
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Roos, S., Y. Kanai, P. D. Prasad, T. L. Powell, and T. Jansson. "Regulation of placental amino acid transporter activity by mammalian target of rapamycin." American Journal of Physiology-Cell Physiology 296, no. 1 (January 2009): C142—C150. http://dx.doi.org/10.1152/ajpcell.00330.2008.
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The activity of placental amino acid transporters is decreased in intrauterine growth restriction (IUGR), but the underlying regulatory mechanisms have not been established. Inhibition of the mammalian target of rapamycin (mTOR) signaling pathway has been shown to decrease the activity of the system L amino acid transporter in human placental villous fragments, and placental mTOR activity is decreased in IUGR. In the present study, we used cultured primary trophoblast cells to study mTOR regulation of placental amino acid transporters in more detail and to test the hypothesis that mTOR alters amino acid transport activity by changes in transporter expression. Inhibition of mTOR by rapamycin significantly reduced the activity of system A (−17%), system L (−28%), and taurine (−40%) amino acid transporters. mRNA expression of isoforms of the three amino acid transporter systems in response to mTOR inhibition was measured using quantitative real-time PCR. mRNA expression of l-type amino acid transporter 1 (LAT1; a system L isoform) and taurine transporter was reduced by 13% and 50%, respectively; however, mTOR inhibition did not alter the mRNA expression of system A isoforms (sodium-coupled neutral amino acid transporter-1, -2, and -4), LAT2, or 4F2hc. Rapamycin treatment did not significantly affect the protein expression of any of the transporter isoforms. We conclude that mTOR signaling regulates the activity of key placental amino acid transporters and that this effect is not due to a decrease in total protein expression. These data suggest that mTOR regulates placental amino acid transporters by posttranslational modifications or by affecting transporter translocation to the plasma membrane.
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Cleal, J. K., P. E. Day, C. L. Simner, S. J. Barton, P. A. Mahon, H. M. Inskip, K. M. Godfrey, et al. "Placental amino acid transport may be regulated by maternal vitamin D and vitamin D-binding protein: results from the Southampton Women's Survey." British Journal of Nutrition 113, no. 12 (May 5, 2015): 1903–10. http://dx.doi.org/10.1017/s0007114515001178.
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Both maternal 25-hydroxyvitamin D (25(OH)D) concentrations during pregnancy and placental amino acid transporter gene expression have been associated with development of the offspring in terms of body composition and bone structure. Several amino acid transporter genes have vitamin D response elements in their promoters suggesting the possible linkage of these two mechanisms. We aimed to establish whether maternal 25(OH)D and vitamin D-binding protein (VDBP) levels relate to expression of placental amino acid transporters. RNA was extracted from 102 placental samples collected in the Southampton Women's Survey, and gene expression was analysed using quantitative real-time PCR. Gene expression data were normalised to the geometric mean of three housekeeping genes, and related to maternal factors and childhood body composition. Maternal serum 25(OH)D and VDBP levels were measured by radioimmunoassay. Maternal 25(OH)D and VDBP levels were positively associated with placental expression of specific genes involved in amino acid transport. Maternal 25(OH)D and VDBP concentrations were correlated with the expression of specific placental amino acid transporters, and thus may be involved in the regulation of amino acid transfer to the fetus. The positive correlation of VDBP levels and placental transporter expression suggests that delivery of vitamin D to the placenta may be important. This exploratory study identifies placental amino acid transporters which may be altered in response to modifiable maternal factors and provides a basis for further studies.
7
Ericsson, Anette, Bengt Hamark, Nina Jansson, Bengt R. Johansson, Theresa L. Powell, and Thomas Jansson. "Hormonal regulation of glucose and system A amino acid transport in first trimester placental villous fragments." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 288, no. 3 (March 2005): R656—R662. http://dx.doi.org/10.1152/ajpregu.00407.2004.
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Alterations in placental nutrient transfer have been implicated in fetal growth abnormalities. In pregnancies complicated by diabetes and accelerated fetal growth, upregulations of glucose transporter 1 (GLUT1) and amino acid transporter system A have been shown in the syncytiotrophoblast of term placenta. In contrast, intrauterine growth restriction is associated with a downregulation of placental system A transporters. However, underlying mechanisms of transporter regulation are poorly understood, particularly in early pregnancy. In this study, hormonal regulation of placental glucose and system A transporters was investigated. The uptake of 3-O-[methyl-14C]-d-glucose was studied in villous fragments isolated from first trimester (6–13 wk of gestation) and term human placenta. Villous fragments were incubated in buffer containing insulin, leptin, cortisol, growth hormone (GH), prolactin, IGF-I, or under hypo/hyperglycemic conditions for 1 h. Subsequently, 3-O-[methyl-14C]-d-glucose uptake was measured with and without phloretin for 70 s in first trimester tissue and 20 s in term tissue. Methylaminoisobutyric uptake was measured with and without Na+ for 20 min. Glucose uptake was unaltered by hormones or hypo/hyperglycemia. GH decreased system A activity by 31% in first trimester ( P < 0.05). The uptake of glucose was 50% higher in term compared with first trimester fragments and increased markedly between 6 and 13 wk of gestation ( P < 0.05). We conclude that placental glucose transporter activity is not regulated by short exposures to the hormones or glucose concentrations tested. In contrast to term placental villous fragments, system A activity was not regulated by insulin or leptin in first trimester but was downregulated by GH.
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Audette, Melanie C., John R. G. Challis, Rebecca L. Jones, Colin P. Sibley, and Stephen G. Matthews. "Synthetic Glucocorticoid Reduces Human Placental System A Transport in Women Treated With Antenatal Therapy." Journal of Clinical Endocrinology & Metabolism 99, no. 11 (November 1, 2014): E2226—E2233. http://dx.doi.org/10.1210/jc.2014-2157.
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Context: Synthetic glucocorticoids (sGCs) are routinely given to women with threatened preterm labor and have been linked to fetal growth restriction and developmental programming. Reductions in fetal growth are likely to be mediated by placental dysfunction, including altered nutrient transport. sGCs modify the system A neutral amino acid transporter in vitro, but there are no in vivo comparable data in human placenta. Objective: Because ∼30% of women who receive sGCs carry to term, our objective was to examine the short- and longer-term consequences of antenatal sGCs on placental system A transport. Methods and Patients: Placental tissue was collected from women treated with sGCs between 24 hours and 14 days before delivery (24h-14d), 14 days after treatment but before term (14d-term), or at term, compared with healthy term (control) deliveries to measure system A-mediated activity (Na+-dependent [14C]methylaminoisobutyric acid uptake per gram placenta) and mRNA expression. Results: After sGC treatment, system A activity was significantly reduced at term compared with both sGC placentas delivered 24h-14d and compared with controls. Placentae from women treated with sGCs who delivered between 14d-term also had significantly reduced system A activity compared with 24h-14d placentas. SLC38A1 and SLC38A2 mRNA expression was unaffected. However, SLC38A4 was significantly reduced by sGCs at term compared with placentas delivered between 14d-term. Conclusion: We conclude that women who are at risk of preterm labor and receive sGCs but deliver at term have significantly reduced placental system A amino acid transporter activity. Altered placental transporter function could affect fetal growth and may contribute to developmental programming reported in both animal and clinical studies.
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Han, Lyrialle W., Chunying Gao, Yuchen Zhang, Joanne Wang, and Qingcheng Mao. "Transport of Bupropion and its Metabolites by the Model CHO and HEK293 Cell Lines." Drug Metabolism Letters 13, no. 1 (April 30, 2019): 25–36. http://dx.doi.org/10.2174/1872312813666181129101507.
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<P>Background: Bupropion (BUP) is widely used as an antidepressant and smoking cessation aid. There are three major pharmacologically active metabolites of BUP, Erythrohydrobupropion (EB), Hydroxybupropion (OHB) and Threohydrobupropion (TB). At present, the mechanisms underlying the overall disposition and systemic clearance of BUP and its metabolites have not been well understood, and the role of transporters has not been studied. </P><P> Objective: The goal of this study was to investigate whether BUP and its active metabolites are substrates of the major hepatic uptake and efflux transporters. </P><P> Method: CHO or HEK293 cell lines or plasma membrane vesicles that overexpress OATP1B1, OATP1B3, OATP2B1, OATP4A1, OCT1, BCRP, MRP2 or P-gp were used in cellular or vesicle uptake and inhibition assays. Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) was used to quantify transport activity. </P><P> Results: BUP and its major active metabolites were actively transported into the CHO or HEK293 cells overexpressing OATP1B1, OATP1B3 or OATP2B1; however, such cellular active uptake could not be inhibited at all by prototypical inhibitors of any of the OATP transporters. These compounds were not transported by OCT1, BCRP, MRP2 or P-gp either. These results suggest that the major known hepatic transporters likely play a minor role in the overall disposition and systemic clearance of BUP and its active metabolites in humans. We also demonstrated that BUP and its metabolites were not transported by OATP4A1, an uptake transporter on the apical membrane of placental syncytiotrophoblasts, suggesting that OATP4A1 is not responsible for the transfer of BUP and its metabolites from the maternal blood to the fetal compartment across the placental barrier in pregnant women. Conclusion: BUP and metabolites are not substrates of the major hepatic transporters tested and thus these hepatic transporters likely do not play a role in the overall disposition of the drug. Our results also suggest that caution should be taken when using the model CHO and HEK293 cell lines to evaluate potential roles of transporters in drug disposition.</P>
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Vinot, C., L. Gavard, J. M. Tréluyer, S. Manceau, E. Courbon, J. M. Scherrmann, X. Declèves, et al. "Placental Transfer of Maraviroc in anEx VivoHuman Cotyledon Perfusion Model and Influence of ABC Transporter Expression." Antimicrobial Agents and Chemotherapy 57, no. 3 (January 7, 2013): 1415–20. http://dx.doi.org/10.1128/aac.01821-12.
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ABSTRACTNowadays, antiretroviral therapy is recommended during pregnancy to prevent mother-to-child transmission of HIV. However, for many antiretroviral drugs, including maraviroc, a CCR5 antagonist, very little data exist regarding placental transfer. Besides, various factors may modulate this transfer, including efflux transporters belonging to the ATP-binding cassette (ABC) transporter superfamily. We investigated maraviroc placental transfer and the influence of ABC transporter expression on this transfer using the human cotyledon perfusion model. Term placentas were perfusedex vivofor 90 min with maraviroc (600 ng/ml) either in the maternal-to-fetal (n= 10 placentas) or fetal-to-maternal (n= 6 placentas) direction. Plasma concentrations were determined by ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Fetal transfer rates (FTR) and clearance indexes (CLI) were calculated as ratios of fetal to maternal concentrations at steady state (mean values between 30 and 90 min) and ratios of FTR of maraviroc to that of antipyrine, respectively. ABC transporter gene expression levels were determined by quantitative reverse transcription (RT)-PCR and ABCB1 protein expression by Western blotting. For the maternal-to-fetal direction, the mean FTR and CLI were 8.0% ± 3.0 and 0.26 ± 0.07, respectively, whereas the mean CLI was 0.52 ± 0.23 for the fetal-to-maternal direction. We showed a significant inverse correlation between maraviroc CLI andABCC2,ABCC10, andABCC11placental gene expression levels (P< 0.05). To conclude, we report a low maraviroc placental transfer probably involving ABC efflux transporters and thus in all likelihood associated with a limited fetal exposition. Nevertheless, these results would need to be supported byin vivodata obtained from paired maternal and cord blood samples.
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Rosario, Fredrick J., Nina Jansson, Yoshikatsu Kanai, Puttur D. Prasad, Theresa L. Powell, and Thomas Jansson. "Maternal Protein Restriction in the Rat Inhibits Placental Insulin, mTOR, and STAT3 Signaling and Down-Regulates Placental Amino Acid Transporters." Endocrinology 152, no. 3 (March 1, 2011): 1119–29. http://dx.doi.org/10.1210/en.2010-1153.
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The mechanisms underlying reduced fetal growth in response to maternal protein restriction are not well established. Maternal levels of insulin, IGF-I, and leptin are decreased in rats fed a low protein (LP) diet. Because these hormones stimulate placental amino acid transporters in vitro, we hypothesized that maternal protein restriction inhibits placental leptin, insulin/IGF-I, and mammalian target of rapamycin signaling and down-regulates the expression and activity of placental amino acid transporters. Pregnant rats were fed either an isocaloric low protein (LP, 4% protein) or control diet (18% protein) and studied at gestational day (GD)15, GD19, or GD21 (term 23). At GD19 and GD21, placental expression of phosphorylated eukaryotic initiation factor 4E binding protein 1 (Thr-36/46 or Thr-70) and phosphorylated S6 ribosomal protein (Ser-235/236) was decreased in the LP group. In addition, placental expression of phosphorylated S6 kinase 1 (Thr-389), phosphorylated Akt (Thr-308), and phosphorylated signal transducer and activator of transcription 3 (Tyr-705) was reduced at GD21. In microvillous plasma membranes (MVM) isolated from placentas of LP animals, protein expression of the sodium-coupled neutral amino acid transporter (SNAT)2 and the large neutral amino acid transporters 1 and 2 was reduced at GD19 and GD21. MVM SNAT1 protein expression was reduced at GD21 in LP rats. SNAT4 and 4F2 heavy chain expression in MVM was unaltered. System A and L amino acid transporter activity was decreased in MVM from LP animals at GD19 and GD21. In conclusion, maternal protein restriction inhibits placental insulin, mammalian target of rapamycin signaling, and signal transducer and activator of transcription 3 signaling, which is associated with a down-regulation of placental amino acid transporters. We speculate that maternal endocrine and metabolic control of placental nutrient transport reduces fetal growth in response to protein restriction.
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Lynch, Cameron, Asghar Ali, Victoria Kennedy, Amelia R. Tanner, Quinton A. Winger, and Russell V. Anthony. "PSII-34 Placental GLUT3 (SLC2A3) RNA interference: Impact on fetal growth at mid-gestation." Journal of Animal Science 98, Supplement_4 (November 3, 2020): 378. http://dx.doi.org/10.1093/jas/skaa278.665.
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Abstract Glucose is the predominant energy substrate for fetal oxidative processes and growth, and is taken up by the placenta and transported to the fetus by the facilitative transporters GLUT1 (SLC2A1) and GLUT3 (SLC2A3). SLC2A1 is the most abundant placental transporter, and as such is believed to be the primary glucose transporter in human and sheep placenta. However, SLC2A3 exhibits a six-fold greater glucose transport capacity, and in sheep, SLC2A3 is localized to the apical trophoblast membrane, whereas SLC2A1 is predominantly localized to the basolateral membrane, indicating that both may be required for optimal fetal development. It was our objective to use placenta-specific RNA interference (RNAi) to diminish SLC2A3, and determine the impact at mid-gestation (75 dGA) in sheep. Single hatched blastocysts were harvested and the trophectoderm was infected with lentiviral constructs expressing either a scramble control (SC) or SLC2A3-specific (GLUT3-RNAi) short-hairpin RNA, and then surgically transferred into a synchronized recipient. The resulting pregnancies underwent ultrasound Doppler velocimetry and fetal measurements at 70 dGA, and a terminal surgery at 75 dGA for collection of uterine and umbilical arterial and venous blood, fetal and placental measurements and tissue samples. Due to a lack of fetal sex x treatment interactions, statistical comparisons between SC (n = 6) and GLUT3-RNAi (n = 6) pregnancies were made by Student’s T-test. At 70 dGA, while umbilical artery velocimetry was not impacted, biparietal diameter (P ≤ 0.10), femur length and tibia length (P ≤ 0.05) were reduced in GLUT3-RNAi pregnancies. These results were confirmed at 75 dGA surgery, as GLUT3-RNAi fetuses had reduced fetal weight (P ≤ 0.10), head circumference (P ≤ 0.05), femur length (P ≤ 0.05), and tibia length (P ≤ 0.05). While it has been suggested that GLUT3 is predominantly important in late gestation, these preliminary data indicate that GLUT3 is important for normal fetal development during the first-half of gestation as well. Supported by NIH grant HD094952.
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St-Pierre, M. V., T. Stallmach, A. Freimoser Grundschober, J. F. Dufour, M. A. Serrano, J. J. G. Marin, Y. Sugiyama, and P. J. Meier. "Temporal expression profiles of organic anion transport proteins in placenta and fetal liver of the rat." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 287, no. 6 (December 2004): R1505—R1516. http://dx.doi.org/10.1152/ajpregu.00279.2003.
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Physiological cholestasis linked to immature hepatobiliary transport systems for organic anions occurs in rat and human neonates. In utero, the placenta facilitates vectorial transfer of certain fetal-derived solutes to the maternal circulation for elimination. We compared the ontogenesis of organic anion transporters in the placenta and the fetal liver of the rat to assess their relative abundance throughout gestation and to determine whether the placenta compensates for the late maturation of transporters in the developing liver. The mRNA of members of the organic anion transporting polypeptide (Oatp) superfamily, the multidrug resistance protein (Mrp) family, one organic anion transporter (OAT), and the bile acid carriers Na+-taurocholate cotransporting polypeptide (Ntcp) and bile salt export pump (Bsep) was quantified by real-time PCR. The most abundant placental transporters were Oatp4a1, whose mRNA increased 10-fold during gestation, and Mrp1. Mrp1 immunolocalized predominantly to epithelial cells of the endoplacental yolk sac, suggesting an excretory role that sequesters fetal-derived solutes in the yolk sac cavity, and faintly to the basal syncytiotrophoblast surface. The mRNA levels of Oatp2b1, Mrp3, and Bsep in the placenta exceeded those in the fetal liver until day 20 of gestation, suggesting that the fetus relies on placental clearance of substrates when expression in the developing liver is low. Mrp3 immunolocalized to the epithelium of the endoplacental yolk sac and less abundantly in the labyrinth zone and endothelium of the maternal arteries. The placental expression of Oatp1a1, Oatp1a4, Oatp1a5, Oatp1b2, Oat, Ntcp, Mrp2, and Mrp6 was low.
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Horackova, Hana, Rona Karahoda, Lukas Cerveny, Veronika Vachalova, Ronja Ebner, Cilia Abad, and Frantisek Staud. "Effect of Selected Antidepressants on Placental Homeostasis of Serotonin: Maternal and Fetal Perspectives." Pharmaceutics 13, no. 8 (August 20, 2021): 1306. http://dx.doi.org/10.3390/pharmaceutics13081306.
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Depression is a prevalent condition affecting up to 20% of pregnant women. Hence, more than 10% are prescribed antidepressant drugs, mainly serotonin reuptake inhibitors (SSRIs) and selective serotonin and noradrenaline reuptake inhibitors (SNRIs). We hypothesize that antidepressants disturb serotonin homeostasis in the fetoplacental unit by inhibiting serotonin transporter (SERT) and organic cation transporter 3 (OCT3) in the maternal- and fetal-facing placental membranes, respectively. Paroxetine, citalopram, fluoxetine, fluvoxamine, sertraline, and venlafaxine were tested in situ (rat term placenta perfusion) and ex vivo (uptake studies in membrane vesicles isolated from healthy human term placenta). All tested antidepressants significantly inhibited SERT- and OCT3-mediated serotonin uptake in a dose-dependent manner. Calculated half-maximal inhibitory concentrations (IC50) were in the range of therapeutic plasma concentrations. Using in vitro and in situ models, we further showed that the placental efflux transporters did not compromise mother-to-fetus transport of antidepressants. Collectively, we suggest that antidepressants have the potential to affect serotonin levels in the placenta or fetus when administered at therapeutic doses. Interestingly, the effect of antidepressants on serotonin homeostasis in rat placenta was sex dependent. As accurate fetal programming requires optimal serotonin levels in the fetoplacental unit throughout gestation, inhibition of SERT-/OCT3-mediated serotonin uptake may help explain the poor outcomes of antidepressant use in pregnancy.
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Hayward, Christina E., Susan L. Greenwood, Colin P. Sibley, Philip N. Baker, John R. G. Challis, and Rebecca L. Jones. "Effect of maternal age and growth on placental nutrient transport: potential mechanisms for teenagers' predisposition to small-for-gestational-age birth?" American Journal of Physiology-Endocrinology and Metabolism 302, no. 2 (January 15, 2012): E233—E242. http://dx.doi.org/10.1152/ajpendo.00192.2011.
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Teenagers have an increased risk of delivering small-for-gestational-age (SGA) infants. Young maternal age and continued skeletal growth have been implicated as causal factors. In growing adolescent sheep, impaired placental development and nutrient transfer cause reduced birth weight. In human pregnancies, SGA is associated with reduced placental amino acid transport. Maternal growth has no effect on placental morphology or cell turnover, but growing teenagers have higher birth weight:placental weight ratios than nongrowing teenagers. We hypothesized that placental nutrient transporter activity would be affected by maternal age and/or growth status. Placentas from teenagers and adults were collected. Teenagers were defined as growing or nongrowing based on knee height measurements. System A amino acid transporter activity was quantified as sodium-dependent uptake of [14C]methylaminoisobutyric acid into placental fragments. Teenagers had lower placental system A activity than adults ( P < 0.05). In adults, placental system A activity was lower in SGA infants than appropriate-for-gestational-age (AGA) infants ( P < 0.05). In teenagers, AGA and SGA infants had lower placental system A activity than AGA infants born to adults ( P < 0.05). Placental system A activity was higher in growing teenagers than in nongrowing teenagers ( P < 0.001). Placental mRNA expression of system A transporter isoforms SLC38A1 and -2 was lower in teenagers than in adults ( P < 0.05) but did not differ between growing and nongrowing teenagers. There was no difference in transporter protein expression/localization between cohorts. Teenagers have inherently reduced placental transport, which may underlie their susceptibility to delivering SGA infants. Growing teenagers appear to overcome this susceptibility by stimulating the activity, but not expression, of system A transporters.
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Roos, Sara, Theresa L. Powell, and Thomas Jansson. "Placental mTOR links maternal nutrient availability to fetal growth." Biochemical Society Transactions 37, no. 1 (January 20, 2009): 295–98. http://dx.doi.org/10.1042/bst0370295.
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The mTOR (mammalian target of rapamycin) signalling pathway functions as a nutrient sensor, both in individual cells and, more globally, in organs such as the fat body in Drosophila and the hypothalamus in the rat. The activity of placental amino acid transporters is decreased in IUGR (intrauterine growth restriction), and recent experimental evidence suggests that these changes contribute directly to the restricted fetal growth. We have shown that mTOR regulates the activity of the placental L-type amino acid transporter system and that placental mTOR activity is decreased in IUGR. The present review summarizes the emerging evidence implicating placental mTOR signalling as a key mechanism linking maternal nutrient and growth factor concentrations to amino acid transport in the human placenta. Since fetal growth is critically dependent on placental nutrient transport, placental mTOR signalling plays an important role in the regulation of fetal growth.
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Emoto, Akiko, Fumihiko Ushigome, Noriko Koyabu, Hiroshi Kajiya, Koji Okabe, Shoji Satoh, Kiyomi Tsukimori, Hitoo Nakano, Hisakazu Ohtani, and Yasufumi Sawada. "H+-linked transport of salicylic acid, an NSAID, in the human trophoblast cell line BeWo." American Journal of Physiology-Cell Physiology 282, no. 5 (May 1, 2002): C1064—C1075. http://dx.doi.org/10.1152/ajpcell.00179.2001.
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We investigated the transport of salicylic acid and l-lactic acid across the placenta using the human trophoblast cell line BeWo. We performed uptake experiments and measured the change in intracellular pH (pHi). The uptakes of [14C]salicylic acid andl-[14C]lactic acid were temperature- and extracellular pH-dependent and saturable at higher concentrations. Both uptakes were also reduced by FCCP, nigericin, and NaN3. Various nonsteroidal anti-inflammatory drugs (NSAIDs) strongly inhibited the uptake of l-[14C]lactic acid. Salicylic acid and ibuprofen noncompetitively inhibited the uptake ofl-[14C]lactic acid. α-Cyano-4-hydroxycinnamate (CHC), a monocarboxylate transporter inhibitor, suppressed the uptake ofl-[14C]lactic acid but not that of [14C]salicylic acid. CHC also suppressed the decrease of pHi induced by l-lactic acid but had little effect on that induced by salicylic acid or diclofenac. These results suggest that NSAIDs are potent inhibitors of lactate transporters, although they are transported mainly by a transport system distinct from that for l-lactic acid.
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Bzoskie, L., L. Blount, K. Kashiwai, Y. T. Tseng, W. W. Hay, and J. F. Padbury. "Placental norepinephrine clearance: in vivo measurement and physiological role." American Journal of Physiology-Endocrinology and Metabolism 269, no. 1 (July 1, 1995): E145—E149. http://dx.doi.org/10.1152/ajpendo.1995.269.1.e145.
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The intrauterine clearance rate of catecholamines is higher than in newborn animals or in adults. The separate contributions of the fetus and placenta to this clearance are not known. The placenta is a site of expression of the amine plasma membrane transporters that mediate this process. To determine the physiological role of this placental transporter in vivo, we studied fetal sheep at 123 days with common umbilical vein (UV), fetal arterial (AO), and venous catheters. Tritiated norepinephrine ([3H]NE) was infused to determine the kinetics of placental and fetal NE appearance and clearance rates. Umbilical flow was determined by [3H]NE infusion. Placental and total (fetal-placental) NE clearance rates were determined by measurement of [3H]NE from simultaneously drawn UV and AO samples. Total clearance was 99 +/- 8 ml.kg-1.min-1. Placental fractional [3H]NE extraction was 21% and accounted for 48% of total clearance. Fetal plasma NE production rate was 85 +/- 20 ng.kg-1.min-1. We conclude that placental catecholamine clearance is an important metabolic function of the placenta. This mechanism for clearance of the high fetal production rate of catecholamines is vital for fetal homeostasis. We speculate that derangements in placental catecholamine clearance may explain the exaggerated adverse effects on the fetus of drugs like cocaine, which block catecholamine transport.
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Lofthouse, E. M., S. Perazzolo, S. Brooks, I. P. Crocker, J. D. Glazier, E. D. Johnstone, N. Panitchob, et al. "Phenylalanine transfer across the isolated perfused human placenta: an experimental and modeling investigation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 310, no. 9 (May 1, 2016): R828—R836. http://dx.doi.org/10.1152/ajpregu.00405.2015.
Full textAbstract:
Membrane transporters are considered essential for placental amino acid transfer, but the contribution of other factors, such as blood flow and metabolism, is poorly defined. In this study we combine experimental and modeling approaches to understand the determinants of [14C]phenylalanine transfer across the isolated perfused human placenta. Transfer of [14C]phenylalanine across the isolated perfused human placenta was determined at different maternal and fetal flow rates. Maternal flow rate was set at 10, 14, and 18 ml/min for 1 h each. At each maternal flow rate, fetal flow rates were set at 3, 6, and 9 ml/min for 20 min each. Appearance of [14C]phenylalanine was measured in the maternal and fetal venous exudates. Computational modeling of phenylalanine transfer was undertaken to allow comparison of the experimental data with predicted phenylalanine uptake and transfer under different initial assumptions. Placental uptake (mol/min) of [14C]phenylalanine increased with maternal, but not fetal, flow. Delivery (mol/min) of [14C]phenylalanine to the fetal circulation was not associated with fetal or maternal flow. The absence of a relationship between placental phenylalanine uptake and net flux of phenylalanine to the fetal circulation suggests that factors other than flow or transporter-mediated uptake are important determinants of phenylalanine transfer. These observations could be explained by tight regulation of free amino acid levels within the placenta or properties of the facilitated transporters mediating phenylalanine transport. We suggest that amino acid metabolism, primarily incorporation into protein, is controlling free amino acid levels and, thus, placental transfer.
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Vaughan, Owen R., Fredrick Thompson, Ramón A. Lorca, Colleen G. Julian, Theresa L. Powell, Lorna G. Moore, and Thomas Jansson. "Effect of high altitude on human placental amino acid transport." Journal of Applied Physiology 128, no. 1 (January 1, 2020): 127–33. http://dx.doi.org/10.1152/japplphysiol.00691.2019.
Full textAbstract:
Women residing at high altitudes deliver infants of lower birth weight than at sea level. Birth weight correlates with placental system A-mediated amino acid transport capacity, and severe environmental hypoxia reduces system A activity in isolated trophoblast and the mouse placenta. However, the effect of high altitude on human placental amino acid transport remains unknown. We hypothesized that microvillous membrane (MVM) system A and system L amino acid transporter activity is lower in placentas of women living at high altitude compared with low-altitude controls. Placentas were collected at term from healthy pregnant women residing at high altitude (HA; >2,500 m; n = 14) or low altitude (LA; <1,700 m; n = 14) following planned, unlabored cesarean section. Birth weight, but not placenta weight, was 13% lower in HA pregnancies (2.88 ± 0.11 kg) compared with LA (3.30 ± 0.07 kg, P < 0.01). MVM erythropoietin receptor abundance, determined by immunoblot, was greater in HA than in LA placentas, consistent with lower placental oxygen levels at HA. However, there was no effect of altitude on MVM system A or L activity, determined by Na+-dependent [14C]methylaminoisobutyric acid uptake and [3H]leucine uptake, respectively. MVM abundance of glucose transporters (GLUTs) 1 and 4 and basal membrane GLUT4 were also similar in LA and HA placentas. Low birth weights in the neonates of women residing at high altitude are not a consequence of reduced placental amino acid transport capacity. These observations are in general agreement with studies of IUGR babies at low altitude, in which MVM system A activity is downregulated only in growth-restricted babies with significant compromise. NEW & NOTEWORTHY Babies born at high altitude are smaller than at sea level. Birth weight is dependent on growth in utero and, in turn, placental nutrient transport. We determined amino acid transport capacity in placentas collected from women resident at low and high altitude. Altitude did not affect system A amino acid transport across the syncytiotrophoblast microvillous membrane, suggesting that impaired placental amino acid transport does not contribute to reduced birth weight in this high-altitude population.
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Ford, Dianne. "Intestinal and placental zinc transport pathways." Proceedings of the Nutrition Society 63, no. 1 (February 2004): 21–29. http://dx.doi.org/10.1079/pns2003320.
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Mammalian members of the cation diffusion facilitator (CDF) and zrt-, irt-like protein (ZIP) families of Zn transporters, initially identified in Saccharomyces cerevisiae and Arabidopsis thalania spp., have been cloned during the last 8 years and have been classified as families SLC30 and SLC39 respectively. The cloning of human Zn transporters ZnT-like transporter 1 (hZTL1)/ZnT5 (SLC30A5) and hZIP4 (SLC39A4) were major advances in the understanding of the molecular mechanisms of dietary Zn absorption. Both transporters are localised at the enterocyte apical membrane and are, therefore, potentially of fundamental importance in dietary Zn uptake. hZTL1 mediates Zn uptake when expressed in Xenopus laevis oocytes and hZIP4 is mutated in most cases of the inherited Zn deficiency disease acrodermatitis enteropathica. Localisation of hZTL1/ZnT5 at the apical membrane of the placental syncytiotrophoblast indicates a fundamental role in the transfer of Slc30 Zn to the foetus. Observations in rodent models indicate that in the intestine increased Zn availability increases expression of Zn transporters. Human intestinal Caco-2 cells show a similar response to increasing the Zn2+ concentration of the nutrient medium in relation to the expression of mRNA corresponding to several Zn transporters and that of ZnT1 (SLC30A1) and hZTL1/ZnT5 proteins. In the human placental cell line JAR, however, expression at the mRNA level of a number of Zn transporters is not modified by Zn availability, whilst ZnT1 and hZTL1/ZnT5 proteins are reduced under Zn-supplemented conditions. These differences between Caco-2 and JAR cells in Zn transporter gene responses to Zn supply may reflect the different extracellular Zn concentrations encountered by the corresponding cell types in vitro.
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Selvaratnam, Johanna, Haiyan Guan, James Koropatnick, and Kaiping Yang. "Metallothionein-I- and -II-deficient mice display increased susceptibility to cadmium-induced fetal growth restriction." American Journal of Physiology-Endocrinology and Metabolism 305, no. 6 (September 15, 2013): E727—E735. http://dx.doi.org/10.1152/ajpendo.00157.2013.
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Maternal cadmium exposure induces fetal growth restriction (FGR), but the underlying mechanisms remain largely unknown. The placenta is the main organ known to protect the fetus from environmental toxins such as cadmium. In this study, we examine the role of the two key placental factors in cadmium-induced FGR. The first is placental enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is known to protect the fetus from exposure to high cortisol levels and subsequently FGR, and the second the cadmium binding/sequestering proteins metallotheionein (MT)-I and -II. Using the MT-I/II −/− mouse model, pregnant mice were administered cadmium, following which pups and placentas were collected and examined. MT-I/II−/− pups exposed to cadmium were significantly growth restricted, but neither placental weight nor 11β-HSD2 was altered. Although cadmium administration did not result in any visible structural changes in the placenta, increased apoptosis was detected in MT-I/II−/− placentas following cadmium exposure, with a significant increase in levels of both p53 and caspase 3 proteins. Additionally, glucose transporter (GLUT1) was significantly reduced in MT-I/II−/− placentas of pups exposed to cadmium, whereas zinc transporter (ZnT-1) remained unaltered. Taken together, these results demonstrate that MT-I/II−/− mice are more vulnerable to cadmium-induced FGR. The present data also suggest that increased apoptosis and reduced GLUT1 expression in the placenta contribute to the molecular mechanisms underlying cadmium-induced FGR.
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Li, Heng, Etsuko Wada, and Keiji Wada. "Maternal Administration of the Herbal Medicine Toki-Shakuyaku-San Promotes Fetal Growth and Placental Gene Expression in Normal Mice." American Journal of Chinese Medicine 41, no. 03 (January 2013): 515–29. http://dx.doi.org/10.1142/s0192415x13500377.
Full textAbstract:
Toki-shakuyaku-san (TSS), an herbal formula based on traditional Chinese medicine, is commonly used in obstetrics. To examine the effects of TSS on the normal mouse fetus and placenta, TSS was administered to normal pregnant mice and their placentas and fetuses were studied. First, the effects of maternal TSS treatment on implantation were investigated. Administration of TSS from gestation day 0.5 (G0.5) to G6.5 showed that litter size was not altered at embryonic day 11.5 (E11.5), but the number of resorbed fetuses was slightly decreased. Then, to investigate effects on fetal and placental growths after implantation, TSS was administered from G5.5. At E14.5, the body weight of fetuses from TSS-treated dams was significantly increased. Gene expression of insulin-like growth factor 2 (Igf2), one of the most important modulators of fetal growth, was significantly increased in the placentas and fetuses of TSS-treated dams. In addition, the expression of particular placental developmental genes and nutrient transporter genes was significantly increased in TSS-treated placentas. At E18.5, after longer-term administration of TSS, fetal and placental weights were not altered, but the expression of the placental developmental and nutrient transporter genes remained elevated compared with controls. These results suggest that maternal TSS treatment in normal mice enhances the expression of Igf2, placental developmental genes and nutrient transporter genes, resulting in increased fetal weight. No obvious changes were observed in the expression of these genes after longer-term maternal TSS treatment.
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Bloise, Enrrico, Jair R. S. Braga, Cherley B. V. Andrade, Guinever E. Imperio, Lilian M. Martinelli, Roberto A. Antunes, Karina R. Silva, et al. "Altered Umbilical Cord Blood Nutrient Levels, Placental Cell Turnover and Transporter Expression in Human Term Pregnancies Conceived by Intracytoplasmic Sperm Injection (ICSI)." Nutrients 13, no. 8 (July 28, 2021): 2587. http://dx.doi.org/10.3390/nu13082587.
Full textAbstract:
Assisted reproductive technologies (ART) may increase risk for abnormal placental development, preterm delivery and low birthweight. We investigated placental morphology, transporter expression and paired maternal/umbilical fasting blood nutrient levels in human term pregnancies conceived naturally (n = 10) or by intracytoplasmic sperm injection (ICSI; n = 11). Maternal and umbilical vein blood from singleton term (>37 weeks) C-section pregnancies were assessed for levels of free amino acids, glucose, free fatty acids (FFA), cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), very low-density lipoprotein (VLDL) and triglycerides. We quantified placental expression of GLUT1 (glucose), SNAT2 (amino acids), P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) (drug) transporters, and placental morphology and pathology. Following ICSI, placental SNAT2 protein expression was downregulated and umbilical cord blood levels of citrulline were increased, while FFA levels were decreased at term (p < 0.05). Placental proliferation and apoptotic rates were increased in ICSI placentae (p < 0.05). No changes in maternal blood nutrient levels, placental GLUT1, P-gp and BCRP expression, or placental histopathology were observed. In term pregnancies, ICSI impairs placental SNAT2 transporter expression and cell turnover, and alters umbilical vein levels of specific nutrients without changing placental morphology. These may represent mechanisms through which ICSI impacts pregnancy outcomes and programs disease risk trajectories in offspring across the life course.
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Zhou, Fanfan, Mei Hong, and Guofeng You. "Regulation of human organic anion transporter 4 by progesterone and protein kinase C in human placental BeWo cells." American Journal of Physiology-Endocrinology and Metabolism 293, no. 1 (July 2007): E57—E61. http://dx.doi.org/10.1152/ajpendo.00696.2006.
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Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-human immunodeficiency virus therapeutics, anti-tumor drugs, antibiotics, antihypertensives, and anti-inflammatories. hOAT4 is abundantly expressed in the placenta. In the current study, we examined the regulation of hOAT4 by pregnancy-specific hormones progesterone (P4) and 17β-estradiol (E2) and by protein kinase C (PKC) in human placental BeWo cells. P4 induced a time- and concentration-dependent downregulation of hOAT4 transport activity, whereas E2 had no effect on hOAT4 function. The downregulation of hOAT4 activity by P4 mainly resulted from a decreased cell surface expression without a change in total cell expression of the transporter, kinetically revealed as a decreased Vmax without significant change in Km. Activation of PKC by phorbol 12,13-dibutyrate also resulted in an inhibition of hOAT4 activity through a decreased cell surface expression of the transporter. However, P4-induced downregulation of hOAT4 activity could not be prevented by treating hOAT4-expressing cells with the PKC inhibitor staurosporine. We concluded that both P4 and activation of PKC inhibited hOAT4 activity through redistribution of the transporter from cell surface to the intracellular compartments. However, P4 regulates hOAT4 activity by mechanisms independent of PKC pathway.
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Ceckova, Martina, Josef Reznicek, Zuzana Ptackova, Lukas Cerveny, Fabian Müller, Marian Kacerovsky, Martin F. Fromm, Jocelyn D. Glazier, and Frantisek Staud. "Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine." Antimicrobial Agents and Chemotherapy 60, no. 9 (July 11, 2016): 5563–72. http://dx.doi.org/10.1128/aac.00648-16.
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ABSTRACTLamivudine is one of the antiretroviral drugs of choice for the prevention of mother-to-child transmission (MTCT) in HIV-positive women. In this study, we investigated the relevance of drug efflux transporters P-glycoprotein (P-gp) (MDR1 [ABCB1]), BCRP (ABCG2), MRP2 (ABCC2), and MATE1 (SLC47A1) for the transmembrane transport and transplacental transfer of lamivudine. We employedin vitroaccumulation and transport experiments on MDCK cells overexpressing drug efflux transporters,in situ-perfused rat term placenta, and vesicular uptake in microvillous plasma membrane (MVM) vesicles isolated from human term placenta. MATE1 significantly accelerated lamivudine transport in MATE1-expressing MDCK cells, whereas no transporter-driven efflux of lamivudine was observed in MDCK-MDR1, MDCK-MRP2, and MDCK-BCRP monolayers. MATE1-mediated efflux of lamivudine appeared to be a low-affinity process (apparentKmof 4.21 mM andVmaxof 5.18 nmol/mg protein/min in MDCK-MATE1 cells). Consistent within vitrotransport studies, the transplacental clearance of lamivudine was not affected by P-gp, BCRP, or MRP2. However, lamivudine transfer across dually perfused rat placenta and the uptake of lamivudine into human placental MVM vesicles revealed pH dependency, indicating possible involvement of MATE1 in the fetal-to-maternal efflux of the drug. To conclude, placental transport of lamivudine does not seem to be affected by P-gp, MRP2, or BCRP, but a pH-dependent mechanism mediates transport of lamivudine in the fetal-to-maternal direction. We suggest that MATE1 might be, at least partly, responsible for this transport.
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Jones, H. N., T. Jansson, and T. L. Powell. "IL-6 stimulates system A amino acid transporter activity in trophoblast cells through STAT3 and increased expression of SNAT2." American Journal of Physiology-Cell Physiology 297, no. 5 (November 2009): C1228—C1235. http://dx.doi.org/10.1152/ajpcell.00195.2009.
Full textAbstract:
Changes in placental nutrient transport are closely associated with abnormal fetal growth. However, the molecular mechanisms underlying the regulation of placental amino acid transporters are unknown. We demonstrate that physiological concentrations of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α stimulate the activity of amino acid transporter system A, but not system L, in cultured human primary trophoblast cells. Both cytokines increased the gene and protein expression of the Na+-coupled neutral amino acid transporter (SNAT)2 isoform and upregulated SNAT1 protein expression. IL-6 increased Tyr705 phosphorylation of signal transducer and activator of transcription 3 (STAT3). In cells transfected with small interfering RNA (siRNA) targeting STAT3, the RNA and protein expression of SNAT2, but not SNAT1, was reduced and the stimulating effect of IL-6 on system A activity was abolished. Despite eliciting similar responses in amino acid transport activity and transporter expression, TNF-α effects on system A activity were not mediated through the JAK/STAT pathway. In conclusion, we have identified a novel regulatory pathway involving increased gene expression of the SNAT2 isoform mediated by a STAT-dependent pathway, which links IL-6 to increased activity of system A, a ubiquitously expressed transporter of neutral amino acids. From these new findings, we propose that upregulation of amino acid transporters by cytokines may contribute to increased placental nutrient transport and fetal overgrowth, which are commonly found in pregnancies complicated by maternal diabetes and obesity.
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Osses, N., L. Sobrevia, C. Cordova, SM Jarvis, and DL Yudilevich. "Transport and metabolism of adenosine in diabetic human placenta." Reproduction, Fertility and Development 7, no. 6 (1995): 1499. http://dx.doi.org/10.1071/rd9951499.
Full textAbstract:
Pregnancy complicated by diabetes is a relatively frequent event and may result in fetal embriopathy. However, little is known regarding whether placental transport functions are altered. In this study, we have compared the activity of the nitrobenzylthioinosine (NBMPR)-sensitive adenosine transporter and adenosine metabolism in human placental brush-border- and basal-membrane vesicles from placentas of normal and diabetic pregnancies. Neither [3H]NBMPR binding, a marker of the facilitative-diffusion nucleoside transporter in the human placenta, nor adenosine metabolism exhibited a significant difference in either the brush-border- or the basal-membrane vesicles between the normal and diabetic group, except for an increased affinity in [3H]NBMPR binding at the basal side in diabetic placenta. This result contrasts with an earlier finding using the same group of patients that adenosine transport is downregulated in umbilical vein endothelial cells from diabetic pregnancies. It is concluded that adenosine transport is modulated selectively in different tissues in diabetic pregnancies.
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Matoba, Shogo, Shoko Nakamuta, Kento Miura, Michiko Hirose, Hirosuke Shiura, Takashi Kohda, Nobuaki Nakamuta, and Atsuo Ogura. "Paternal knockout of Slc38a4/SNAT4 causes placental hypoplasia associated with intrauterine growth restriction in mice." Proceedings of the National Academy of Sciences 116, no. 42 (September 30, 2019): 21047–53. http://dx.doi.org/10.1073/pnas.1907884116.
Full textAbstract:
The placenta is critical in mammalian embryonic development because the embryo’s supply of nutrients, including amino acids, depends solely on mother-to-embryo transport through it. However, the molecular mechanisms underlying this amino acid supply are poorly understood. In this study, we focused on system A amino acid transporters Slc38a1/SNAT1, Slc38a2/SNAT2, and Slc38a4/SNAT4, which carry neutral, short-side-chain amino acids, to determine their involvement in placental or embryonic development. A triple-target CRISPR screen identified Slc38a4/SNAT4 as the critical amino acid transporter for placental development in mice. We established mouse lines from the CRISPR founders with large deletions in Slc38a4 and found that, consistent with the imprinted paternal expression of Slc38a4/SNAT4 in the placenta, paternal knockout (KO) but not maternal KO of Slc38a4/SNAT4 caused placental hypoplasia associated with reduced fetal weight. Immunostaining revealed that SNAT4 was widely expressed in differentiating cytotrophoblasts and maturing trophoblasts at the maternal–fetal interface. A blood metabolome analysis revealed that amino acid concentrations were globally reduced in Slc38a4/SNAT4 mutant embryos. These results indicated that SNAT4-mediated amino acid transport in mice plays a major role in placental and embryonic development. Given that expression of Slc38a4 in the placenta is conserved in other species, our Slc38a4/SNAT4 mutant mice could be a promising model for the analysis of placental defects leading to intrauterine growth restriction in mammals.
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Johnson, Gregory A., Avery C. Kramer, Chelsie Steinhauser, Heewon Seo, Bryan A. McLendon, Robert C. Burghardt, Guoyao Wu, and Fuller W. Bazer. "410 Steroids Regulate SLC2A1 and SLC2A3 to Deliver Glucose into Trophectoderm for Metabolism via Glycolysis." Journal of Animal Science 98, Supplement_4 (November 3, 2020): 188–89. http://dx.doi.org/10.1093/jas/skaa278.348.
Full textAbstract:
Abstract The conceptuses (embryo/fetus and placental membranes) of pigs require energy to support elongation and implantation, and amounts of glucose and fructose increase in the uterine lumen during the peri-implantation period. Conceptuses from Day 16 of pregnancy were incubated with either 14C-glucose or 14C-fructose and amounts of radiolabeled CO2 released from the conceptuses measured to determine rates of oxidation of glucose and fructose. Both glucose and fructose transport into conceptuses, and glucose is preferentially metabolized in the presence of fructose, while fructose is actively metabolized in the absence of glucose and to a lesser extent in the presence of glucose. Endometrial and placental expression of glucose transporters SLC2A1, SLC2A2, SCL2A3 and SLC2A4 were determined. SLC2A1 mRNA and protein, and SLC2A4 mRNA were abundant in the uterine luminal epithelium of pregnant compared to cycling gilts, and increased in response to progesterone and conceptus-secreted estrogen. SLC2A2 mRNA was expressed weakly by conceptus trophectoderm on Day 15 of pregnancy, while SLC2A3 mRNA was abundant in trophectoderm/chorion throughout pregnancy. Therefore, glucose can be transported into the uterine lumen by SLC2A1, and then into conceptuses by SLC2A3. On Day 60 of gestation, the cell-specific expression of these transporters was more complex, suggesting that glucose and fructose transporters are precisely regulated in a spatial-temporal pattern along the uterine-placental interface of pigs to maximize hexose sugar transport to the pig conceptus/placenta.
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Langmann, Thomas, Richard Mauerer, Alexandra Zahn, Christoph Moehle, Mario Probst, Wolfgang Stremmel, and Gerd Schmitz. "Real-Time Reverse Transcription-PCR Expression Profiling of the Complete Human ATP-Binding Cassette Transporter Superfamily in Various Tissues." Clinical Chemistry 49, no. 2 (February 1, 2003): 230–38. http://dx.doi.org/10.1373/49.2.230.
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Abstract Background: ATP-binding cassette (ABC) transporters are involved in many physiologic processes, such as lipid transport, sterol homeostasis, immune mechanisms, and drug transport, and cause various human inherited diseases. Thus, the analysis of ABC transporter mRNA expression profiles for basic research, especially in the field of lipid metabolism, for clinical diagnosis, and for monitoring of drug effects is of great interest. Methods: We have developed a rapid, accurate, and highly sensitive real-time reverse transcription-PCR (RT-PCR) method for detection and quantification of all 47 currently known members of the ABC transporter superfamily. Our expression analysis is based on relative quantification using a calibration curve method. With our assay, expression monitoring of a large number of RNA samples in a 384-well format with only 50 ng of total RNA is possible. Results: In contrast to previous expression analyses of single ABC genes, our method allows the rapid and complete analysis of all ABC transporters in given RNA samples. We used our newly established expression panel to study the gene expression of all human ABC transporters in 20 different human tissues. As a result, we identified tissues with high transcriptional activity for ABC transporters. These organs are mainly involved in secretory function (adrenal gland), metabolic function (liver), barrier function (lung, trachea, small intestine), and tropic function (placenta, uterus). Conclusions: Our RT-PCR assay allows rapid, high-throughput transcriptional profiling of the complete ABC transporter superfamily and thus provides a new enabling tool for research, clinical diagnosis of disease, and drug testing and development.
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Jansson, Thomas, Marisol Castillo-Castrejon, Madhulika B. Gupta, Theresa L. Powell, and Fredrick J. Rosario. "Down-regulation of placental Cdc42 and Rac1 links mTORC2 inhibition to decreased trophoblast amino acid transport in human intrauterine growth restriction." Clinical Science 134, no. 1 (January 2020): 53–70. http://dx.doi.org/10.1042/cs20190794.
Full textAbstract:
Abstract Intrauterine growth restriction (IUGR) increases the risk for perinatal complications and metabolic and cardiovascular disease later in life. The syncytiotrophoblast (ST) is the transporting epithelium of the human placenta, and decreased expression of amino acid transporter isoforms in the ST plasma membranes is believed to contribute to IUGR. Placental mechanistic target of rapamycin Complex 2 (mTORC2) signaling is inhibited in IUGR and regulates the trafficking of key amino acid transporter (AAT) isoforms to the ST plasma membrane; however, the molecular mechanisms are unknown. Cdc42 and Rac1 are Rho-GTPases that regulate actin-binding proteins, thereby modulating the structure and dynamics of the actin cytoskeleton. We hypothesized that inhibition of mTORC2 decreases AAT expression in the plasma membrane and amino acid uptake in primary human trophoblast (PHT) cells mediated by down-regulation of Cdc42 and Rac1. mTORC2, but not mTORC1, inhibition decreased the Cdc42 and Rac1 expression. Silencing of Cdc42 and Rac1 inhibited the activity of the System L and A transporters and markedly decreased the trafficking of LAT1 (System L isoform) and SNAT2 (System A isoform) to the plasma membrane. mTORC2 inhibition by silencing of rictor failed to decrease AAT following activation of Cdc42/Rac1. Placental Cdc42 and Rac1 protein expression was down-regulated in human IUGR and was positively correlated with placental mTORC2 signaling. In conclusion, mTORC2 regulates AAT trafficking in PHT cells by modulating Cdc42 and Rac1. Placental mTORC2 inhibition in human IUGR may contribute to decreased placental amino acid transfer and reduced fetal growth mediated by down-regulation of Cdc42 and Rac1.
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Ruis, Matthew T., Kylie D. Rock, Samantha M. Hall, Brian Horman, Heather B. Patisaul, and Heather M. Stapleton. "PBDEs Concentrate in the Fetal Portion of the Placenta: Implications for Thyroid Hormone Dysregulation." Endocrinology 160, no. 11 (September 25, 2019): 2748–58. http://dx.doi.org/10.1210/en.2019-00463.
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Abstract During pregnancy, the supply of thyroid hormone (TH) to the fetus is critically important for fetal growth, neural development, metabolism, and maintenance of pregnancy. Additionally, in cases where maternal and placental TH regulation is significantly altered, there is an increased risk of several adverse pregnancy outcomes. It is unclear what may be disrupting placental TH regulation; however, studies suggest that environmental contaminants, such as polybrominated diphenyl ethers (PBDEs), could be playing a role. In this study, Wistar rats were gestationally exposed to a mixture of PBDEs for 10 days. THs and PBDEs were quantified in paired maternal serum, dissected placenta, and fetuses, and mRNA expression of transporters in the placenta was assessed. Significantly higher concentrations of PBDEs were observed in the fetal portion of the placenta compared with the maternal side, suggesting that PBDEs are actively transported across the interface. PBDEs were also quantified in 10 recently collected human maternal and fetal placental tissues; trends paralleled observations in the rat model. We also observed an effect of PBDEs on T3 levels in dam serum, as well as suggestive changes in the T3 levels of the placenta and fetus that varied by fetal sex. mRNA expression in the placenta also significantly varied by fetal sex and dose. These observations suggest the placenta is a significant modifier of fetal exposures, and that PBDEs are impacting TH regulation in a sex-specific manner during this critical window of development.
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Shrestha, Nirajan, Olivia J. Holland, Nykola L. Kent, Anthony V. Perkins, Andrew J. McAinch, James S. M. Cuffe, and Deanne H. Hryciw. "Maternal High Linoleic Acid Alters Placental Fatty Acid Composition." Nutrients 12, no. 8 (July 23, 2020): 2183. http://dx.doi.org/10.3390/nu12082183.
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Fetal development is modulated by maternal nutrition during pregnancy. The dietary intake of linoleic acid (LA), an essential dietary n-6 polyunsaturated fatty acid (PUFA), has increased. We previously published that increased LA consumption during pregnancy does not alter offspring or placental weight but fetal plasma fatty acid composition; the developing fetus obtains their required PUFA from the maternal circulation. However, it is unknown if increased maternal linoleic acid alters placental fatty acid storage, metabolism, transport, and general placental function. Female Wistar-Kyoto rats were fed either a low LA diet (LLA; 1.44% of energy from LA) or high LA diet (HLA; 6.21% of energy from LA) for 10 weeks before pregnancy and during gestation. Rats were sacrificed at embryonic day 20 (E20, term = 22 days) and placentae collected. The labyrinth of placentae from one male and one female fetus from each litter were analyzed. High maternal LA consumption increased placental total n-6 and LA concentrations, and decreased total n-3 PUFA, alpha-linolenic acid (ALA), and docosahexaenoic acid (DHA). Fatty acid desaturase 1 (Fads1), angiopoietin-like 4 (Angptl4), and diacylglycerol lipase beta (Daglb) mRNA were downregulated in placentae from offspring from HLA dams. Maternal high LA downregulated the fatty acid transport protein 4 (Fatp4) and glucose transporter 1 (Slc2a1) mRNA in placentae. IL-7 and IL-10 protein were decreased in placentae from offspring from HLA dams. In conclusion, a high maternal LA diet alters the placental fatty acid composition, inflammatory proteins, and expressions of nutrient transporters, which may program deleterious outcomes in offspring.
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Braun, Doreen, Eva K. Wirth, Franziska Wohlgemuth, Nathalie Reix, Marc O. Klein, Annette Grüters, Josef Köhrle, and Ulrich Schweizer. "Aminoaciduria, but normal thyroid hormone levels and signalling, in mice lacking the amino acid and thyroid hormone transporter Slc7a8." Biochemical Journal 439, no. 2 (September 28, 2011): 249–55. http://dx.doi.org/10.1042/bj20110759.
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LAT2 (system L amino acid transporter 2) is composed of the subunits Slc7a8/Lat2 and Slc3a2/4F2hc. This transporter is highly expressed along the basolateral membranes of absorptive epithelia in kidney and small intestine, but is also abundant in the brain. Lat2 is an energy-independent exchanger of neutral amino acids, and was shown to transport thyroid hormones. We report in the present paper that targeted inactivation of Slc7a8 leads to increased urinary loss of small neutral amino acids. Development and growth of Slc7a8−/− mice appears normal, suggesting functional compensation of neutral amino acid transport by alternative transporters in kidney, intestine and placenta. Movement co-ordination is slightly impaired in mutant mice, although cerebellar development and structure remained inconspicuous. Circulating thyroid hormones, thyrotropin and thyroid hormone-responsive genes remained unchanged in Slc7a8−/− mice, possibly because of functional compensation by the thyroid hormone transporter Mct8 (monocarboxylate transporter 8), which is co-expressed in many cell types. The reason for the mild neurological phenotype remains unresolved.
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Sferruzzi-Perri, A. N., O. R. Vaughan, P. M. Coan, M. C. Suciu, R. Darbyshire, M. Constancia, G. J. Burton, and A. L. Fowden. "Placental-Specific Igf2 Deficiency Alters Developmental Adaptations to Undernutrition in Mice." Endocrinology 152, no. 8 (June 14, 2011): 3202–12. http://dx.doi.org/10.1210/en.2011-0240.
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The pattern of fetal growth is a major determinant of the subsequent health of the infant. We recently showed in undernourished (UN) mice that fetal growth is maintained until late pregnancy, despite reduced placental weight, through adaptive up-regulation of placental nutrient transfer. Here, we determine the role of the placental-specific transcript of IGF-II (Igf2P0), a major regulator of placental transport capacity in mice, in adapting placental phenotype to UN. We compared the morphological and functional responses of the wild-type (WT) and Igf2P0-deficient placenta in WT mice fed ad libitium or 80% of the ad libitium intake. We observed that deletion of Igf2P0 prevented up-regulation of amino acid transfer normally seen in UN WT placenta. This was associated with a reduction in the proportion of the placenta dedicated to nutrient transport, the labyrinthine zone, and its constituent volume of trophoblast in Igf2P0-deficient placentas exposed to UN on d 16 of pregnancy. Additionally, Igf2P0-deficient placentas failed to up-regulate their expression of the amino acid transporter gene, Slc38a2, and down-regulate phosphoinositide 3-kinase-protein kinase B signaling in response to nutrient restriction on d 19. Furthermore, deleting Igf2P0 altered maternal concentrations of hormones (insulin and corticosterone) and metabolites (glucose) in both nutritional states. Therefore, Igf2P0 plays important roles in adapting placental nutrient transfer capacity during UN, via actions directly on the placenta and/or indirectly through the mother.
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James-Allan, Laura B., Jaron Arbet, Stephanie B. Teal, Theresa L. Powell, and Thomas Jansson. "Insulin Stimulates GLUT4 Trafficking to the Syncytiotrophoblast Basal Plasma Membrane in the Human Placenta." Journal of Clinical Endocrinology & Metabolism 104, no. 9 (May 21, 2019): 4225–38. http://dx.doi.org/10.1210/jc.2018-02778.
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AbstractContextPlacental transport capacity influences fetal glucose supply. The syncytiotrophoblast is the transporting epithelium in the human placenta, expressing glucose transporters (GLUTs) and insulin receptors (IRs) in its maternal-facing microvillous plasma membrane (MVM) and fetal-facing basal plasma membrane (BM).ObjectiveThe objectives of this study were to (i) 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 (ii) assess the effect of insulin on GLUT4 plasma membrane trafficking in human placental explants.Design, Setting, and ParticipantsPlacental tissue was collected across gestation from women with normal body mass index (BMI) and mothers with obesity with appropriate for gestational age and macrosomic infants. MVM and BM were isolated.Main Outcome MeasuresProtein expression of GLUT4, GLUT1, and IR were determined by western blot.ResultsGLUT4 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 women with obesity 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 women but not women with obesity.ConclusionWe 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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Lager, Susanne, and Theresa L. Powell. "Regulation of Nutrient Transport across the Placenta." Journal of Pregnancy 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/179827.
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Abnormal fetal growth, both growth restriction and overgrowth, is associated with perinatal complications and an increased risk of metabolic and cardiovascular disease later in life. Fetal growth is dependent on nutrient availability, which in turn is related to the capacity of the placenta to transport these nutrients. The activity of a range of nutrient transporters has been reported to be decreased in placentas of growth restricted fetuses, whereas at least some studies indicate that placental nutrient transport is upregulated in fetal overgrowth. These findings suggest that changes in placental nutrient transport may directly contribute to the development of abnormal fetal growth. Detailed information on the mechanisms by which placental nutrient transporters are regulated will therefore help us to better understand how important pregnancy complications develop and may provide a foundation for designing novel intervention strategies. In this paper we will focus on recent studies of regulatory mechanisms that modulate placental transport of amino acids, fatty acids, and glucose.
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Liu, Ning, Zhaolai Dai, Yunchang Zhang, Jingqing Chen, Ying Yang, Guoyao Wu, Patrick Tso, and Zhenlong Wu. "Maternal L-proline supplementation enhances fetal survival, placental development, and nutrient transport in mice†." Biology of Reproduction 100, no. 4 (November 10, 2018): 1073–81. http://dx.doi.org/10.1093/biolre/ioy240.
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Abstract L-Proline (proline) in amniotic fluid was markedly increased during pregnancy in both pigs and sheep. However, in vivo data to support a beneficial effect of proline on fetal survival are not available. In this study, pregnant C57BL/6J mice were fed a purified diet supplemented with or without 0.50% proline from embryonic day 0.5 (E0.5) to E12.5 or term. Results indicated that dietary supplementation with proline to gestating mice enhanced fetal survival, reproductive performance, the concentrations of proline, arginine, aspartic acid, and tryptophan in plasma and amniotic fluid, while decreasing the concentrations of ammonia and urea in plasma and amniotic fluid. Placental mRNA levels for amino acid transporters, including Slc36a4, Slc38a2, Slc38a4, Slc6a14, and Na+/K+ ATPase subunit-1α (Atp1a1), fatty acid transporter Slc27a4, and glucose transporters Slc2a1 and Slc2a3, were augmented in proline-supplemented mice, compared with the control group. Histological analysis showed that proline supplementation enhanced labyrinth zone in the placenta of mice at E12.5, mRNA levels for Vegf, Vegfr, Nos2, and Nos3, compared with the controls. Western blot analysis showed that proline supplementation increased protein abundances of phosphorylated (p)-mTORC1, p-ribosomal protein S6 kinase (p70S6K), and p-eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), as well as the protein level of GCN2 (a negative regulator of mTORC1 signaling). Collectively, our results indicate a novel functional role of proline in improving placental development and fetal survival by enhancing placental nutrient transport, angiogenesis, and protein synthesis.
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Van Gronigen Case, Gerialisa, Kathryn M. Storey, Lauren E. Parmeley, and Laura C. Schulz. "Effects of maternal nutrient restriction during the periconceptional period on placental development in the mouse." PLOS ONE 16, no. 1 (January 14, 2021): e0244971. http://dx.doi.org/10.1371/journal.pone.0244971.
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Maternal undernutrition has detrimental effects on fetal development and adult health. Total caloric restriction during early pregnancy followed by adequate nutrition for the remainder of gestation, is particularly linked to cardiovascular and metabolic disease risks during adulthood. The placenta is responsible for transport of nutrients from the maternal to fetal circulation, and the efficiency with which it does so can be adjusted to the maternal nutrient supply. There is evidence that placental adaptations to nutrient restriction in early pregnancy may be retained even when adequate nutrition is restored later in pregnancy, leading to a potential mismatch between placental efficiency and maternal nutrient supplies. However, in the mouse, 50% caloric restriction from days 1.5–11.5 of gestation, while temporarily altering placental structure and gene expression, had no significant effect on day 18.5. The periconceptional period, during which oocyte maturation, fertilization, and preimplantation development occur may be especially critical in creating lasting impact on the placenta. Here, mice were subjected to 50% caloric restriction from 3 weeks prior to pregnancy through d11.5, and then placental structure, the expression of key nutrient transporters, and global DNA methylation levels were examined at gestation d18.5. Prior exposure to caloric restriction increased maternal blood space area, but decreased expression of the key System A amino acid transporter Slc38a4 at d18.5. Neither placental and fetal weights, nor placental DNA methylation levels were affected. Thus, total caloric restriction beginning in the periconceptional period does have a lasting impact on placental development in the mouse, but without changing placental efficiency.
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Vaughan, Owen R., Katarzyna Maksym, Elena Silva, Kenneth Barentsen, Russel V. Anthony, Thomas L. Brown, Sara L. Hillman, et al. "Placenta-specific Slc38a2/SNAT2 knockdown causes fetal growth restriction in mice." Clinical Science 135, no. 17 (August 31, 2021): 2049–66. http://dx.doi.org/10.1042/cs20210575.
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Abstract Fetal growth restriction (FGR) is a complication of pregnancy that reduces birth weight, markedly increases infant mortality and morbidity and is associated with later-life cardiometabolic disease. No specific treatment is available for FGR. Placentas of human FGR infants have low abundance of sodium-coupled neutral amino acid transporter 2 (Slc38a2/SNAT2), which supplies the fetus with amino acids required for growth. We determined the mechanistic role of placental Slc38a2/SNAT2 deficiency in the development of restricted fetal growth, hypothesizing that placenta-specific Slc38a2 knockdown causes FGR in mice. Using lentiviral transduction of blastocysts with a small hairpin RNA (shRNA), we achieved 59% knockdown of placental Slc38a2, without altering fetal Slc38a2 expression. Placenta-specific Slc38a2 knockdown reduced near-term fetal and placental weight, fetal viability, trophoblast plasma membrane (TPM) SNAT2 protein abundance, and both absolute and weight-specific placental uptake of the amino acid transport System A tracer, 14C-methylaminoisobutyric acid (MeAIB). We also measured human placental SLC38A2 gene expression in a well-defined term clinical cohort and found that SLC38A2 expression was decreased in late-onset, but not early-onset FGR, compared with appropriate for gestational age (AGA) control placentas. The results demonstrate that low placental Slc38a2/SNAT2 causes FGR and could be a target for clinical therapies for late-onset FGR.
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Gao, Lu, Chunmei Lv, Chen Xu, Yuan Li, Xiaorui Cui, Hang Gu, and Xin Ni. "Differential Regulation of Glucose Transporters Mediated by CRH Receptor Type 1 and Type 2 in Human Placental Trophoblasts." Endocrinology 153, no. 3 (March 1, 2012): 1464–71. http://dx.doi.org/10.1210/en.2011-1673.
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Glucose transport across the placenta is mediated by glucose transporters (GLUT), which is critical for normal development and survival of the fetus. Regulatory mechanisms of GLUT in placenta have not been elucidated. Placental CRH has been implicated to play a key role in the control of fetal growth and development. We hypothesized that CRH, produced locally in placenta, could act to modulate GLUT in placenta. To investigate this, we obtained human placentas from uncomplicated term pregnancies and isolated and cultured trophoblast cells. GLUT1 and GLUT3 expressions in placenta were determined, and effects of CRH on GLUT1 and GLUT3 were examined. GLUT1 and GLUT3 were identified in placental villous syncytiotrophoblasts and the endothelium of vessels. Treatment of cultured placental trophoblasts with CRH resulted in an increase in GLUT1 expression while a decrease in GLUT3 expression in a dose-dependent manner. Cells treated with either CRH antibody or nonselective CRH receptor (CRH-R) antagonist astressin showed a decrease in GLUT1 and an increase in GLUT3 expression. CRH-R1 antagonist antalarmin decreased GLUT1 expression while increased GLUT3 expression. CRH-R2 antagonist astressin2b increased the expression of both GLUT1 and GLUT3. Knockdown of CRH-R1 decreased GLUT1 expression while increased GLUT3 expression. CRH-R2 knockdown caused an increase in both GLUT1 and GLUT3 expression. Our data suggest that, in placenta, CRH produced locally regulates GLUT1 and GLUT3 expression, CRHR1 and CRHR2-mediated differential regulation of GLUT1 and GLUT3 expression. Placental CRH may regulate the growth of fetus and placenta by modulating the expression of GLUT in placenta during pregnancy.
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RITCHIE, James W. A., and Peter M. TAYLOR. "Role of the System L permease LAT1 in amino acid and iodothyronine transport in placenta." Biochemical Journal 356, no. 3 (June 8, 2001): 719–25. http://dx.doi.org/10.1042/bj3560719.
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The feto-placental unit relies on a maternal supply of indispensable amino acids and iodothyronines for early development and normal growth. We examined the role of the System L transporter in placental uptake of these substances, using the human placental choriocarcinoma cell line BeWo as a model experimental system. BeWo cells express both heavy (4F2hc) and light (LAT1, LAT2) chains of the System L holotransporter. Saturable transport of both l-[3H]tryptophan and [125I]tri-iodo-l-thyronine in BeWo cells includes components sensitive to inhibition by the System-L-specific substrate 2-endoamino-bicycloheptane-2-carboxylic acid; kinetic properties of these components indicate that the 4F2hc-LAT1 transporter isoform is likely to predominate for the carriage of both substances at physiologically relevant concentrations. Both 4F2hc and LAT1 proteins are also expressed in human placental membranes and LAT1 at least is localized largely to the syncytiotrophoblast layer of the term human placenta. The 4F2hc-LAT1 transporter might therefore serve a vital role in supplying the developing fetus and the placenta with both thyroid hormones and indispensable amino acids from the maternal circulation.
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Das, Utpala G., Jing He, Richard A. Ehrhardt, William W. Hay, and Sherin U. Devaskar. "Time-dependent physiological regulation of ovine placental GLUT-3 glucose transporter protein." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 279, no. 6 (December 1, 2000): R2252—R2261. http://dx.doi.org/10.1152/ajpregu.2000.279.6.r2252.
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We immunolocalized the GLUT-3 glucose transporter isoform versus GLUT-1 in the late-gestation epitheliochorial ovine placenta, and we examined the effect of chronic maternal hyperglycemia and hypoglycemia on placental GLUT-3 concentrations. GLUT-3 was limited to the apical surface of the trophoectoderm, whereas GLUT-1 was on the basolateral and apical surfaces of this cell layer and in the epithelial cells lining the placental uterine glands. GLUT-3 concentrations declined at 17–20 days of chronic hyperglycemia ( P < 0.05), associated with increased uterine and uteroplacental net glucose uptake rate, but a normal fetal glucose uptake rate was observed. Chronic hypoglycemia did not change GLUT-3 concentrations, although uterine, uteroplacental, and fetal net glucose uptake rates were decreased. Thus maternal hyperglycemia causes a time-dependent decline in the entire placental glucose transporter pool (GLUT-1 and GLUT-3). In contrast, maternal hypoglycemia decreases GLUT-1 but not GLUT-3, resulting in a relatively increased GLUT-3 contribution to the placental glucose transporter pool, which could maintain glucose delivery to the placenta relative to the fetus when maternal glucose is low.
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Overgaard, Maria Dahl, Christina Søndergaard Duvald, Mikkel Holm Vendelbo, Steen Bønløkke Pedersen, Steen Jakobsen, Aage Kristian Olsen Alstrup, Emmeli Mikkelsen, Per Glud Ovesen, and Michael Pedersen. "Biodistribution of [11C]-Metformin and mRNA Expression of Placentae Metformin Transporters in the Pregnant Chinchilla." Contrast Media & Molecular Imaging 2019 (April 30, 2019): 1–6. http://dx.doi.org/10.1155/2019/9787340.
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Background. While metformin is the first-line pharmacological treatment of diabetes mellitus type 2, this drug is not considered safe to use in pregnant women because of its unknown consequences for the fetus. In this study, we aimed to investigate the biodistribution of metformin in the pregnant chinchilla, a species exhibiting placental characteristics comparable with the pregnant woman. Furthermore, we aimed to investigate the expression of metformin transporters in humans and chinchillas, respectively, in order to evaluate the pregnant chinchilla as a novel animal model for the use of metformin in pregnancy. Methods. Three chinchillas in the last part of gestation were injected with [11C]-metformin and scanned by PET/CT for 70 minutes to visualize the distribution. To investigate the difference in expression of placenta transporters between humans and chinchillas, PCR was performed on samples from five chinchilla placentae and seven human placentae. Results. Dynamic PET with [11C]-metformin showed that the metformin distribution in chinchillas was similar to that in nonpregnant humans, with signal from kidneys, liver, bladder, and submandibular glands. Conversely, no radioactive signal was observed from the fetuses, and no metformin was accumulated in the chinchilla fetus when measuring the SUV. PCR of placental mRNA showed that the human placentae expressed OCT3, whereas the chinchilla placentae expressed OCT1. Conclusion. Since metformin did not pass the placenta barrier in the pregnant chinchilla, as it is known to do in humans, we do not suggest the chinchilla as a future animal model of metformin in pregnancies.
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Sayama, Seisuke, Anren Song, and Yang Xia. "Maternal Erythrocyte ENT1-Mediated AMPK Activation and Oxygen Delivery: A Missing Component Counteracting Placental Hypoxia, Dysfunction, and Fetal Growth Restriction." Blood 134, Supplement_1 (November 13, 2019): 341. http://dx.doi.org/10.1182/blood-2019-123053.
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Background: Insufficient oxygen supply is associated with the pathophysiology of fetal growth restriction (FGR). Although the erythrocyte (RBC) is the most abundant and only cell type to deliver oxygen, its function and regulatory mechanism in FGR remains unknown. Recently, adenosine uptake by equilibrative nucleoside transporter 1 (ENT1), a key adenosine transporter expressed in RBCs, was reported to be crucial for RBCs to deliver oxygen. We aimed to investigate the involvement of RBCs' oxygen delivering capacity in maintaining fetal growth by focusing on RBC ENT1. Methods and Results: The mating strategy was to delete ENT1 only on the maternal RBCs but not in the placentas or fetuses to assess the effect of maternal RBC ENT1 on fetal growth. Specifically, EpoR-Cre+ (EPO) female mouse was used as a control and Ent1f/f-EpoR-Cre+ (E1FE) female mouse as an experimental mouse and mated with WT male mouse. As a result, E1FE dams showed FGR phenotype with reduction of 12.9% in fetal weight compared to EPO group. The maternal RBCs showed decrease in p50 and 2,3-BPG in E1FE, indicating decreased oxygen delivery in E1FE RBCs. To determine the molecular basis underlying the FGR phenotype seen in EIFE dams, we conducted a metabolomics screening of the RBCs isolated from controls and EIFE dams. It showed that adenosine metabolism inside the RBCs is the most impacted pathway. Specifically, it showed decrease in adenosine, AMP, and hypoxanthine, but adenine, ADP, and ATP did not show any reduction, implicating that ENT1-mediated uptake of adenosine is largely converted to AMP. We then incubated either WT or ENT1 KO RBCs with isotopically 13C15N labeled adenosine and traced the metabolism of intracellular adenosine derived from labeled adenosine. Indeed, adenosine was rapidly phosphorylated to AMP upon uptake, and 13C15N labeled AMP levels were lower in the ENT1 KO RBCs compared to controls. These findings provide evidence that 1) the most affected metabolic pathway in the RBCs of EIFE dam is adenosine metabolism; 2) ENT1-mediated uptake of extracellular adenosine is largely converted to AMP but not ATP. We hypothesized that decreased AMP/ATP ratio underlies the reduced 2,3-BPG production by lowering AMPK activity and subsequently decreasing BPG mutase (BPGM) activity. We measured AMPK phosphorylation and BPGM activity in the RBCs from E1FE and EPO dams. Both AMPK and BPGM activity were decreased in RBCs of E1FE dams compared to controls. Thus, we conclude that i) adenosine derived from uptake via ENT1 is largely converted to AMP; ii) lack of maternal RBC ENT1 lowers AMP/ATP ratio and activity of AMPK and BPGM in maternal RBC. We conducted immunofluorescence staining to assess hypoxia in the placentas, and confirmed the increased expression of HIF-1α in the placentas from E1FE dams. To determine functional changes of these placentas, we conducted metabolomics profiling in both the placenta and maternal plasma. Of all the metabolites altered, amino acids (AA) were the most reduced metabolites in E1FE placentas. In contrast, AA were the most accumulated in maternal plasma. We then injected isotopically labelled 13C15N AA mix in both controls and EIFE dams 24 hours prior to sacrifice. 13C15N AA level was decreased in the placentas in EIFE compared to the controls, while it was accumulated in plasma of EIFE, indicating reduced AA transporter function in the placentas of EIFE. Finally, we performed real time PCR to quantify the mRNA of the known main transporters of AA in the mouse placenta. It showed reduction of LAT1 mRNA in E1FE placenta, where there was no difference in LAT2, SNAT1, or SNAT2. Western blot of the placenta lysates confirmed the expression of LAT1 was indeed reduced. To validate our mouse finding and determine if HIF-1α elevation directly induces LAT1 mRNA in humans, we treated cultured human trophoblast cell line (HTR-8/SVneo cells) with or without DMOG, a cell permeable prolyl-4-hydroxylase inhibitor. After confirming DMOG upregulated HIF-1α, we found stabilized HIF-1α induced LAT1 mRNA levels. Thus, we conclude that elevated HIF-1α underlies the reduction of LAT1 mRNA in cultured human trophoblasts. Conclusion: Our findings suggest that maternal RBCs' oxygen delivering capacity mediated by ENT1 is essential for maintaining adequate placental oxygenation to support fetal growth via AA transporter function. Strategies to improve RBCs' function to deliver oxygen may provide new therapeutic possibilities for FGR. Figure Disclosures No relevant conflicts of interest to declare.
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Vaughan, O. R., T. L. Powell, and T. Jansson. "Glucocorticoid regulation of amino acid transport in primary human trophoblast cells." Journal of Molecular Endocrinology 63, no. 4 (November 2019): 239–48. http://dx.doi.org/10.1530/jme-19-0183.
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Excess maternal glucocorticoids reduce placental amino acid transport and fetal growth, but whether these effects are mediated directly on the syncytiotrophoblast remains unknown. We hypothesised that glucocorticoids inhibit mechanistic target of rapamycin (mTOR) signaling and insulin-stimulated System A amino acid transport activity in primary human trophoblast (PHT) cells. Syncytialised PHTs, isolated from term placentas (n = 15), were treated with either cortisol (1 μM) or dexamethasone (1 μM), ± insulin (1 nM) for 24 h. Compared to vehicle, dexamethasone increased mRNA expression, but not protein abundance of the mTOR suppressor, regulated in development and DNA damage response 1 (REDD1). Dexamethasone enhanced insulin receptor abundance, activated mTOR complex 1 and 2 signaling and stimulated System A activity, measured by Na+-dependent 14C-methylaminoisobutyric acid uptake. Cortisol also activated mTORC1 without significantly altering insulin receptor or mTORC2 read-outs or System A activity. Both glucocorticoids downregulated expression of the glucocorticoid receptor and the System A transporter genes SLC38A1, SLC38A2 and SLC38A4, without altering SNAT1 or SNAT4 protein abundance. Neither cortisol nor dexamethasone affected System L amino acid transport. Insulin further enhanced mTOR and System A activity, irrespective of glucocorticoid treatment and despite downregulating its own receptor. Contrary to our hypothesis, glucocorticoids do not inhibit mTOR signaling or cause insulin resistance in cultured PHT cells. We speculate that glucocorticoids stimulate System A activity in PHT cells by activating mTOR signaling, which regulates amino acid transporters post-translationally. We conclude that downregulation of placental nutrient transport in vivo following excess maternal glucocorticoids is not mediated by a direct effect on the placenta.
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Jones, H. N., C. J. Ashworth, K. R. Page, and H. J. McArdle. "Expression and adaptive regulation of amino acid transport system A in a placental cell line under amino acid restriction." Reproduction 131, no. 5 (May 2006): 951–60. http://dx.doi.org/10.1530/rep.1.00808.
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Trans-placental transport of amino acids is vital for the developing fetus. Using the BeWo cell line as a placental model, we investigated the effect of restricting amino acid availability on amino acid transport system type A. BeWo cells were cultured either in amino acid-depleted (without non-essential amino acids) or control media for 1, 3, 5 or 6 h. System A function was analysed using α(methyl-amino)isobutyric acid (MeAIB) transcellular transport studies. Transporter (sodium coupled neutral amino acid transporter (SNAT1/2)) expression was analysed at mRNA and protein level by Northern and Western blotting respectively. Localisation was carried out using immunocytochemistry. MeAIB transcellular transport was significantly (P< 0.05) increased by incubation of the cells in amino acid-depleted medium for 1 h, and longer incubation times caused further increases in the rate of transfer. However, the initial response was not accompanied by an increase in SNAT2 mRNA; this occurred only after 3 h and further increased for the rest of the 6-h incubation. Similarly, it took several hours for a significant increase in SNAT2 protein expression. In contrast, relocalisation of existing SNAT2 transporters occurred within 30 min of amino acid restriction and continued throughout the 6-h incubation. When the cells were incubated in medium with even lower amino acid levels (without non-essential plus 0.5 × essential amino acids), SNAT2 mRNA levels showed further significant (P< 0.0001) up-regulation. However, incubation of cells in depleted medium for 6 h caused a significant (P= 0.014) decrease in the expression of SNAT1 mRNA. System L type amino acid transporter 2 (LAT2) expression was not changed by amino acid restriction, indicating that the responses seen in the system A transporters were not a general cell response. These data have shown that placental cells adaptin vitroto nutritional stress and have identified the physiological, biochemical and genomic mechanisms involved.
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Ellery, Stacey J., Padma Murthi, Miranda L. Davies-Tuck, Paul A. Della Gatta, Anthony K. May, Greg M. Kowalski, Damien L. Callahan, et al. "Placental creatine metabolism in cases of placental insufficiency and reduced fetal growth." Molecular Human Reproduction 25, no. 8 (July 19, 2019): 495–505. http://dx.doi.org/10.1093/molehr/gaz039.
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Abstract Creatine is a metabolite involved in cellular energy homeostasis. In this study, we examined placental creatine content, and expression of the enzymes required for creatine synthesis, transport and the creatine kinase reaction, in pregnancies complicated by low birthweight. We studied first trimester chorionic villus biopsies (CVBs) of small for gestational age (SGA) and appropriately grown infants (AGA), along with third trimester placental samples from fetal growth restricted (FGR) and healthy gestation-matched controls. Placental creatine and creatine precursor (guanidinoacetate—GAA) levels were measured. Maternal and cord serum from control and FGR pregnancies were also analyzed for creatine concentration. mRNA expression of the creatine transporter (SLC6A8); synthesizing enzymes arginine:glycine aminotransferase (GATM) and guanidinoacetate methyltransferase (GAMT); mitochondrial (mtCK) and cytosolic (BBCK) creatine kinases; and amino acid transporters (SLC7A1 & SLC7A2) was assessed in both CVBs and placental samples. Protein levels of AGAT (arginine:glycine aminotransferase), GAMT, mtCK and BBCK were also measured in placental samples. Key findings; total creatine content of the third trimester FGR placentae was 43% higher than controls. The increased creatine content of placental tissue was not reflected in maternal or fetal serum from FGR pregnancies. Tissue concentrations of GAA were lower in the third trimester FGR placentae compared to controls, with lower GATM and GAMT mRNA expression also observed. No differences in the mRNA expression of GATM, GAMT or SLC6A8 were observed between CVBs from SGA and AGA pregnancies. These results suggest placental creatine metabolism in FGR pregnancies is altered in late gestation. The relevance of these changes on placental bioenergetics should be the focus of future investigations.
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Jansson, T., EA Cowley, and NP Illsley. "Cellular localization of glucose transporter messenger RNA in human placenta." Reproduction, Fertility and Development 7, no. 6 (1995): 1425. http://dx.doi.org/10.1071/rd9951425.
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High levels of expression of the glucose transporter (GLUT) isoforms 1 and 3 have been demonstrated in the human placenta by Northern blotting. However, the cellular localization of placental GLUT mRNA has not been described. Furthermore, recent preliminary kinetic data indicate that GLUT 2 might be present in syncytiotrophoblast. Human placental tissue from preterm (16-22 weeks) and term pregnancies was collected for identification and localization of glucose transporter mRNA. Following paraffin embedding, sections were cut and in situ hybridization was performed with fluorescein-labelled cRNA. In addition, immunoblotting and immunocytochemistry were carried out using an anti-GLUT 2 antibody. GLUT 1 mRNA was highly expressed in syncytiotrophoblast cells at term. GLUT 1 expression was much less abundant in non-syncytial cells. In contrast, GLUT 3 mRNA was present in lower amounts and more evenly distributed between syncytial and other placental cells. GLUT 1 mRNA was also highly abundant in preterm syncytiotrophoblast. The cellular distributions of GLUT 1 and GLUT 3 mRNA in the preterm placentas were similar to those in term tissue. With regard to GLUT 1, these findings correlate well with cellular localization and gestational development of GLUT 1 protein. No GLUT 2 protein was detected. It is concluded that GLUT 1 is the main isoform involved in transplacental glucose transport in the human.