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Original Studies |
Institute of Histology and Embryology (T.H., G.Do.) and the Institute of Hygiene (S.B.), University of Graz, A-8010 Graz, Austria; the Department of Obstetrics and Gynecology, University of Graz Medical School (T.H., G.De.), A-8036 Graz, Austria; the Institute of Anatomy, Free University of Berlin (R.G.), D-14195 Berlin, Germany; Max Planck Institute of Psychiatry (M.E., J.M.R., F.H.), D-80804 Munich, Germany; and the Department of Medicine, University of Queensland, Royal Brisbane Hospital (D.B.), Herston, Queensland 4029, Australia
Address all correspondence and requests for reprints to: Dr. Tom Hahn, Institute of Histology and Embryology, University of Graz, Harrachgasse 21, A-8010 Graz, Austria. E-mail: tom.hahn{at}kfunigraz.ac.at
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Humoral or endocrine factors regulating transplacental glucose transfer, in addition to the maternal to fetal concentration gradient, are largely unknown. Despite the presence of insulin receptors, placental glucose transport and metabolism are insulin independent (6, 7). Glucose itself can up- or down-regulate placental GLUT1 (8, 9). Glucocorticoids (GC) specifically inhibit glucose transport in a variety of peripheral tissues, such as skeletal muscle, adipocytes, and endothelial cells (10, 11, 12, 13, 14, 15). High affinity, low capacity GC receptors (GR) have been identified in the placenta of various species, including man, rat, and mouse (16, 17, 18, 19, 20). Thus, it is reasonable to hypothesize that GCs can regulate glucose transporter expression in the placenta similar to that in the aforementioned tissues. This would have important clinical implications, because GC-induced down-regulation of the placental glucose transport system(s) may contribute to the genesis of the deleterious side-effects of GC treatment during pregnancy, such as the higher incidence of growth-retarded fetuses (21, 22, 23, 24).
Therefore, in a first step the present study addressed the question of whether GCs affect placental glucose transporter expression in human and rodent placentas. The synthetic GC triamcinolone-acetonide (TA), which specifically binds to GR in placental cytosol (16), was administered to cultured human trophoblast cells and pregnant rats instead of dexamethasone, which is also commonly used for experimental studies on GC action because the latter binds with lower affinity to placental GR, if at all (25). Moreover, dexamethasone is a poor substrate for the important prereceptor signaling factor 11ß-hydroxysteroid dehydrogenase-2 (26, 27), the enzyme that regulates locally active GC concentrations by converting GC to inactive products (22, 28, 29). In addition, glucose transporter expression was investigated in placentas of transgenic mice bearing an antisense GR gene construct.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mononucleated trophoblast cells were isolated from 15 term human placentas after uncomplicated pregnancy and vaginal delivery as described in detail previously (6). Briefly, villous material was digested with a 0.125% trypsin solution (Life Technologies, Paisley, UK), and the released cells were loaded on top of a Percoll (Pharmacia Biotech, Uppsala, Sweden) gradient ranging from 10–70%. After centrifugation, the band containing trophoblast cells was removed. After extensive washings, the trophoblast cells were highly purified using immunomagnetic particles (Dynabeads M-280, Dynal, Hamburg, Germany), which had been conjugated with the monoclonal antibody W6/32 (Serotec, Kidlington, UK) against human leukocyte antigen (HLA) class I. In the human placenta this antibody reacts only with stromal cells, macrophages, endothelium, and extravillous trophoblast. It does not identify villous trophoblast, which is devoid of HLA class I antigens (30).
Trophoblast cells were plated at a density of 500 cells/mm2 into Falcon culture flasks (Becton Dickinson and Co., Heidelberg, Germany). The cells were cultured in DMEM (Life Technologies) supplemented with 15% defined FBS (HyClone Laboratories, Inc., Logan, UT), 100 µg/mL streptomycin (Life Technologies), 100 IU/mL penicillin (Life Technologies), and 100 µg/mL Amphotericin (Life Technologies) at 37°C in a humidified atmosphere of 5% CO2-air. Trophoblast cells were allowed to recover from the trypsinization for 24 h before starting the experiments. After this period (time zero) the cells were cultured in the presence or absence (controls) of 0.5, 5, and 50 µmol/L of the synthetic GC TA (Volon A 40, Squibb-von Heiden, Munich, Germany) for another 24 h, as TA binding to placental cytosol peaks after 20 h of incubation in vitro (16). Moreover, in pilot experiments carried out at 12, 24, and 36 h, the maximum response was found after 24 h, with no additional increase in response thereafter. Media were changed after 24 h in culture and were stored at -40°C for further analysis together with those collected at the end of the 24-h TA incubation period, i.e. 48 h after isolation.
Cell characterization
The viability of the trophoblast cells was assessed after 24 and 48 h in culture by 1) 0.05% trypan blue (JRH Biosciences, Crawley Down, UK) dye exclusion during a 2-min incubation, and 2) measuring the concentrations of ß-hCG (OPUS sandwich immunoassay, Behring Diagnostics, Inc., Westwood, MA) secreted into the culture media.
Immunohistochemistry at the light microscopic level was performed immediately after isolation and, in addition, after 48 h in culture. Cells were fixed in acetone (5 min at -20°C) and incubated with the following monoclonal antibodies: anticytokeratin clone NCL5D3 (1:50; Monosan, Uden, The Netherlands) for identification of trophoblast cells (31), and W6/32 (1:10) and anti-CD68 (1:50; Monosan) for monocyte and macrophage identification. Fluorescein isothiocyanate-conjugated Ulex europeaeus lectin (1:10; Sigma Chemical Co.) was employed for the identification of endothelial cells (32). Immunoreactivity was visualized using a fluorescein isothiocyanate-conjugated goat antimouse secondary antibody (1:20; Dianova, Hamburg, Germany).
Rat placenta
Animal studies were conducted in accord with the principles and procedures outlined by The Endocrine Society. White Wistar rats were kept under a 12-h light, 12-h dark cycle (lights on, 0600–1800 h) under standardized conditions (22 C; constant humidity, 60 ± 5%) with free access to Altromin standard diet (Altromin, Lage-Lippe, Germany) and tap water. They were mated between 0800–1000 h, and impregnated females were identified by the presence of copulatory plugs; this day was designated gestational day 1. Rats (n = 6) were injected ip with a single dose of 0.38 mg/kg BW TA (Squibb-von Heyden) dissolved in a 0.9% NaCl solution on gestational day 16. The control animals were injected with 0.9% NaCl solution only. Serum glucose levels and maternal body weights were determined each day between gestational days 16–21. The animals were killed on gestational day 21 under deep ether anesthesia, and fetuses and placentas were removed. Total placental tissue was cut out for further analysis. The weights of the fetuses and placentas and the number of implantations were recorded. The total length of gestation in the rat is 22 days. Gestational days 16–21 cover the period when maturation of the rat fetal adrenal normally occurs (33).
Mouse placenta
Animal studies were conducted in accord with the principles and procedures outlined by The Endocrine Society. B6C/3F1 mice were bred and reared under a 12-h light, 12-h dark cycle (lights on, 0700–1900 h) under standardized conditions (22°C; constant humidity, 60 ± 5%) with free access to Altromin standard diet (Altromin) and tap water. In transgenic animals (line 1.3) (40) type II GR gene expression was partially knocked out by formation of GR antisense ribonucleic acid (RNA) complementary to the 3'-noncoding region of the GR messenger RNA (mRNA), leading to reduced GR production, capacity, and function (34, 35). Placentas were obtained on gestational day 17 after sacrificing normal and transgenic mice (n = 5) under deep ether anesthesia. Total placental tissue was cut out for further analysis. The total length of gestation in mice is 20 days. The weights of newborn 1-day-old mice were recorded.
Electron microscopy of cultured trophoblast cells
The cells were washed with phosphate-buffered saline (PBS) and fixed for 10 min in cold (-20 C) methanol. The fixative was replaced after 10 s. The cells were washed three times for 5 min each time with PBS and then postfixed with 2% glutaraldehyde (Fluka Chemie, Buchs, Switzerland) in PBS for 30 min at room temperature. Subsequently, they were treated with 2% osmium tetroxide in cacodylate buffer at room temperature for 20 min. The cells were washed with cacodylate buffer (three times, 10 min each time) and subsequently with distilled water for 10 min. Samples were dehydrated in 70% ethanol, which was replaced three times after each 15 min. Afterward they were contrasted with 0.5% uranyl acetate in 1% phosphorotungsten acid and 70% ethanol for 30 min and further dehydrated in 80%, 90%, and (twice) 100% ethanol for each 15 min. The samples were embedded in resin (TAAB Laboratories Equipment Ltd., Aldermaston, UK) after preinfiltration with a terpineol-resin mixture (1:1 and 1:3, respectively, for each 15 min). Ultrathin (50 nm) sections were examined with a Zeiss 902 electron microscope (Carl Zeiss, Inc., New York, NY) at an accelerating voltage of 80 kilovolts.
Immunohistochemistry of placenta samples
Acetone-fixed cryostat sections (8 µm) of term human, rat, and mouse placental tissue were immunolabeled for 30 min at room temperature using polyclonal antisera against a 21-amino acid peptide of the GLUT1 carboxyl-terminus, a 31-amino acid peptide of the human GLUT3 carboxyl-terminus [both were provided by Dr. S. W. Cushman, NIH (Bethesda, MD), and Hoffmann-La Roche (Nutley, NJ)] and a 12-amino acid peptide of the mouse GLUT3 carboxyl-terminus (Chemicon, Temecula, CA), respectively, each diluted 1:500 in PBS. After three washings in PBS for 5 min each, sections were incubated for 30 min with goat antirabbit IgG conjugated with horseradish-peroxidase (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA; dilution, 1:100). Again, the sections were washed three times in PBS for 5 min each time, and then immunolabeling was visualized by exposing the sections to 3-amino-9-ethylcarbazole (Sigma Chemical Co.)-dimethylformamide (0.4 mg/mL) solution for 3 min in the dark. The sections were counterstained with hemalum. Control sections were incubated using antisera preadsorbed with 10 µg/mL of the corresponding peptide (Pichem, Graz, Austria) used for immunization of the antibody-generating rabbits.
Northern blotting
Total RNA from rat and mice placental labyrinth as well as from cultured human trophoblast cells was isolated using the RNeasy Mini Kit (Qiagen, Santa Clarita, CA). The quantity and purity of RNA were determined by absorbance readings at 260 and 280 nm.
For Northern blot analysis, 20 µg total RNA were denatured in 6%
formaldehyde and size-fractionated by electrophoresis on 1%
agarose-2.2 mol/L formaldehyde gels. The integrity and relative amounts
of the RNA were assessed by UV visualization of the ribosomal RNA.
Total RNA was then transferred to nylon membranes (Hybond
N+, Amersham, Aylesbury, UK) by capillary
blotting and fixed by UV cross-linking (Stratagene,
Cambridge, UK). The filters were hybridized with random primed
[
-32P]deoxy-CTP
(Amersham)-labeled, near full-length human GLUT1 and GLUT3
complementary DNA probes (American Type Culture Collection, Manassas, VA) under high stringency conditions in
solutions containing 0.15 mol/L sodium phosphate, 1 mmol/L
ethylenediamine tetraacetate, 7% SDS, and 1% BSA at 65°C. The
hybridized filters were then washed twice in 2 x SSC (standard
saline citrate)-0.1% SDS at room temperature and once in 1 x
SSC-0.1% SDS at 65°C and autoradiographed with Hyperfilm
(Amersham) at -70 C. Exposure times were adjusted to lie
within the linear range of the films. The autoradiograms were scanned
with a Hirschmann Elscript 400 laser densitometer and quantified using
Elscript software (Hirschmann, Munich, Germany).
To correct for transfer efficiency, the filters were stripped by washing twice at 100 C in 1 x Tris-ethylenediamine tetraacetate-0.1% SDS and then rehybridized with a human glyceraldehyde-3-phosphate dehydrogenase complementary DNA probe (Clontech, Palo Alto, CA). Densitometer readings of the GLUT1 and GLUT3 autoradiograms were normalized with the respective glyceraldehyde-3-phosphate dehydrogenase values, which were unaffected by GC exposure.
SDS-PAGE and Western blotting
Cellular proteins from rat and mice placental labyrinth as well as from cultured human trophoblast cells were solubilized in Laemmli sample buffer (Sigma Chemical Co.) supplemented with Complete protease inhibitor cocktail (Boehringer Mannheim, Mannheim, Germany). Insoluble material was removed by centrifugation at 100,000 x g for 1 h at 4 C. Samples were either used immediately or stored for up to 10 days at -70 C. Before electrophoresis, samples were boiled for 3 min at 100 C.
Equal amounts of protein, determined according to the method of Lowry et al. (36), were subjected to SDS-PAGE on 8–18% gradient gels (ExcelGel, Pharmacia Biotech) using SDS buffer strips (ExcelGel, Pharmacia Biotech). Samples were run for 150 min at a constant 600 volts, 50 mA, and 30 watts. Proteins were transferred onto nitrocellulose membranes (Pharmacia Biotech) by semidry electroblotting in a buffer containing 0.2 mol/L glycine, 25 mmol/L Tris, and 20% methanol for 45 min at 30 volts, 100 mA, and 6 watts. Successful transfer was confirmed by Ponceau S (Sigma Chemical Co.) staining of the blots.
The membranes were blocked for 12 h with 5% nonfat dry milk (Bio-Rad Laboratories, Inc., Hercules, CA) and 0.1% Tween-20 (Sigma Chemical Co.) in 0.14 mol/L Tris-buffered saline, pH 7.2–7.4, at 4 C. The same solution was used for subsequent washings and as diluent for the antibodies. The blotting membranes were incubated for 1 h at room temperature with rabbit antisera against GLUT1 and GLUT3, as listed in the immunocytochemistry section above (dilutions: GLUT1, 1:10,000; GLUT3, 1:3,000), or against the GR (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) diluted 1:500 for the detection of mouse placental GC binding sites, respectively. After washing, the membranes were further incubated with goat antirabbit IgG horseradish peroxidase conjugate (Bio-Rad Laboratories, Inc.) diluted 1:10,000 (GLUT1), 1:5,000 (GLUT3), or 1:1,000 (GR) for 1 h at room temperature. After three washings in Tris-buffered saline, pH 7.2–7.4, the immunolabeling was visualized using the chemiluminescence-based SuperSignal CL-HRP Substrate System (Pierce Chemical Co., Rockford, IL) according to the instructions of the manufacturer. Membranes were exposed to Hyperfilm (Amersham), which was subsequently scanned using a Hirschmann Elscript 400 laser densitometer and quantified with Elscript software (Hirschmann). In pilot experiments, the linear range of the densitometer and software was determined.
Control blots were incubated with antisera preadsorbed with the corresponding oligo-peptide sequences (10 µg/mL; Pichem) used for the immunization of the antibody-generating rabbits.
Statistics
Except for weans and placental weights of mice (presented as the mean ± SD), experimental data were not normally distributed (Kolmogoroff-Smirnov test) and thus are presented as the median with the range. Statistical analysis was performed using two-way ANOVA, followed by Tukey’s highest significant difference (HSD) test, one-way nonparametric ANOVA (Kruskal-Wallis or Friedmann procedure), followed by the Mann-Whitney U test and Wilcoxon signed rank test, respectively, if appropriate. P < 0.05 was chosen to identify significant differences.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In human term placental villi, the strongest GLUT1
immunoreactivity was found in the microvillous syncytiotrophoblast
membrane. Labeling was also detected in the villous trophoblast cells
and in the endothelium of fetal vessels (not shown). GLUT3 staining was
found in endothelial cells (Fig. 1
), but
could not be detected in the human trophoblast.
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and 3). In general, cytotrophoblast cells
in the rodents were rather weakly stained compared with all other cell
populations of the placental labyrinth.
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The viability of the cells was more than 90% by trypan blue exclusion. The immunohistochemical reaction pattern of the mononucleated trophoblast cell preparations revealed approximately 85% reactivity with the cytokeratin antibody immediately after isolation, and 90–95% were stained after 48 h in culture. Ten percent of the freshly prepared cells reacted with W6/32 against HLA, and this level was reduced to about 5% 48 h later. Anti-CD68 for monocyte and macrophage labeled 5% of the cells after isolation and less than 5% after 48 h. Less than 1% of the cells were stained with the endothelial cell marker Ulex europeaeus lectin.
The cells had an intact plasma membrane, showed an internal architecture characteristic of trophoblast cells, and had a microvillous membrane on one side (not shown). They appeared as populations forming aggregates in culture and did not fuse to multinucleated syncytia even after 48 h.
TA administration resulted in a marked dose-dependent increase in
hCGß levels released into the medium during the 24- to 48-h culture
period (Fig. 4).
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Serum glucose levels in rats fed ad libitum were
elevated only on days 1 and 2 after TA administration and even
decreased into the hypoglycemic range during the following period of
gestation in the TA-treated rats (Fig. 5).
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GC effects on placenta weight and fetal/weanling body weight of rats and mice
On gestational day 21 in TA-treated rats, placental and fetal
weights were lower by 53% and 37%, respectively (P <
0.05, by Mann-Whitney U test) than in the control animals (Table 1).
The total number of implantations was unaffected by TA application. The
placental weight of transgenic mice was reduced by 28%
(P < 0.05, by Mann-Whitney U test), and 1-day-old
neonates of mice bearing an antisense GR gene construct were lighter by
20% (P < 0.05, by Mann-Whitney U test) than controls
(Table 1).
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Type II GR protein levels in the placenta were decreased, on the
average, by 28 ± 5.6% (mean ± SD;
P < 0.05, by Mann-Whitney U test) in mice carrying a
gene construct that impairs the efficient expression of the
respective gene (Fig. 6).
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The measured effects expressed relative to the controls
(P < 0.05, by Mann-Whitney U test) are summarized in
Table 2. GLUT1 mRNA and protein were
down-regulated in cultured human placental trophoblast cells and in rat
placenta after TA administration as well as after knocking down the
GR gene expression in the placentas of mice (Figs. 7 and 8).
In cultured trophoblast cells, this suppressive effect was clearly dose
dependent (Figs. 9 and 10).
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). However, GLUT3 protein levels were decreased
by TA in a dose-dependent manner, similarly to GLUT1 protein but much
less pronounced. Only 50 µmol/L TA produced a significant
(P < 0.05, by Mann-Whitney U test) effect (Fig. 10).
In the rat placenta, GC treatment resulted in reduced GLUT3 mRNA and
protein levels (Figs. 7 and 8). In contrast, when GR levels were
down-regulated, the amounts of GLUT3 transcript and protein increased
in the mouse placentas (Figs. 7 and 8). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study, the high affinity glucose transporter isoforms GLUT1 and GLUT3 were expressed in cellular placental barriers fronting to the fetal and maternal circulation (endothelium and trophoblast, respectively). Due to their locations, both cell populations play a pivotal role in transplacental glucose transport in the villous-type hemomonochorial human placenta as well as in the labyrinthine hemotrichorial placenta of rat and mouse. The results are in good keeping with previous data on the distribution of GLUT1 in the human, rat, and mouse placenta (40; for review, see Ref. 41). The absence of an immunohistochemical GLUT3 signal in the human trophoblast (42), but its unambiguous identification in this tissue by Northern and Western blotting suggest that GLUT3 density in the trophoblast is below the sensitivity of the immunohistochemical detection method. This is supported by results reported by Jansson et al. (43), who also found a faint GLUT3 band in syncytiotrophoblast membranes by immunoblotting, but the absence of a GLUT3 signal in immunohistochemistry.
Human term placental trophoblast cells have been frequently used to study the hormonal regulation of placental protein and gene expression (44, 45). The cell preparations in the present investigation have been extensively characterized and validated. The results suggest that the cells in culture were viable and highly purified trophoblast cells. The GC-induced increase in hCGß secretion, the major endocrine product of placental trophoblast, confirms data reported previously (44) and might reflect the transcriptional activation of the hCGß gene by GC. A GC-induced stimulation of differentiation of the cultured cells is unlikely, because of the absence of trophoblast cell fusion under the conditions used in this study.
Maternal GC circulate at concentrations 5–10 times higher than those in the fetus (22), and the fetus is not capable of synthesizing its own GC until relatively late in gestation (33, 46). Physiological cortisol levels in maternal plasma during human pregnancy are in the range of 1 µmol/L (47). The highest TA dose administered to the trophoblast cell cultures in the present study corresponds to the TA concentration in blood resulting after iv injection of a dose recommended by the manufacturers for therapy in humans. The TA dose injected ip to the rats is at least 4-fold less than this iv dose.
Both GLUT1 and GLUT3 transcripts and protein were significantly down-regulated in isolated human trophoblast cells and in rat placentas by GCs, suggesting regulation at the transcriptional level. To the best of our knowledge, this is the first report of a GC effect on GLUT3 expression. In the few studies addressing GC action on GLUT1 expression, decreased mRNA and protein were also found in 3T3-F442A adipose cells and rat adipocytes (12, 13), where GLUT1 is coexpressed with GLUT4. Further indirect evidence that the GC-induced inhibition of glucose transport might be due to a down-regulation of GLUT protein is provided by kinetic studies in nonplacental tissues, in which the maximum velocity of glucose transfer was decreased after GC exposure, whereas the Km was unchanged (48, 49). The theoretical possibility of a GC-induced conformational change in GLUT with resulting reduced affinity is, therefore, rather unlikely. Moreover, TA does not change the integrity of cellular membranes (49), which could have altered glucose transport rates independent of the total amount of GLUTs present in the membrane (50, 51). However, we cannot rule out other GC-mediated mechanisms as potential suppressors of placental glucose transport, e.g. translocation/redistribution of transporters from the plasma membrane to an internal location such as in human foreskin fibroblasts (52), or the induction of specific proteins, which may decrease either the number of functional transporters or their intrinsic activity (48).
Hyperglycemia is one of the well known systemic effects following GC treatment. Thus, elevated glucose concentrations might have affected placental GLUT expression (9). However, in the rat model, a single injection of TA resulted in only short term hyperglycemia, followed by hypoglycemia. This hypoglycemia may be the reason for the smaller fetuses and placentas as well as for the markedly reduced weight gain of TA-treated rats during gestational days 16 and 21. The GC-induced (relative) weight loss in rodents is not without precedent (26, 53) and has been attributed to decreased food intake (54). Transgenic mice carrying the GR antisense construct also eat less, have lower serum glucose levels (35), and have growth-retarded fetuses and placentae compared with the controls. In the light of these facts, altered nutritional glucose consumption is unlikely to have caused the down-regulation of GLUTs, especially because glucose deprivation usually causes up-regulation of GLUTs in noninsulin-responsive tissues such as the placenta (8, 55). Moreover, the human trophoblast cells were cultured under physiological glucose concentrations, yet their GLUTs were down-regulated similar to those in TA-treated rats.
As GC usually down-regulate the GR in several tissues, including rat and mouse placentas (53, 56, 57), we used a transgenic mouse model to investigate whether genetically induced GR dysfunction per se might produce changes in GLUT expression that resemble the effects of GC exposure. This mouse model has already proven useful in studying the effects of GR deficiency on energy balance (35) and hypothalamic-pituitary-adrenal axis regulation (58). In various tissues of the transgenic animals, GR mRNA and GC-binding sites are reduced by 30–70% and 20–50%, respectively (34). Our results confirm that the transgenic mice also carry a transgene in the placenta that interferes with the expression of the endogenous gene for the type II GR. Reduced placental GR expression was accompanied by a decrease in GLUT1 but an increase in GLUT3 levels. Obviously, in the mouse placenta, both transporters are divergently regulated via the GR. Up-regulated placental GLUT3 may be unable to compensate for insufficient GLUT1 function, because the newborn weanlings of these mice have reduced weight. In parallel to the impaired GR production, capacity, and function (34, 35), the transgenic mice fail to suppress the hypothalamic-pituitary-adrenal axis (34), resulting in elevated levels of the endogenous GC corticosterone (34). Therefore, the data from the mouse model further strengthen the hypothesis that increased GC levels specifically modulate GLUT expression via the GR. Changes in gene transcription might occur through negative and positive GC response elements identified in the GLUT promoter regions (29, 59, 60).
Collectively, we conclude that the synthetic GC triamcinolone is a potent regulator of human and rodent placental GLUT1 and GLUT3 expression. This effect is mediated by the GR. We speculate that GC-induced down-regulation of the placental glucose transporter systems contributes to the retarded fetal and placental growth observed with GC treatment. This would represent a pathogenetic mechanism different from that leading to intrauterine growth retardation in the absence of GC treatment, in which trophoblast GLUT1 is not altered (43). However, it is difficult to determine the cause and effect relationships, and the growth restriction could occurred first, followed by an appropriate down-regulation of the transporters so as to match fetal size.
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Acknowledgments |
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Footnotes |
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Received June 11, 1998.
Revised November 5, 1998.
Accepted November 25, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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5-4 isomerase in the rat
adrenal as revealed by immunocytochemistry and in situ
hybridization. Endocrinology. 129:2687–2692.This article has been cited by other articles:
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 D. Hahn, A. Blaschitz, E.T. Korgun, I. Lang, G. Desoye, G. Skofitsch, and G. Dohr From maternal glucose to fetal glycogen: expression of key regulators in the human placenta Mol. Hum. Reprod., December 1, 2001; 7(12): 1173 - 1178. [Abstract] [Full Text] [PDF]
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 E. Turkay Korgun, R. Demir, A. Hammer, G. Dohr, G. Desoye, G. Skofitsch, and T. Hahn Glucose Transporter Expression in Rat Embryo and Uterus During Decidualization, Implantation, and Early Postimplantation Biol Reprod, November 1, 2001; 65(5): 1364 - 1370. [Abstract] [Full Text] [PDF]
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P. D. Gluckman Editorial: Nutrition, Glucocorticoids, Birth Size, and Adult Disease Endocrinology, May 1, 2001; 142(5): 1689 - 1691. [Full Text]
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