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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 11 4367-4372
Copyright © 2000 by The Endocrine Society

Original Studies

Expression of Na+/I- Symporter and Pendred Syndrome Genes in Trophoblast Cells1

Jean-Michel Bidart, Ludovic Lacroix, Danielle Evain-Brion, Bernard Caillou, Vladimir Lazar, René Frydman, Dominique Bellet, Sebastiano Filetti and Martin Schlumberger

Departments of Clinical Biology (J.M.B., L.L., V.L., D.B.), Pathology (B.C.), and Nuclear Medicine (M.S.), Institut Gustave-Roussy, 94805 Villejuif, France; INSERM U-427 (D.E.-B.), Laboratoire d’Immunologie des Tumeurs, ESA 8067, Centre National de la Recherche Scientifique (J.M.B., D.B.), Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, 75006 Paris, France; Service de Gynécologie Obstétrique, Hôpital Antoine Béclère (R.F.), 92141 Clamart, France; and Dipartimento di Medicina Sperimentale e Clinica, Policlinico Mater Domini (S.F.), 88100 Catanzaro, Italy

Address all correspondence and requests for reprints to: Dr. J. M. Bidart, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France. E-mail: bidart{at}igr.fr


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Placental iodide transport is critical for the fetal thyroid function, but the molecular mechanisms of this transport are not understood. The expression of two recently identified iodide transporters, namely the sodium/iodide symporter (NIS) and pendrin, the product of the gene responsible for the Pendred syndrome (PDS), was studied using real-time kinetic quantitative PCR and immunohistochemistry 1) in placental tissues collected at different gestational ages and 2) in primary cultures of villous cytotrophoblast cells (VCT) that differentiate and fuse over 2–3 days in vitro to form villous syncytiotrophoblast (VSCT) cells.

Both NIS and PDS genes are expressed in placenta, albeit at low levels compared with those in thyroid tissue. NIS gene expression in placental samples from first trimester and term pregnancies was similar. In contrast, the expression of PDS gene was higher in term than in first trimester pregnancy samples. In vitro, NIS gene was expressed at a high level in VCT obtained from first trimester pregnancy, and its expression decreased by 3- to 4-fold during the differentiation of VCT in VSCT. Expression of NIS was lower (up to 30-fold) in VCT obtained in placental samples from third trimester than from first trimester pregnancy. In contrast, the expression of PDS gene was low in VCT and increased by 5- to 10-fold during VSCT formation; this was observed in cells isolated from placental samples of both first trimester and term pregnancies. Immunohistochemical analysis showed that NIS protein was present on the entire membrane of VCT, whereas pendrin was mainly located at the brush border membrane of VSCT, facing the mother. In conclusion, 1) NIS and PDS genes are differently expressed in the placenta during gestation; and 2) whereas pendrin is expressed at the brush border membrane of syncytiotrophoblast cells, NIS protein is mainly located in the cytotrophoblast layer.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
BY 10–13 WEEKS gestation the fetal thyroid develops the characteristic colloid follicular structure, and by about the 12–13th week it becomes able to accumulate iodide and to synthesize thyroid hormones (1). Iodide available for the fetal thyroid gland results from circulating maternal iodide and deiodination of iodothyronines within the placenta (2). The placenta assumes the passage of iodide and iodothyronines from mother to fetus (1, 2, 3). Indeed, the multinucleated villous syncytiotrophoblast (VSCT), which is formed by fusion of the underlying layer of villous cytotrophoblast cells (VCT), is in contact with maternal blood (4). Syncytiotrophoblast (SCT) cells constitute the active endocrine unit of the placenta, secreting hormones such as hCG and human placental lactogen into the maternal circulation, and control the transport of nutriments, including peptides and ions (5). Although several physiological and pharmacological studies documented ion efflux and influx through the placenta (6), the molecular mechanisms of iodide transport from mother to fetus remain unknown (2).

In contrast, significant progress has been accomplished in understanding the transcellular transport of iodide from the basolateral to the apical membrane of the thyrocyte (7, 8). The sodium/iodide symporter (NIS), a transmembrane glycoprotein located at the basolateral pole, is responsible for iodide uptake from blood by an active, energy-dependent process (9, 10). Pendrin, the product of the gene responsible for Pendred syndrome (PDS), an autosomal recessive disease characterized by goiter and congenital sensorineural deafness, was recently identified in the thyroid gland; it was localized by immunohistochemistry at the apical pole of the thyrocyte and was shown in vitro to act as a transporter of chloride and iodide (11, 12, 13, 14, 15).

In the present study we examine whether these two iodide transporters are expressed in trophoblast cells. By using real-time kinetic quantitative RT-PCR, we analyzed both NIS and PDS gene expression in placental tissues collected at different gestational ages as well as in primary culture of cytotrophoblast cells that differentiate and fuse over 2–3 days in vitro to form syncytiotrophoblast cells. By immunohistochemistry we analyze the localization of the products of these two genes in the villous tissue. Our results showed that 1) NIS and PDS genes are differently expressed during gestation; and 2) whereas pendrin immunostained the brush border membrane of syncytiotrophoblast cells, NIS protein is mainly located in the membrane of cytotrophoblast cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissue samples

First trimester placental tissues were obtained from the Service de Gynécologie Obstétrique at the Hôpital Antoine-Béclère from voluntary pregnancy terminations. Term placental tissues were obtained at the time of cesarean sections. All tissues were obtained in accordance with protocols approved previously by the local human studies committee. Placental samples were used for cytotrophoblast cell isolation as described below. They were immediately frozen in liquid nitrogen and stored at -80 C for preparation of messenger ribonucleic acid (mRNA) and for immunohistochemical studies. Three samples of normal thyroid tissue, obtained from the tissue bank at Institut Gustave-Roussy, were pooled and used as controls in the analysis of mRNA levels.

Cell culture

To obtain cytotrophoblast cells and syncytiotrophoblast cells, villous tissue from either early or term placental tissues was dissected free of membranes and vessels, rinsed, and minced in Ca2+- and Mg2+-free HBSS. After digestion by trypsin-deoxyribonuclease, cells were fractionated on a discontinuous Percoll gradient (16). A homogeneous population, consisting of more than 90% viable cytotrophoblast cells as assessed by their phenotypic expression of trophoblast markers, was obtained (17). Cells were then plated onto 60-mm culture dishes (3 x 106 cells/dish) in 3 mL DMEM supplemented with 25 mmol/L HEPES, 2 mmol/L glutamine, 20% heat-inactivated FCS, and antibiotics (100 IU/mL penicillin and 100 mg/mL streptomycin) and were maintained at 37 C in humidified 5% CO2-95% air. Cells were scrapped after a 24-h incubation, corresponding to VCT, and after a 72-h incubation, corresponding to the differentiation of VCT into VSCT. To further investigate the regulation of the expression of both NIS and PDS genes, 0.1 mmol/L 8-bromo-cAMP was added to VCT for a 24-h incubation. Cells were then scrapped and analyzed (18).

Determination of mRNA level using real-time RT-PCR

Total RNA was isolated from either tissue samples or cultured trophoblast cells (VCT or VSCT) using the DNA/RNA extraction Midi kit according to the manufacturer’s instructions (QIAGEN, Hilden, Germany). The total RNA concentration was determined at 260 nm, and its quality was assessed by conventional gel electrophoresis. One microgram of total RNA from each sample was reverse transcribed in a 20-µL volume reaction using 50 U Moloney murine leukemia virus reverse transcriptase, 20 U ribonuclease inhibitor (Perkin-Elmer Corp., PE Applied Biosystems, Foster City, CA), 1 mmol/L dA/T/C/G (Amersham Pharmacia Biotech, Uppsala, Sweden), 5 mmol/L MgCl2, 10 mmol/L Tris-HCl (pH 8.3), 10 mmol/L KCl, and 50 pmol/L random hexamers (Perkin-Elmer Corp., PE Applied Biosystems). The complementary DNAs were then diluted 1:20 in nuclease-free H2O (Promega Corp., Madison, WI).

Real-time quantitative RT-PCR was conducted as previously described (19). Briefly, oligonucleotide primers and TaqMan probes for NIS, PDS, and hCGß genes were designed to be intron spanning, using the computer program Primer Express (Perkin-Elmer Corp., PE Applied Biosystems). They were purchased from Perkin-Elmer Corp., PE Applied Biosystems, and their sequences are presented in Table 1Go. PCR reaction was carried out to produce amplicons that were subsequently analyzed by gel electrophoresis and sequencing. Real-time quantitative RT-PCR was achieved in 96 sample tubes/assay using a complementary DNA equivalent of 20 ng/total RNA·50 µL/tube with the TaqMan PCR core reagent kit according to the manufacturer’s instructions; 1 x buffer A, 5 mmol/L MgCl2, 200 µmol/L dA/C/G, 400 µmol/L dU, 1.25 U AmpliTaq Gold DNA polymerase, 2.5 U uracil N-glycosylase, 100 mmol/L TaqMan probe, and 200 mmol/L of each primer. PCR was developed on the ABI Prism 7700 Sequence Detector (Perkin-Elmer Corp., PE Applied Biosystems). To normalize for differences in the amount of total RNA added to the reaction, amplification of 18S ribosomal RNA was performed as an endogenous control. Primers and probes for 18S RNA were purchased from Perkin-Elmer Corp., PE Applied Biosystems.


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  		Table 1. Sequences of primer pairs and TaqMan probes

 
To validate the real-time RT-PCR method, standard curves for NIS, PDS, hCGß, and 18S ribosomal RNA were constructed from PCR products that were serially diluted in nuclease-free H2O. The efficiency of each standard curve, as determined by its slope, allowed us to quantify the gene expression profile in each specimen by using the comparative threshold cycle method according to the manufacturer’s instructions. The input amount of targeted mRNA of villous cells was determined as standard curve. For each sample, the targeted mRNA amount was divided by 18S ribosomal RNA to determine a normalized ratio. The calibrators were constituted of a pool of five normal thyroid tissues for NIS and PDS genes and a pool of five term placental tissues for hCGß; they were used as the 1 x sample (or 100%), and all other levels were expressed as an n-fold difference relative to these calibrators. Experiments were performed in duplicate for each point, and the intraassay coefficient of variation was less than 1%.

Immunohistochemistry

Serial frozen cryostat tissue sections (5 µm) were cut and fixed in acetone for 10 min. These sections were then incubated for 30 min with either the anti-pendrin or anti-NIS antiserum, diluted at 1:75 and 1:500, respectively. The production and the characteristics of the two antiserum have been described previously (14, 20). Sections were then washed three times in Tris-HCl buffer for 5 min and incubated with a biotinylated antibody (EnVision Labeled Polymer, DAKO Corp., Carpinteria, CA). They were washed again three times and incubated with peroxidase-labeled streptavidin (Universal LSAB2 kit/HRP, DAKO Corp.) for 10 min. After three further washes, staining was completed after incubation with substrate chromogen solution (DAKO Corp.). Negative controls were obtained by incubating sections with preimmune antisera and immune antisera preabsorbed with an excess of the corresponding peptide.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
NIS and PDS gene expression in placental samples

NIS and PDS gene transcripts were detected in placental villous tissues collected at early (n = 24) and late pregnancies (n = 21). A quantitative assessment of these two mRNA transcripts studied was generated by comparative amplification curves obtained by using real-time RT-PCR of the genes together with the hCGß and ribosomal 18S RNAs (Fig. 1Go).



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  		Figure 1. Comparative amplification plots of NIS, PDS, and hCGß mRNAs plus ribosomal 18S RNA in representative samples of thyroid and placental tissues. Twenty nanograms of total RNA were used in the TaqMan PCR assay. T, Thyroid tissue; P, placental tissue, 14 weeks gestation.

 
As presented in Fig. 2Go, a greater intersamples variability of the levels of these transcripts was detected. However, in early pregnancies, a significant level of NIS transcripts was detected, but was 130- to 5,000-fold (median, 250-fold) lower than that in normal thyroid tissues. In these tissues, PDS was barely expressed; it was 1,000- to 10,000-fold (median, 2500-fold) lower than in normal thyroid tissues. Mean and median values obtained for NIS in samples from third trimester pregnancies were similar to those observed in early pregnancies. In contrast, PDS mRNA abundance in late gestation was increased up to 10-fold compared with the level in first trimester pregnancy samples.



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  		Figure 2. Expression of NIS, PDS, and hCGß transcripts in placental samples obtained from first trimester pregnancies (FTP) and third trimester pregnancies (TTP). Data represent the normalized gene expression ratio divided by the calibrator ratio. A pool of normal thyroid tissues was used as the calibrator for NIS and PDS genes. A third trimester placenta was used as the calibrator for the hCGß gene.

 
As a control, we investigated the expression of the hCGß gene that is known to be mainly expressed during the first trimester of pregnancy. Indeed, expression of the hCGß gene was 14-fold higher in placental samples from early pregnancy than in those from third trimester pregnancy. In this regard, placental samples obtained at different stages of pregnancy were homogeneous, as no differences were observed in 18S RNA.

NIS and PDS gene expression during differentiation of cytotrophoblast cells

To address the question of which trophoblastic cell type expresses NIS and/or PDS genes, the levels of their transcripts were analyzed during in vitro syncytiotrophoblast formation that occurred within 72 h after platting VCT cells isolated from placenta. This morphological change is associated with a large increase in hCGß mRNA, as presented in Fig. 3CGo. The level of hCGß mRNA increased up to 70-fold during the differentiation of VCT in VSCT when trophoblastic cells are isolated from first trimester placenta, whereas expression of hCGß gene was low in cell cultures obtained from third trimester placenta.



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  		Figure 3. NIS, PDS, and hCGß expression during differentiation of cytotrophoblast cells isolated from first trimester placenta (FTP) and third trimester placenta (TTP). Data are expressed as ratios of NIS (A), PDS (B), or hCGß (C) mRNA levels normalized by 18S RNA level; thyroid mRNA and placenta mRNA pools were used as calibrators for NIS and PDS and for hCGß, respectively. NIS, PDS, and hCGß gene expressions were analyzed in cytotrophoblast cells after 24 h of culture (CT), which differentiates in syncytiotrophoblast cells after 72 h of culture (ST). Results are the mean of three culture dishes. *, P < 0.05; **, P < 0.005; ***, P < 0.0001.

 
In VCT obtained from first trimester placenta, the level of NIS expression decreased by 3- to 4-fold during their differentiation in VSCT (Fig. 3AGo). Expression of NIS was lower (up to 30-fold) in VCT isolated from third trimester pregnancy than in VCT isolated from first trimester pregnancy. In contrast to the NIS gene, the PDS gene appeared to be weakly expressed in VCT, and its level of transcription increased 5- to 10-fold during the formation of VSCT (Fig. 3BGo). Furthermore, this pattern of expression was relatively similar in cells isolated from first and third trimester placentas. After exposure of VCT to 8-bromo-cAMP, a 3-fold increase in NIS gene expression level was observed, whereas PDS gene expression remained unchanged (data not shown). As expected, hCGß gene expression was increased by 6.5-fold.

Immunohistochemistry

By immunohistochemical analysis, we examined whether NIS and PDS mRNAs are translated and analyzed the protein distribution in human placental tissue. Indeed, the two immunoreactive iodide transporters were detected in human placenta, but at different locations. Thus, immunostaining of the NIS protein was present on the entire membrane of cytotrophoblast cells (Fig. 4Go, top), and pendrin staining was mainly localized at the border membrane, facing the mother, of syncytiotrophoblast cells (Fig. 4Go, bottom).



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  		Figure 4. Localization of pendrin and NIS proteins in a villous trophoblastic tissue. Top, NIS protein appears to be located in the plasma membrane of cytotrophoblast contacting the syncytium (magnification, x250). Bottom, Immunostaining of pendrin on the brush border membrane facing the mother (magnification, x250).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Fetal thyroid function depends largely on placenta functional activity, which by acting as a barrier between maternal-fetal compartments (being totally or relatively impermeable to the maternal TSH and thyroid hormones, respectively) or through the synthesis of enzymes (i.e. deiodinase enzyme system) or polypeptide or hormone (hCG and TRH) may regulate the fetal iodothyronine synthesis. Iodine supply is essential for fetal thyroid function, and iodide readily crosses the placenta (1). However, the mechanism underlying iodide transplacental transport is not fully understood. In this regard, we investigated whether the two genes encoding well documented (NIS) or still potential (PDS) iodide transporters are expressed in the placenta.

Our results show that both NIS and PDS genes are expressed in the placenta, albeit at much lower levels than in the thyroid tissue. The expression of the NIS gene in the placenta is in accordance with its expression in most tissues and organs able to transport iodide, particularly in exocrine glands (21, 22). However, its unexpected preferential expression in cytotrophoblast cells suggests that it may actively transport iodide from the villous syncytiotrophoblast layer, in contact with the maternal blood, toward the fetus. Furthermore, its apparent absence of polarization in cytotrophoblast is in contrast with that observed in thyrocytes and extrathyroidal cells (20). Although a large variation in NIS expression was observed from one sample to another, there was no difference in the mean and median levels of transcripts in tissue samples obtained from either first trimester or term pregnancy. However, in in vitro experiments, NIS expression appeared to be higher in cytotrophoblast cells obtained from first trimester placenta than in cells obtained from term placenta. Exposure of cytotrophoblast cells to 8-bromo-cAMP induced NIS gene expression, in accordance with the presence of a cAMP-responsive element in the NIS gene promoter (23).

PDS gene expression appears to be restricted to thyrocytes, to a limited set of cell types within the ear, and to kidney (24). Pendrin acts as a sodium-independent transporter of chloride and iodide (12, 15, 25). Its location in the syncytiotrophoblast cells is compatible with several observations demonstrating that these cells control anion efflux, particularly I- and Cl- (26). The increase in PDS gene expression during gestation is in agreement with a marked maternal to fetal gradient of iodide through the villous syncytiotrophoblast layer during the second and third trimesters (1, 2). However, the precise mechanism of the iodide transcellular transport through the villous layer remains unclear. Indeed, pendrin location at the brush border membrane facing the mother would imply a different direction of iodide transport compared with the model proposed for thyrocytes (15).

The mechanisms involved in the differential trophoblast expression of NIS and PDS genes remain unknown. In thyrocytes, estradiol down-regulates NIS expression (27). In human placenta, estradiol stimulates the differentiation of cytotrophoblast into syncytiotrophoblast (28). Therefore, it remains to be determined whether estradiol, which is produced in large amounts by the trophoblast, down-regulates NIS expression directly at the gene level (29) or indirectly by stimulating syncytiotrophoblast differentiation.

Finally, our observations would be of potential value for understanding the potential hazards due to accidental exposure to radioiodine during pregnancy (30, 31, 32). Indeed, the embryo and fetus present an extreme sensitivity to radionuclides, particularly to radioiodine (32). Furthermore, they also may be of interest to determine the physiopathological effects of iodide deficiency or iodide excess during pregnancy.


   Acknowledgments
 
We acknowledge Monique Talbot for expert technical assistance with immunohistochemistry.


   Footnotes
 
1 This work was supported by grants from the Projets IFR 1999 at Institut Gustave-Roussy and Electricité de France. Back

Received April 21, 2000.

Revised July 31, 2000.

Accepted August 7, 2000.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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