Divergence of Iodine and Thyroid Hormones in the Fetal and Maternal Parts of Human-Term Placenta

Abstract

The human placenta is an important organ that forms a barrier where maternal and fetal exchange takes place. The placenta transport iodine to the fetal circulation by transfer of maternal iodine and deiodination of thyroid hormones (THs). The aim of the study was to examine the distribution of iodine and thyroid hormone transporters in the maternal and fetal sides of human-term placenta. A cross-sectional study was performed at the First Affiliated Hospital of China Medical University. Placental samples (maternal and fetal surfaces) were collected from 113 healthy-term pregnant women. The iodine content; the concentration of thyroxine (T4), triiodothyronine (T3), and reverse T3 (rT3); and the enzyme activity of placental type 2 iodothyronine deiodinase (D2) and D3 were examined. The mRNA and protein localization/expression of iodine and thyroid hormone transporters in the placenta were also studied. We also analyzed the association between expression level of Na+/I− symporter (NIS), thyroid hormone transporter protein, D3 activity in maternal and fetal surfaces of placenta with iodine content, and thyroid hormone levels. Iodine levels in placental samples from the maternal side were significantly higher than those in samples from the fetal side. T3 and T4 expression in fetal placenta was significantly lower than in maternal placenta. D3 activity in the fetal side of the placentas was significantly higher than that in the maternal side. The mRNA and protein expression of monocarboxylate transporters 8 (MCT8), L-amino acid transporters 1 (LAT1), organic anion transporting polypeptides 4A1 (OATP4A1), and TH binding protein transthyretin (TTR) were significantly increased in maternal side, while the NIS expression was higher in fetal side of human-term placenta. In conclusion, the enzymatic deiodination of thyroid hormones forms a barrier which reduces transplacental passage of the hormones and that the maternal part of the placenta is the primary factor in the mechanism regulating the hormonal transfer.

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References

  1. 1.

    Glinoer D (1997) The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 18(3):404–433. https://doi.org/10.1210/edrv.18.3.0300

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Delange F (2001) Iodine deficiency as a cause of brain damage. Postgrad Med J 77(906):217–220

    CAS  Article  Google Scholar 

  3. 3.

    Delange F (1998) Screening for congenital hypothyroidism used as an indicator of the degree of iodine deficiency and of its control. Thyroid 8(12):1185–1192. https://doi.org/10.1089/thy.1998.8.1185

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Moleti M, Trimarchi F, Vermiglio F (2014) Thyroid physiology in pregnancy. Endocr Pract 20(6):589–596. https://doi.org/10.4158/EP13341.RA

    Article  PubMed  Google Scholar 

  5. 5.

    Bidart JM, Lacroix L, Evain-Brion D, Caillou B, Lazar V, Frydman R, Bellet D, Filetti S, Schlumberger M (2000) Expression of Na+/I- symporter and Pendred syndrome genes in trophoblast cells. J Clin Endocrinol Metab 85(11):4367–4372. https://doi.org/10.1210/jcem.85.11.6969

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Mitchell AM, Manley SW, Morris JC, Powell KA, Bergert ER, Mortimer RH (2001) Sodium iodide symporter (NIS) gene expression in human placenta. Placenta 22(2–3):256–258. https://doi.org/10.1053/plac.2000.0609

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Di Cosmo C, Fanelli G, Tonacchera M, Ferrarini E, Dimida A, Agretti P, De Marco G, Vitti P, Pinchera A, Bevilacqua G, Naccarato AG, Viacava P (2006) The sodium-iodide symporter expression in placental tissue at different gestational age: an immunohistochemical study. Clin Endocrinol 65(4):544–548. https://doi.org/10.1111/j.1365-2265.2006.02577.x

    CAS  Article  Google Scholar 

  8. 8.

    Manley SW, Li H, Mortimer RH (2005) The BeWo choriocarcinoma cell line as a model of iodide transport by placenta. Placenta 26(5):380–386. https://doi.org/10.1016/j.placenta.2004.07.004

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Bernal J (2007) Thyroid hormone receptors in brain development and function. Nature clinical practice. Endocrinol Metab 3(3):249–259. https://doi.org/10.1038/ncpendmet0424

    CAS  Article  Google Scholar 

  10. 10.

    Koopdonk-Kool JM, de Vijlder JJ, Veenboer GJ, Ris-Stalpers C, Kok JH, Vulsma T, Boer K, Visser TJ (1996) Type II and type III deiodinase activity in human placenta as a function of gestational age. J Clin Endocrinol Metab 81(6):2154–2158. https://doi.org/10.1210/jcem.81.6.8964844

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Salvatore D, Bartha T, Harney JW, Larsen PR (1996) Molecular biological and biochemical characterization of the human type 2 selenodeiodinase. Endocrinology 137(8):3308–3315. https://doi.org/10.1210/endo.137.8.8754756

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Kohrle J (1999) Local activation and inactivation of thyroid hormones: the deiodinase family. Mol Cell Endocrinol 151(1–2):103–119

    CAS  Article  Google Scholar 

  13. 13.

    Chan S, Kachilele S, Hobbs E, Bulmer JN, Boelaert K, McCabe CJ, Driver PM, Bradwell AR, Kester M, Visser TJ, Franklyn JA, Kilby MD (2003) Placental iodothyronine deiodinase expression in normal and growth-restricted human pregnancies. J Clin Endocrinol Metab 88(9):4488–4495. https://doi.org/10.1210/jc.2003-030228

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Grumbach MM, Werner SC (1956) Transfer of thyroid hormone across the human placenta at term. J Clin Endocrinol Metab 16(10):1392–1395. https://doi.org/10.1210/jcem-16-10-1392

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Vulsma T, Gons MH, de Vijlder JJ (1989) Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 321(1):13–16. https://doi.org/10.1056/NEJM198907063210103

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    James SR, Franklyn JA, Kilby MD (2007) Placental transport of thyroid hormone. Best practice and research. Clin Endocrinol Metab 21(2):253–264. https://doi.org/10.1016/j.beem.2007.03.001

    CAS  Article  Google Scholar 

  17. 17.

    Chan SY, Vasilopoulou E, Kilby MD (2009) The role of the placenta in thyroid hormone delivery to the fetus. Nature clinical practice. Endocrinol Metab 5(1):45–54. https://doi.org/10.1038/ncpendmet1026

    CAS  Article  Google Scholar 

  18. 18.

    Landers KA, McKinnon BD, Li H, Subramaniam VN, Mortimer RH, Richard K (2009) Carrier-mediated thyroid hormone transport into placenta by placental transthyretin. J Clin Endocrinol Metab 94(7):2610–2616. https://doi.org/10.1210/jc.2009-0048

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Sato K, Sugawara J, Sato T, Mizutamari H, Suzuki T, Ito A, Mikkaichi T, Onogawa T, Tanemoto M, Unno M, Abe T, Okamura K (2003) Expression of organic anion transporting polypeptide E (OATP-E) in human placenta. Placenta 24(2–3):144–148

    CAS  Article  Google Scholar 

  20. 20.

    Chan SY, Franklyn JA, Pemberton HN, Bulmer JN, Visser TJ, McCabe CJ, Kilby MD (2006) Monocarboxylate transporter 8 expression in the human placenta: the effects of severe intrauterine growth restriction. J Endocrinol 189(3):465–471. https://doi.org/10.1677/joe.1.06582

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Kinne A, Kleinau G, Hoefig CS, Gruters A, Kohrle J, Krause G, Schweizer U (2010) Essential molecular determinants for thyroid hormone transport and first structural implications for monocarboxylate transporter 8. J Biol Chem 285(36):28054–28063. https://doi.org/10.1074/jbc.M110.129577

  22. 22.

    van Mullem AA, van Gucht ALM, Visser WE, Meima ME, Peeters RP, Visser TJ (2016) Effects of thyroid hormone transporters MCT8 and MCT10 on nuclear activity of T3. Mol Cell Endocrinol 437:252–260. https://doi.org/10.1016/j.mce.2016.07.037

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Ritchie JW, Taylor PM (2001) Role of the system L permease LAT1 in amino acid and iodothyronine transport in placenta. Biochem J 356(Pt 3):719–725

    CAS  Article  Google Scholar 

  24. 24.

    Landers KA, Li H, Subramaniam VN, Mortimer RH, Richard K (2013) Transthyretin-thyroid hormone internalization by trophoblasts. Placenta 34(8):716–718. https://doi.org/10.1016/j.placenta.2013.05.005

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    McKinnon B, Li H, Richard K, Mortimer R (2005) Synthesis of thyroid hormone binding proteins transthyretin and albumin by human trophoblast. J Clin Endocrinol Metab 90(12):6714–6720. https://doi.org/10.1210/jc.2005-0696

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Patel J, Landers KA, Li H, Mortimer RH, Richard K (2011) Ontogenic changes in placental transthyretin. Placenta 32(11):817–822. https://doi.org/10.1016/j.placenta.2011.09.007

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Reyns GE, Janssens KA, Buyse J, Kuhn ER, Darras VM (2002) Changes in thyroid hormone levels in chicken liver during fasting and refeeding. Comp Biochem Physiol B Biochem Mol Biol 132(1):239–245

    CAS  Article  Google Scholar 

  28. 28.

    Reyns GE, Verhoelst CH, Kuhn ER, Darras VM, Van der Geyten S (2005) Regulation of thyroid hormone availability in liver and brain by glucocorticoids. Gen Comp Endocrinol 140(2):101–108. https://doi.org/10.1016/j.ygcen.2004.10.006

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Castro MI, Braverman LE, Alex S, Wu CF, Emerson CH (1985) Inner-ring deiodination of 3,5,3′-triiodothyronine in the in situ perfused guinea pig placenta. J Clin Invest 76(5):1921–1926. https://doi.org/10.1172/JCI112188

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Obregon MJ, Ruiz de Ona C, Hernandez A, Calvo R, Escobar del Rey F, Morreale de Escobar G (1989) Thyroid hormones and 5′-deiodinase in rat brown adipose tissue during fetal life. Am J Phys 257(5 Pt 1):E625–E631. https://doi.org/10.1152/ajpendo.1989.257.5.E625

    CAS  Article  Google Scholar 

  31. 31.

    Hernandez A, Obregon MJ (1995) Presence of growth factors-induced type III iodothyronine 5-deiodinase in cultured rat brown adipocytes. Endocrinology 136(10):4543–4550. https://doi.org/10.1210/endo.136.10.7664675

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Burns R, O'Herlihy C, Smyth PP (2013) Regulation of iodide uptake in placental primary cultures. Eur Thyroid J 2(4):243–251. https://doi.org/10.1159/000356847

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Li H, Patel J, Mortimer RH, Richard K (2012) Ontogenic changes in human placental sodium iodide symporter expression. Placenta 33(11):946–948. https://doi.org/10.1016/j.placenta.2012.08.002

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Schroder-van der Elst JP, van der Heide D, Kastelijn J, Rousset B, Obregon MJ (2001) The expression of the sodium/iodide symporter is up-regulated in the thyroid of fetuses of iodine-deficient rats. Endocrinology 142(9):3736–3741. https://doi.org/10.1210/endo.142.9.8377

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Mortimer RH, Galligan JP, Cannell GR, Addison RS, Roberts MS (1996) Maternal to fetal thyroxine transmission in the human term placenta is limited by inner ring deiodination. J Clin Endocrinol Metab 81(6):2247–2249. https://doi.org/10.1210/jcem.81.6.8964859

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Cooper E, Gibbens M, Thomas CR, Lowy C, Burke CW (1983) Conversion of thyroxine to 3,3′,5′-triiodothyronine in the guinea pig placenta: in vivo studies. Endocrinology 112(5):1808–1815. https://doi.org/10.1210/endo-112-5-1808

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Kurlak LO, Mistry HD, Kaptein E, Visser TJ, Broughton Pipkin F (2013) Thyroid hormones and their placental deiodination in normal and pre-eclamptic pregnancy. Placenta 34(5):395–400. https://doi.org/10.1016/j.placenta.2013.02.009

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Weeke J, Dybkjaer L, Granlie K, Eskjaer Jensen S, Kjaerulff E, Laurberg P, Magnusson B (1982) A longitudinal study of serum TSH, and total and free iodothyronines during normal pregnancy. Acta Endocrinol 101(4):531–537

    CAS  Article  Google Scholar 

  39. 39.

    Laurberg P, Andersen SL, Pedersen IB, Andersen S, Carle A (2013) Screening for overt thyroid disease in early pregnancy may be preferable to searching for small aberrations in thyroid function tests. Clin Endocrinol 79(3):297–304. https://doi.org/10.1111/cen.12232

    Article  Google Scholar 

  40. 40.

    Huang SA, Dorfman DM, Genest DR, Salvatore D, Larsen PR (2003) Type 3 iodothyronine deiodinase is highly expressed in the human uteroplacental unit and in fetal epithelium. J Clin Endocrinol Metab 88(3):1384–1388. https://doi.org/10.1210/jc.2002-021291

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Steinsapir J, Bianco AC, Buettner C, Harney J, Larsen PR (2000) Substrate-induced down-regulation of human type 2 deiodinase (hD2) is mediated through proteasomal degradation and requires interaction with the enzyme's active center. Endocrinology 141(3):1127–1135. https://doi.org/10.1210/endo.141.3.7355

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Akturk M, Oruc AS, Danisman N, Erkek S, Buyukkagnici U, Unlu E, Tazebay UH (2013) Na+/I- symporter and type 3 iodothyronine deiodinase gene expression in amniotic membrane and placenta and its relationship to maternal thyroid hormones. Biol Trace Elem Res 154(3):338–344. https://doi.org/10.1007/s12011-013-9748-y

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Perez-Lopez FR (2007) Iodine and thyroid hormones during pregnancy and postpartum. Gynecol Endocrinol 23(7):414–428. https://doi.org/10.1080/09513590701464092

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Loubiere LS, Vasilopoulou E, Bulmer JN, Taylor PM, Stieger B, Verrey F, McCabe CJ, Franklyn JA, Kilby MD, Chan SY (2010) Expression of thyroid hormone transporters in the human placenta and changes associated with intrauterine growth restriction. Placenta 31(4):295–304. https://doi.org/10.1016/j.placenta.2010.01.013

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Cleal JK, Glazier JD, Ntani G, Crozier SR, Day PE, Harvey NC, Robinson SM, Cooper C, Godfrey KM, Hanson MA, Lewis RM (2011) Facilitated transporters mediate net efflux of amino acids to the fetus across the basal membrane of the placental syncytiotrophoblast. J Physiol 589(Pt 4):987–997. https://doi.org/10.1113/jphysiol.2010.198549

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Prasad PD, Wang H, Huang W, Kekuda R, Rajan DP, Leibach FH, Ganapathy V (1999) Human LAT1, a subunit of system L amino acid transporter: molecular cloning and transport function. Biochem Biophys Res Commun 255(2):283–288. https://doi.org/10.1006/bbrc.1999.0206

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Gaccioli F, Aye IL, Roos S, Lager S, Ramirez VI, Kanai Y, Powell TL, Jansson T (2015) Expression and functional characterisation of system L amino acid transporters in the human term placenta. Reprod Biol Endocrinol 13:57. https://doi.org/10.1186/s12958-015-0054-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Hoeltzli SD, Smith CH (1989) Alanine transport systems in isolated basal plasma membrane of human placenta. Am J Phys 256(3 Pt 1):C630–C637. https://doi.org/10.1152/ajpcell.1989.256.3.C630

    CAS  Article  Google Scholar 

  49. 49.

    Lewis RM, Glazier J, Greenwood SL, Bennett EJ, Godfrey KM, Jackson AA, Sibley CP, Cameron IT, Hanson MA (2007) L-serine uptake by human placental microvillous membrane vesicles. Placenta 28(5–6):445–452. https://doi.org/10.1016/j.placenta.2006.06.014

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Fujiwara K, Adachi H, Nishio T, Unno M, Tokui T, Okabe M, Onogawa T, Suzuki T, Asano N, Tanemoto M, Seki M, Shiiba K, Suzuki M, Kondo Y, Nunoki K, Shimosegawa T, Iinuma K, Ito S, Matsuno S, Abe T (2001) Identification of thyroid hormone transporters in humans: different molecules are involved in a tissue-specific manner. Endocrinology 142(5):2005–2012. https://doi.org/10.1210/endo.142.5.8115

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Sun X, Lu L, Shan L, Shan Z, Teng W (2017) Iodine storage and metabolism of mild to moderate iodine-deficient pregnant rats. Thyroid 27(6):846–851. https://doi.org/10.1089/thy.2016.0611

    CAS  Article  PubMed  Google Scholar 

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Funding

This study was funded by the Chinese National Science Foundation (grant numbers 81170730, 81570709, 81670719) and 973 Plan preliminary research project (2011CB512112).

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SP and CL performed the experimental work, analyzed the results, and composed the manuscript. XX, XZ, and DW performed the study and collected the samples. XL reviewed and edited the manuscript. MS and TM participated in the experiments. SW and YJ collected the general information of study populations and contributed to the interpretation and analysis of data; ZS helped with coordination of this study; WT supervised the statistical analyses; contributed to the design of the study, analyses, and interpretation of the results; and produced the final version of the manuscript.

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Correspondence to Weiping Teng.

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Peng, S., Li, C., Xie, X. et al. Divergence of Iodine and Thyroid Hormones in the Fetal and Maternal Parts of Human-Term Placenta. Biol Trace Elem Res 195, 27–38 (2020). https://doi.org/10.1007/s12011-019-01834-z

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Keywords

  • Iodine
  • Thyroid hormone transporter
  • Maternal placenta
  • Fetal placenta
  • Deiodination