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Thyroid hormone transport across the placenta
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Thyroid hormone transport across the placenta夽 Transport transplacentaire des hormones thyroïdiennes Theo J. Visser Department of Internal Medicine, Erasmus University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
Keywords: Thyroid hormone; Thyroid hormone transporters; Placenta; Pregnancy Mots clés : Hormone thyroïdienne ; Transport transplacentaire ; Grossesse
1. Introduction Thyroid hormone (TH) is a common term for the compounds secreted by thyroid follicles, 3,3 ,5,5 -tetraiodothyronine (thyroxine, T4) and 3,3 ,5-triiodothyronine (T3). The thyroid is the only source of T4 in the body but most T3 is produced by deiodination of T4 in peripheral tissues [1]. Most actions of TH are initiated by binding of T3 to nuclear receptors encoded by the THRA and THRB genes [2,3]. The resultant change in receptor conformation leads to the dissociation of co-repressor complexes and the recruitment of co-activator complexes, changing the expression of TH-responsive genes. T4 may have T3-independent non-genomic actions [4] and its affinity for the nuclear T3 receptors may not be negligible particularly in view of the higher free T4 than T3 levels in serum and perhaps also in tissues. Nevertheless, it is generally accepted that T4 functions predominantly as a prohormone for the active hormone T3 [1]. TH is essential for tissue development, in particular of the brain, and for the regulation of the metabolic activities of the tissues throughout life [3,5]. The biological activity of TH is regulated importantly at the level of target tissues. This involves the local expression of iodothyronine deiodinases, in particular D2 and D3 [1]. D2 converts T4 by outer ring deiodination to T3, whereas D3 converts T4 and T3 by inner ring deiodination to the receptorinactive metabolites 3,3 ,5 -triiodothyronine (reverse T3) and 3,3 -diiodothyronine (3,3 -T2), respectively. D2 and D3 have very different spatiotemporal patterns of expression. D2 is
夽 This article is published in the context of the 59e Journées Internationales d’Endocrinologie, Clinique Henri-Pierre Klotz (09/06–10/06/16, Paris). See Annales d’endocrinologie, volume 77, issue 2, pages 61–178 (June 2016). E-mail address: [email protected]
expressed among other tissues in brain, pituitary, brown adipose tissue (BAT), where it usually reaches highest activities after birth. D3 is also expressed in brain but its activity is highest during fetal development. D3 is also highly expressed in other fetal tissues such as the liver but also at very high levels in the placenta and the pregnant uterus. During early development, low D2 and high D3 expression result in low local T3 levels in favor of tissue growth. Ultimately, decreased D3 expression and increased D2 expression allow an increase in local T3 levels, stimulating cellular differentiation. This local regulation of TH action is an autocrine mechanism in tissues such as BAT where T3 functions in the same cell where it is produced by D2 [6], or a paracrine mechanism in tissues such as the brain where T3 is generated by D2 in astrocytes and provided to neuronal target cells [7]. These neurons may also express D3 to terminate T3 action when this is no longer required. The deiodinases are membrane proteins with their active sites localized in the cytoplasm. TH is also metabolized by sulfation and glucuronidation by intracellular enzymes. Therefore, not only the nuclear action but also the metabolism of TH require the transport of the hormone across the plasma membrane. This does not take place by passive diffusion as was assumed for a long time but is mediated by transporter proteins [7–9]. In addition to the deiodinases, these transporters are crucial in the regulation of local TH activity. 2. Thyroid hormone transporters In the last two decades, several transporters have been identified which are capable of transporting T4, T3 and other iodothyronine derivatives [7,9]. They belong to two main classes of transporters, namely the organic anion transporters and amino acid transporters (Table 1). Among the organic anion
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Table 1 Thyroid hormone transporters. Organic anion transporters NTCP (Na/taurocholate co-transporting polypeptide) OATPs (organic anion transporting polypeptides) Amino acid transporters LAT1,2 (L-type amino acid transporters) MCT8,10 (“monocarboxylate transporters”)
transporters, the Na-taurocholate co-transporting polypeptide (NTCP, SLC10A1) and several members of the Na-independent organic anion transporting polypeptide (OATP, SLCO) family facilitate transport of iodothyronines and/or their sulfate conjugates [10,11]. Among the latter family, OATP1C1 deserves special mention in view of its high selectivity for T4 as the substrate and its specific tissue distribution, with particularly high expression in different brain structures [12,13]. As mentioned above, in human brain, OATP1C1 is especially expressed in astrocytes where it facilitates entry of T4 to allow its conversion to T3 [5,14]. Regarding the amino acid transporters, our group has recently made a detailed characterization of the transport of different iodothyronines and iodotyrosines by the L-type amino acid transporters LAT1-4 [15]. LAT1 and LAT2 are heterodimeric transporters composed of a common heavy chain, SLC3A2, and different light chains, SLC7A5 and SLC7A8, respectively [16]. LAT3 and LAT4 are monomeric proteins from another transporter family; their formal codes are SLC43A1 and SLC43A2, respectively [17]. Although there is little homology between the LAT1/2 and LAT3/4 transporters, they share their preference for large aromatic and branched-chain aliphatic amino acids. With regard to iodothyronine substrates, LAT1 facilitates cellular uptake of T4, T3, rT3, and 3,3 -T2, and LAT2 mediates uptake of T3 and 3,3 -T2. LAT3 and LAT4 do not facilitate uptake of iodothyronines but they mediate the efflux of rT3 and 3,3 -T2 [15]. Particularly effective TH transporters are MCT8 (SLC16A2) and MCT10 (SLC16A10), which belong to the monocarboxylate transporter (MCT) family although they do not transport
monocarboxylates but amino acid derivatives [18–20]. MCT10 is also referred to as TAT1 for T-type amino acid transporter 1, as it shows high specificity for the aromatic amino acids Phe, Tyr and Trp [21]. In addition to these amino acids, MCT10 also effectively facilitates uptake and efflux of iodothyronines, in particular T3. MCT10 is expressed at high levels in liver, intestine, kidney and skeletal muscle and at lower levels in many other tissues. The pathophysiological relevance of TH transporters has been best demonstrated for MCT8. The MCT8 protein is highly homologous to MCT10, in particular in its 12 transmembrane domains. In contrast to MCT10, MCT8 does not facilitate transport of any amino acid but it is very effective in the transport of both T4 and T3 as well as other iodothyronines [18,19]. The MCT8 gene is located on the X chromosome and mutations in MCT8 have been associated with severe X-linked psychomotor retardation, also known as the Allan-Herndon-Dudley syndrome (AHDS) [22,23]. Patients with AHDS also have abnormal serum TH profiles, including low T4 and high T3 levels. MCT8 is highly expressed in liver, adrenal, kidney, thyroid and brain. In the thyroid, it is involved in TH secretion. In the brain, it is especially expressed in endothelial cells of the blood-brain barrier, in epithelial cells of the choroid plexus and in neurons in different brain regions [5,24]. The pathogenesis of AHDS is explained by the important role of MCT8 in brain TH transport. Since TH is essential for brain development, impaired MCT8-mediated supply of TH to important target cells in the brain causes severe damage to the developing brain.
3. Thyroid hormone transport across the placenta TH is crucial for fetal and neonatal development. Since the fetal thyroid starts to secrete significant amounts of TH towards mid-gestation, maternal-fetal transfer of TH across the placenta is particularly important in the first half of pregnancy [5]. However, analysis of serum TH levels in newborns with thyroid agenesis indicates that also later in pregnancy, maternal TH remains an important source for the fetus [25].
Table 2 Thyroid hormone transporters in human placenta. Transporter Placenta MCT8 MCT10 LAT1 LAT2 OATP1A2 OATP4A1 CTBs, STBs MCT8 MCT10 LAT1 LAT2 OATP1A2 OATP4A1
Localization
Findings
Ref.
CTBs, STBs, EVTBs CTBs, STBs, EVTBs – – CTBs, STBs, EVTBs STBs (apical)
Highest expression in TM3 Highest expression in TM3 Similar expression in TM1-3 Similar expression in TM1-3 Similar expression in TM1-3 Similar expression in TM1-3
[32,33] [21,33–36] [33,36] [33,34,36] [33] [33,37]
MVM MVM
CTB→STB: expression ↓
[38–40] [38,39] [38–40] [38,39] [38–40] [38–40]
CTB→STB: expression ↓ MVM MVM MVM
CTB→STB: expression ↑ CTB→STB: expression =
CTB: cytotrophoblast; STB: syncytiotrophoblast; EVT: extravillous trophoblast; TM: trimester; MVM: microvillous membrane.
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Studies by Chan et al. and others have demonstrated the expression of different TH transporters in the human placenta, including MCT8, MCT10, LAT1, LAT2, OATP1A2 and OATP4A1 (Table 2). These transporters have been localized by immunohistochemistry in different cells, although they are often present in the apical (maternal-facing) microvillous membrane (MVM) of syncytiotrophoblasts (STBs). Studies using Mct8, Mct10 and Lat2 knockout mice have suggested that each of these transporters is not essential for fetal development [26–28]. However, Lat1 KO mice are embryonic lethal although it is unlikely that this is primarily due to the lack of transplacental TH transport [29]. Perhaps, several TH transporters need to be inactivated before transport of TH across the placenta is compromised. It is uncertain exactly which cells in the placenta represent a barrier for maternal-fetal TH transfer in the different stages of gestation, although it is clear that STBs play a prominent role in this process. An important aspect of transplacental TH transport is the very high expression of D3 also in STBs [30]. Together with the high expression of D3 in fetal tissues and the pregnant uterus, this accounts for the low fetal serum T3 and high serum rT3 levels. However, it is surprising that any T4 may undergo trans-cellular transport across STBs without being converted by D3 to rT3. This may be explained by an additional route for T4 transport across the placenta, namely as a complex with transthyretin (TTR) [31]. This would involve the production of TTR by STBs and release of this protein at the apical membrane. The TTR-T4 complex would then be endocytosed, involving megalin or a similar scavenger protein, transported across the cells in vesicles and released by exocytosis at the basal (fetal-facing) site of the STBs. 4. Conclusion TH transport across the plasma membrane is the first crucial step allowing the intracellular metabolism and action of the hormone. This does not take place by passive diffusion through the lipid bilayer of the membrane but requires the presence of TH transporters. The most specific TH transporters characterized to-date are MCT8 and OATP1C1, which are fundamental to the regulation of bioactive TH levels in the brain. Transplacental transport is crucial for the transfer of maternal TH to the developing fetus. Probably multiple TH transporters are involved in this process but rate-limiting steps (if any) remain to be identified. Disclosure of interest The author declares that he has no competing interest. References [1] Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 2008;29:898–938. [2] Yen PM. Physiological and molecular basis of thyroid hormone action. Physiol Rev 2001;81:1097–142. [3] Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev 2014;94:355–82.
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[4] Davis PJ, Goglia F, Leonard JL. Nongenomic actions of thyroid hormone. Nat Rev Endocrinol 2016;12:111–21. [5] Bernal J. Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab 2007;3:249–59. [6] Bianco AC, McAninch EA. The role of thyroid hormone and brown adipose tissue in energy homoeostasis. Lancet Diabetes Endocrinol 2013;1: 250–8. [7] Bernal J, Guadano-Ferraz A, Morte B. Thyroid hormone transporters – functions and clinical implications. Nat Rev Endocrinol 2015;11:406–17. [8] Hennemann G, Docter R, Friesema EC, de Jong M, Krenning EP, Visser TJ. Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr Rev 2001;22: 451–76. [9] Visser WE, Friesema EC, Visser TJ. Mini-review: thyroid hormone transporters: the knowns and the unknowns. Mol Endocrinol 2011;25:1–14. [10] Friesema EC, Docter R, Moerings EP, Stieger B, Hagenbuch B, Meier PJ, et al. Identification of thyroid hormone transporters. Biochem Biophys Res Commun 1999;254:497–501. [11] Hagenbuch B. Cellular entry of thyroid hormones by organic anion transporting polypeptides. Best Pract Res Clin Endocrinol Metab 2007;21:209–21. [12] Pizzagalli F, Hagenbuch B, Stieger B, Klenk U, Folkers G, Meier PJ. Identification of a novel human organic anion transporting polypeptide as a high affinity thyroxine transporter. Mol Endocrinol 2002;16:2283–96. [13] Sugiyama D, Kusuhara H, Taniguchi H, Ishikawa S, Nozaki Y, Aburatani H, et al. Functional characterization of rat brain-specific organic anion transporter (Oatp14) at the blood-brain barrier: high affinity transporter for thyroxine. J Biol Chem 2003;278:43489–95. [14] Schnell C, Shahmoradi A, Wichert SP, Mayerl S, Hagos Y, Heuer H, et al. The multispecific thyroid hormone transporter OATP1C1 mediates cellspecific sulforhodamine 101-labeling of hippocampal astrocytes. Brain Struct Funct 2015;220:193–203. [15] Zevenbergen C, Meima ME, Lima de Souza EC, Peeters RP, Kinne A, Krause G, et al. Transport of iodothyronines by human l-type amino acid transporters. Endocrinology 2015;156:4345–55. [16] Taylor PM, Ritchie JW. Tissue uptake of thyroid hormone by amino acid transporters. Best Pract Res Clin Endocrinol Metab 2007;21:237–51. [17] Bodoy S, Fotiadis D, Stoeger C, Kanai Y, Palacin M. The small SLC43 family: facilitator system l amino acid transporters and the orphan EEG1. Mol Aspects Med 2013;34:638–45. [18] Friesema EC, Ganguly S, Abdalla A, Manning Fox JE, Halestrap AP, Visser TJ. Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J Biol Chem 2003;278:40128–35. [19] Friesema EC, Kuiper GG, Jansen J, Visser TJ, Kester MH. Thyroid hormone transport by the human monocarboxylate transporter 8 and its rate-limiting role in intracellular metabolism. Mol Endocrinol 2006;20:2761–72. [20] Friesema EC, Jansen J, Jachtenberg JW, Visser WE, Kester MH, Visser TJ. Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10. Mol Endocrinol 2008;22:1357–69. [21] Kim DK, Kanai Y, Matsuo H, Kim JY, Chairoungdua A, Kobayashi Y, et al. The human T-type amino acid transporter-1: characterization, gene organization, and chromosomal location. Genomics 2002;79:95–103. [22] Friesema EC, Grueters A, Biebermann H, Krude H, von Moers A, Reeser M, et al. Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet 2004;364:1435–7. [23] Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S. A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 2004;74:168–75. [24] Heuer H, Visser TJ. The pathophysiological consequences of thyroid hormone transporter deficiencies: insights from mouse models. Biochim Biophys Acta 2013;1830:3974–8. [25] Vulsma T, Gons MH, de Vijlder JJ. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 1989;321:13–6. [26] Trajkovic M, Visser TJ, Mittag J, Horn S, Lukas J, Darras VM, et al. Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8. J Clin Invest 2007;117:627–35.
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[27] Muller J, Mayerl S, Visser TJ, Darras VM, Boelen A, Frappart L, et al. Tissue-specific alterations in thyroid hormone homeostasis in combined Mct10 and Mct8 deficiency. Endocrinology 2014;155:315–25. [28] Braun D, Wirth EK, Wohlgemuth F, Reix N, Klein MO, Gruters A, et al. Aminoaciduria, but normal thyroid hormone levels and signalling, in mice lacking the amino acid and thyroid hormone transporter Slc7a8. Biochem J 2011;439:249–55. [29] Poncet N, Shi Y-B, Taylor P, Storey K. LAT1 (Slc7a5) null mice are embryonic lethal and exhibit neural tube defects (896.5). FASEB J 2014;28:896.895. [30] Chan S, Kachilele S, Hobbs E, Bulmer JN, Boelaert K, McCabe CJ, et al. Placental iodothyronine deiodinase expression in normal and growthrestricted human pregnancies. J Clin Endocrinol Metab 2003;88:4488–95. [31] Patel J, Landers K, Li H, Mortimer RH, Richard K. Delivery of maternal thyroid hormones to the fetus. Trends Endocrinol Metab 2011;22:164–70. [32] Chan SY, Franklyn JA, Pemberton HN, Bulmer JN, Visser TJ, McCabe CJ, et al. Monocarboxylate transporter 8 expression in the human placenta: the effects of severe intrauterine growth restriction. J Endocrinol 2006;189:465–71. [33] Loubiere LS, Vasilopoulou E, Bulmer JN, Taylor PM, Stieger B, Verrey F, et al. Expression of thyroid hormone transporters in the human placenta and changes associated with intrauterine growth restriction. Placenta 2010;31:295–304. [34] Park SY, Kim JK, Kim IJ, Choi BK, Jung KY, Lee S, et al. Reabsorption of neutral amino acids mediated by amino acid transporter LAT2 and
[35]
[36]
[37]
[38]
[39]
[40]
TAT1 in the basolateral membrane of proximal tubule. Arch Pharm Res 2005;28:421–32. Cleal JK, Glazier JD, Ntani G, Crozier SR, Day PE, Harvey NC, et al. Facilitated transporters mediate net efflux of amino acids to the fetus across the basal membrane of the placental syncytiotrophoblast. J Physiol 2011;589:987–97. Day PE, Ntani G, Crozier SR, Mahon PA, Inskip HM, Cooper C, et al. Maternal factors are associated with the expression of placental genes involved in amino acid metabolism and transport. PLoS One 2015;10:e0143653. Sato K, Sugawara J, Sato T, Mizutamari H, Suzuki T, Ito A, et al. Expression of organic anion transporting polypeptide E (OATP-E) in human placenta. Placenta 2003;24:144–8. Loubiere LS, Vasilopoulou E, Glazier JD, Taylor PM, Franklyn JA, Kilby MD, et al. Expression and function of thyroid hormone transporters in the microvillous plasma membrane of human term placental syncytiotrophoblast. Endocrinology 2012;153:6126–35. Vasilopoulou E, Loubiere LS, Martin-Santos A, McCabe CJ, Franklyn JA, Kilby MD, et al. Differential triiodothyronine responsiveness and transport by human cytotrophoblasts from normal and growth-restricted pregnancies. J Clin Endocrinol Metab 2010;95:4762–70. Berveiller P, Degrelle SA, Segond N, Cohen H, Evain-Brion D, Gil S. Drug transporter expression during in vitro differentiation of first-trimester and term human villous trophoblasts. Placenta 2015;36:93–6.
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ARTICLE IN PRESS Disponible en ligne sur
ScienceDirect www.sciencedirect.com Annales d’Endocrinologie xxx (2016) xxx–xxx
Klotz Communications: Metabolism and Pregnancy
Thyroid hormone transport across the placenta夽 Transport transplacentaire des hormones thyroïdiennes Theo J. Visser Department of Internal Medicine, Erasmus University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
Keywords: Thyroid hormone; Thyroid hormone transporters; Placenta; Pregnancy Mots clés : Hormone thyroïdienne ; Transport transplacentaire ; Grossesse
1. Introduction Thyroid hormone (TH) is a common term for the compounds secreted by thyroid follicles, 3,3 ,5,5 -tetraiodothyronine (thyroxine, T4) and 3,3 ,5-triiodothyronine (T3). The thyroid is the only source of T4 in the body but most T3 is produced by deiodination of T4 in peripheral tissues [1]. Most actions of TH are initiated by binding of T3 to nuclear receptors encoded by the THRA and THRB genes [2,3]. The resultant change in receptor conformation leads to the dissociation of co-repressor complexes and the recruitment of co-activator complexes, changing the expression of TH-responsive genes. T4 may have T3-independent non-genomic actions [4] and its affinity for the nuclear T3 receptors may not be negligible particularly in view of the higher free T4 than T3 levels in serum and perhaps also in tissues. Nevertheless, it is generally accepted that T4 functions predominantly as a prohormone for the active hormone T3 [1]. TH is essential for tissue development, in particular of the brain, and for the regulation of the metabolic activities of the tissues throughout life [3,5]. The biological activity of TH is regulated importantly at the level of target tissues. This involves the local expression of iodothyronine deiodinases, in particular D2 and D3 [1]. D2 converts T4 by outer ring deiodination to T3, whereas D3 converts T4 and T3 by inner ring deiodination to the receptorinactive metabolites 3,3 ,5 -triiodothyronine (reverse T3) and 3,3 -diiodothyronine (3,3 -T2), respectively. D2 and D3 have very different spatiotemporal patterns of expression. D2 is
夽 This article is published in the context of the 59e Journées Internationales d’Endocrinologie, Clinique Henri-Pierre Klotz (09/06–10/06/16, Paris). See Annales d’endocrinologie, volume 77, issue 2, pages 61–178 (June 2016). E-mail address: [email protected]
expressed among other tissues in brain, pituitary, brown adipose tissue (BAT), where it usually reaches highest activities after birth. D3 is also expressed in brain but its activity is highest during fetal development. D3 is also highly expressed in other fetal tissues such as the liver but also at very high levels in the placenta and the pregnant uterus. During early development, low D2 and high D3 expression result in low local T3 levels in favor of tissue growth. Ultimately, decreased D3 expression and increased D2 expression allow an increase in local T3 levels, stimulating cellular differentiation. This local regulation of TH action is an autocrine mechanism in tissues such as BAT where T3 functions in the same cell where it is produced by D2 [6], or a paracrine mechanism in tissues such as the brain where T3 is generated by D2 in astrocytes and provided to neuronal target cells [7]. These neurons may also express D3 to terminate T3 action when this is no longer required. The deiodinases are membrane proteins with their active sites localized in the cytoplasm. TH is also metabolized by sulfation and glucuronidation by intracellular enzymes. Therefore, not only the nuclear action but also the metabolism of TH require the transport of the hormone across the plasma membrane. This does not take place by passive diffusion as was assumed for a long time but is mediated by transporter proteins [7–9]. In addition to the deiodinases, these transporters are crucial in the regulation of local TH activity. 2. Thyroid hormone transporters In the last two decades, several transporters have been identified which are capable of transporting T4, T3 and other iodothyronine derivatives [7,9]. They belong to two main classes of transporters, namely the organic anion transporters and amino acid transporters (Table 1). Among the organic anion
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Table 1 Thyroid hormone transporters. Organic anion transporters NTCP (Na/taurocholate co-transporting polypeptide) OATPs (organic anion transporting polypeptides) Amino acid transporters LAT1,2 (L-type amino acid transporters) MCT8,10 (“monocarboxylate transporters”)
transporters, the Na-taurocholate co-transporting polypeptide (NTCP, SLC10A1) and several members of the Na-independent organic anion transporting polypeptide (OATP, SLCO) family facilitate transport of iodothyronines and/or their sulfate conjugates [10,11]. Among the latter family, OATP1C1 deserves special mention in view of its high selectivity for T4 as the substrate and its specific tissue distribution, with particularly high expression in different brain structures [12,13]. As mentioned above, in human brain, OATP1C1 is especially expressed in astrocytes where it facilitates entry of T4 to allow its conversion to T3 [5,14]. Regarding the amino acid transporters, our group has recently made a detailed characterization of the transport of different iodothyronines and iodotyrosines by the L-type amino acid transporters LAT1-4 [15]. LAT1 and LAT2 are heterodimeric transporters composed of a common heavy chain, SLC3A2, and different light chains, SLC7A5 and SLC7A8, respectively [16]. LAT3 and LAT4 are monomeric proteins from another transporter family; their formal codes are SLC43A1 and SLC43A2, respectively [17]. Although there is little homology between the LAT1/2 and LAT3/4 transporters, they share their preference for large aromatic and branched-chain aliphatic amino acids. With regard to iodothyronine substrates, LAT1 facilitates cellular uptake of T4, T3, rT3, and 3,3 -T2, and LAT2 mediates uptake of T3 and 3,3 -T2. LAT3 and LAT4 do not facilitate uptake of iodothyronines but they mediate the efflux of rT3 and 3,3 -T2 [15]. Particularly effective TH transporters are MCT8 (SLC16A2) and MCT10 (SLC16A10), which belong to the monocarboxylate transporter (MCT) family although they do not transport
monocarboxylates but amino acid derivatives [18–20]. MCT10 is also referred to as TAT1 for T-type amino acid transporter 1, as it shows high specificity for the aromatic amino acids Phe, Tyr and Trp [21]. In addition to these amino acids, MCT10 also effectively facilitates uptake and efflux of iodothyronines, in particular T3. MCT10 is expressed at high levels in liver, intestine, kidney and skeletal muscle and at lower levels in many other tissues. The pathophysiological relevance of TH transporters has been best demonstrated for MCT8. The MCT8 protein is highly homologous to MCT10, in particular in its 12 transmembrane domains. In contrast to MCT10, MCT8 does not facilitate transport of any amino acid but it is very effective in the transport of both T4 and T3 as well as other iodothyronines [18,19]. The MCT8 gene is located on the X chromosome and mutations in MCT8 have been associated with severe X-linked psychomotor retardation, also known as the Allan-Herndon-Dudley syndrome (AHDS) [22,23]. Patients with AHDS also have abnormal serum TH profiles, including low T4 and high T3 levels. MCT8 is highly expressed in liver, adrenal, kidney, thyroid and brain. In the thyroid, it is involved in TH secretion. In the brain, it is especially expressed in endothelial cells of the blood-brain barrier, in epithelial cells of the choroid plexus and in neurons in different brain regions [5,24]. The pathogenesis of AHDS is explained by the important role of MCT8 in brain TH transport. Since TH is essential for brain development, impaired MCT8-mediated supply of TH to important target cells in the brain causes severe damage to the developing brain.
3. Thyroid hormone transport across the placenta TH is crucial for fetal and neonatal development. Since the fetal thyroid starts to secrete significant amounts of TH towards mid-gestation, maternal-fetal transfer of TH across the placenta is particularly important in the first half of pregnancy [5]. However, analysis of serum TH levels in newborns with thyroid agenesis indicates that also later in pregnancy, maternal TH remains an important source for the fetus [25].
Table 2 Thyroid hormone transporters in human placenta. Transporter Placenta MCT8 MCT10 LAT1 LAT2 OATP1A2 OATP4A1 CTBs, STBs MCT8 MCT10 LAT1 LAT2 OATP1A2 OATP4A1
Localization
Findings
Ref.
CTBs, STBs, EVTBs CTBs, STBs, EVTBs – – CTBs, STBs, EVTBs STBs (apical)
Highest expression in TM3 Highest expression in TM3 Similar expression in TM1-3 Similar expression in TM1-3 Similar expression in TM1-3 Similar expression in TM1-3
[32,33] [21,33–36] [33,36] [33,34,36] [33] [33,37]
MVM MVM
CTB→STB: expression ↓
[38–40] [38,39] [38–40] [38,39] [38–40] [38–40]
CTB→STB: expression ↓ MVM MVM MVM
CTB→STB: expression ↑ CTB→STB: expression =
CTB: cytotrophoblast; STB: syncytiotrophoblast; EVT: extravillous trophoblast; TM: trimester; MVM: microvillous membrane.
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Studies by Chan et al. and others have demonstrated the expression of different TH transporters in the human placenta, including MCT8, MCT10, LAT1, LAT2, OATP1A2 and OATP4A1 (Table 2). These transporters have been localized by immunohistochemistry in different cells, although they are often present in the apical (maternal-facing) microvillous membrane (MVM) of syncytiotrophoblasts (STBs). Studies using Mct8, Mct10 and Lat2 knockout mice have suggested that each of these transporters is not essential for fetal development [26–28]. However, Lat1 KO mice are embryonic lethal although it is unlikely that this is primarily due to the lack of transplacental TH transport [29]. Perhaps, several TH transporters need to be inactivated before transport of TH across the placenta is compromised. It is uncertain exactly which cells in the placenta represent a barrier for maternal-fetal TH transfer in the different stages of gestation, although it is clear that STBs play a prominent role in this process. An important aspect of transplacental TH transport is the very high expression of D3 also in STBs [30]. Together with the high expression of D3 in fetal tissues and the pregnant uterus, this accounts for the low fetal serum T3 and high serum rT3 levels. However, it is surprising that any T4 may undergo trans-cellular transport across STBs without being converted by D3 to rT3. This may be explained by an additional route for T4 transport across the placenta, namely as a complex with transthyretin (TTR) [31]. This would involve the production of TTR by STBs and release of this protein at the apical membrane. The TTR-T4 complex would then be endocytosed, involving megalin or a similar scavenger protein, transported across the cells in vesicles and released by exocytosis at the basal (fetal-facing) site of the STBs. 4. Conclusion TH transport across the plasma membrane is the first crucial step allowing the intracellular metabolism and action of the hormone. This does not take place by passive diffusion through the lipid bilayer of the membrane but requires the presence of TH transporters. The most specific TH transporters characterized to-date are MCT8 and OATP1C1, which are fundamental to the regulation of bioactive TH levels in the brain. Transplacental transport is crucial for the transfer of maternal TH to the developing fetus. Probably multiple TH transporters are involved in this process but rate-limiting steps (if any) remain to be identified. Disclosure of interest The author declares that he has no competing interest. References [1] Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 2008;29:898–938. [2] Yen PM. Physiological and molecular basis of thyroid hormone action. Physiol Rev 2001;81:1097–142. [3] Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev 2014;94:355–82.
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Please cite this article in press as: Visser TJ. Thyroid hormone transport across the placenta. Ann Endocrinol (Paris) (2016), http://dx.doi.org/10.1016/j.ando.2016.07.006