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Traversing barriers – How thyroid hormones pass placental, blood-brain and blood-cerebrospinal fluid barriers
Kelly Landers, Kerry Richard
PII: S0303-7207(17)30054-0
DOI: 10.1016/j.mce.2017.01.041
Reference: MCE 9814
To appear in: Molecular and Cellular Endocrinology
Received Date: 13 October 2016
Revised Date: 19 January 2017
Accepted Date: 24 January 2017
Please cite this article as: Landers, K., Richard, K., Traversing barriers – How thyroid hormones passplacental, blood-brain and blood-cerebrospinal fluid barriers, Molecular and Cellular Endocrinology(2017), doi: 10.1016/j.mce.2017.01.041.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service toour customers we are providing this early version of the manuscript. The manuscript will undergocopyediting, typesetting, and review of the resulting proof before it is published in its final form. Pleasenote that during the production process errors may be discovered which could affect the content, and alllegal disclaimers that apply to the journal pertain.
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Traversing barriers – how thyroid hormones pass placental, blood-brain and 1
blood-cerebrospinal fluid barriers 2
Kelly Landersa and Kerry Richarda,b,c 3
aConjoint Endocrine Laboratory, Chemical Pathology, Pathology Queensland, 4
Queensland Health, Herston, Qld 4029, bSchool of Medicine, University of 5
Queensland, Herston, Qld 4029, cSchool of Biomedical Sciences, Queensland 6
University of Technology, Brisbane, Qld 4000. 7
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Corresponding author and person to who reprint requests should be addressed: 9
Kerry Richard, Ph.D., Conjoint Endocrine Laboratory, Level 9, Bancroft Centre, 300 10
Herston Road, Herston, Queensland 4029, Australia, Phone: +61 7 3362 0495, Fax: 11
+61 7 3646 8842 12
Email: [email protected] 13
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ABSTRACT 26
Thyroid hormone is essential for normal human fetal growth and brain development. 27
As the fetal thyroid does not secrete thyroid hormones until about 18 weeks gestation, 28
early fetal brain development depends on passage of maternal hormone across the 29
placenta into the fetal circulation. To reach the fetal brain, maternally derived and 30
endogenously produced thyroid hormone has to cross the blood-brain and blood-31
cerebrospinal fluid barriers. In this review we will discuss the complex biological 32
barriers (involving membrane transporters, enzymes and distributor proteins) that 33
must be overcome to ensure that the developing human brain has adequate exposure 34
to thyroid hormone. 35
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Key words: thyroid hormone, placenta, brain, blood–brain barrier, blood-37
cerebrospinal fluid barrier 38
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1. Introduction 51
Thyroid hormones (TH) are essential for normal human fetal development and 52
especially important in the development of the central nervous system. The 53
hypothalamic-pituitary-thyroid (HPT) axis begins to develop at around 5 weeks 54
gestation and while there is some TH synthesis at about 12 weeks, significant amounts 55
of TH are not produced until after the 18th week of gestation. This means that the 56
developing fetus requires an adequate and timely supply of TH from its mother 57
through the placenta. In order to reach the developing fetal brain, TH in the fetal 58
circulation then must traverse the blood-brain barrier (BBB) and the blood-59
cerebrospinal fluid barrier (BCSFB). Each of these barriers (placental and brain) have 60
unique structures comprised of cells that express different TH membrane transporters, 61
metabolising enzymes and distributor proteins. 62
1.1 Membrane transporters 63
Due to the lipophilic nature of THs, it was historically believed that THs could 64
passively traverse membranes. However, THs are charged and cannot cross a 65
phospholipid bilayer (Schweizer and Kohrle, 2013). Over the last two decades several 66
membrane transporters capable of transporting TH have been identified (see (Visser, 67
2000, Visser et al., 2008, Visser et al., 2011)) including the organic anion transporting 68
polypeptides OATP1A2, OATP4A1 and OATP1C1, the L-type amino acid 69
transporters LAT1 and LAT2 (Friesema et al., 2001) and the more recently described 70
specific TH transporter monocarboxylate transporters MCT8 and MCT10 (Friesema 71
et al., 2003). 72
1.2 Metabolising enzymes 73
During vertebrate development, the action of TH is coordinated by three 74
iodothyronine deiodinases: Type 1 (D1), Type 2 (D2) and Type 3 (D3), that differ in 75
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substrate specificity and tissue distribution. D2 is an outer ring deiodinase that 76
converts transcriptionally inactive thyroxine (T4) to active triiodothyronine (T3). 77
Conversely D3 is an inner ring deiodinase that inactivates T3 to diiodothyronine (T2) 78
or T4 to reverse triiodothyronine (rT3). D1 has both inner and outer ring deiodinase 79
activity. For a review on deiodinases see (Dentice and Salvatore, 2011). The balance 80
of D2 and D3 activity plays an important role in fetal development by ensuring safe 81
levels of TH are maintained (Richard K et al., 1998). 82
In addition to deiodination, THs are metabolised by conjugation of the phenolic 83
hydroxyl group with sulfate or glucuronic acid (Wu et al., 2005). Sulfation and 84
glucuronidation increase water-solubility of the substrates, which facilitates biliary 85
and/or urinary clearance. Sulfation of TH is catalysed by sulfotransferases and 86
desulfation by arylsulfatases. TH sulfates are the preferred substrates for deiodination 87
(Visser, 1994) and are rapidly degraded in liver by D1. In the presence of low D1 88
activity, T3 sulfate may function as a reservoir of inactive hormone from which active 89
T3 may be recovered by arylsulfatases (Visser, 1994). Glucuronidation of TH is 90
catalysed by UDP-glucuronyltransferases that utilise UDP-glucuronic acid as a 91
cofactor. Glucuronidation of TH appears to be more important in rodents than in 92
humans (Visser et al., 1993). 93
1.3 TH Distributor proteins 94
In serum, TH is bound to three hepatically synthesised distributor proteins, which are, 95
in order of their affinity for T4, thyroxine binding globulin (TBG), transthyretin 96
(TTR) and albumin (Chopra, 1996). The extent of overall binding is great such that 97
the free T4 concentration in serum is less than 0.1% of total T4. TTR is also 98
synthesised by several other cell types including placenta (McKinnon et al., 2005) and 99
choroid plexus (Herbert et al., 1986) and plays a role in transporting TH into cells 100
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(Landers et al., 2009, Landers et al., 2013, Schreiber et al., 1990). Several intracellular 101
TH binding proteins have also been identified that may modify TH transport and 102
access to nuclear TH receptors including alpha-1-antitrypsin, alpha-1-acid glycoprotein 103
and mu-crystallin (Barsano and DeGroot, 1993, Barsano and DeGroot, 2012, 104
McKinnon et al., 2005, Suzuki et al., 2007). 105
2. The Placental Barrier 106
2.1 Placental structure 107
The human placenta is a highly specialised organ that actively exchanges nutrients 108
and waste between the maternal and fetal circulations. During the first 10-12 weeks of 109
gestation, the fetus is bathed in amniotic fluid and is completely surrounded by the 110
placenta through which maternal-fetal exchange occurs (Gude et al., 2004). During 111
this time, the placenta is primarily made up of cytotrophoblasts, which undergo 112
proliferation and differentiation into a multinucleated syncytium called the 113
syncytiotrophoblast (Gude et al., 2004, Huppertz and Peeters, 2005) and transport of 114
nutrients and waste between maternal and fetal circulations occurs across these two 115
layers of cells (Gude et al., 2004). By the 13th week of pregnancy (Foidart et al., 1992) 116
the hemochorial plate is formed allowing chorionic villi to be perfused by maternal 117
blood (Huppertz and Peeters, 2005). At this time, the placental barrier consists of four 118
layers, the maternal facing syncytiotrophoblasts, a layer of cytotrophoblasts, 119
connective tissue and the endothelial cells lining the fetal capillaries. The utero-120
placental unit consists of the chorionic plate derived from the fetal chorionic sac and 121
the basal plate derived from maternal endometrium. In between these two regions is 122
the intervillous space where chorionic villi are bathed in maternal blood introduced 123
through maternal spiral arteries. The placental barrier is formed by the tight layer of 124
multinucleated syncytiotrophoblasts, located on the chorionic villi that separate 125
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maternal blood from fetal capillaries and is the layer of cells through which maternal-126
fetal exchange occurs (Fig.1). 127
2.2 Placental TH transport 128
For many years it was thought that the placenta was impermeable to thyroid hormones 129
(TH) despite early studies demonstrating that radiolabeled TH crossed the placenta 130
(Fisher et al., 1964). Later, the discovery of high D3 activity suggested that 131
intracellular deiodination may provide the barrier to placental TH transport (Roti et 132
al., 1981). However in 1989, Vulsma et al (Vulsma et al., 1989) demonstrated that 133
fetuses unable to produce TH had significant (but low) circulating TH levels at birth 134
providing evidence of materno-fetal transfer of TH. 135
Since then the presence of both T3 and T4 have been identified in the fetal 136
exocoelomic cavity and in fetal tissues from 5 weeks gestation although the fetal 137
thyroid gland does not start to function until around 18 weeks gestation (Calvo et al., 138
2002). Additionally in early pregnancy fetal brain T4 levels reflect maternal serum 139
levels (Chan et al., 2009, Ferreiro et al., 1988). 140
Transport of TH across the trophoblast cell membrane was first reported in 1992 141
(Mitchell et al., 1992). Since then, six transporters have been identified in placental 142
tissue; LAT1 (Ritchie and Taylor, 2001) and LAT2 (Park et al., 2005), OATP1A2 143
(Patel et al., 2003) and OATP4A1 (Sato et al., 2003) and MCT8 (Chan et al., 2006) 144
and MCT10 (Kim et al., 2001) (for a review see (Patel et al., 2011)). MCT8, MCT10, 145
OATP1A2, OATP4A1 and LAT1 are all expressed in syncytiotrophoblasts while 146
MCT8, MCT10 and OATP1A2 are expressed in cytotrophoblasts (Loubiere et al., 147
2010). All of these transporters, with the exception of MCT8, also transport other 148
ligands (Loubiere et al., 2010). The large numbers of placental TH transporters 149
suggests some functional redundancy. 150
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2.3 Placental metabolising enzymes 151
Once the TH enters the trophoblast cell it is vulnerable to deiodination by D2 or the 152
more highly expressed inactivating D3 (Koopdonk-Kool et al., 1996). D2 is found in 153
the villous cytotrophoblast in the first trimester and the syncytiotrophoblast in the 154
third trimester whereas D3 is localised to the syncytiotrophoblasts in both the first and 155
third trimesters (Chan et al., 2003). D3 activity in human placenta is up to 400 times 156
greater than that of D2 (Koopdonk-Kool et al., 1996) and, using the perfused human 157
placenta it has been demonstrated that, unless D3 activity is inhibited, T4 cannot cross 158
the placenta in significant amounts (Mortimer et al., 1996). 159
Several sulfotransferase (SULT) enzymes are expressed in placenta, particularly those 160
of the SULT1A family (Stanley et al., 2001). Despite this, very little THs sulfation 161
occurs in human placenta (Stanley et al., 2001). 162
2.4 Placental TH Distributor Proteins 163
Human placenta synthesises several TH distributor proteins including transthyretin 164
(TTR), albumin, α-1-antitrypsin and α-1-acid glycoprotein (McKinnon et al., 2005). 165
The nonsteroidal antiinflammatory drug mefenamic acid is a potent inhibitor of T4 166
protein binding and incubation of placental homogenates with mefenamic acid 167
increases deiodination of T4, most probably because T4 displaced from TTR, 168
albumin, and possibly other thyroid hormone binding proteins would be more 169
available for deiodination (McKinnon et al., 2005). This strongly suggests that TTR 170
and possibly other TH distributor proteins are involved in the safe transfer of TH from 171
mother to fetus across the placenta (Landers et al., 2013). TTR produced by human 172
placenta is mainly secreted across the apical membrane toward the maternal 173
circulation (Mortimer et al., 2012). TTR is also endocytosed through the apical 174
membrane of trophoblasts and uptake is increased by TH binding (Landers et al., 175
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2009). Uptake of the TTR-TH complex is through a receptor-mediated mechanism 176
(Landers et al., 2013) and is greater in a low oxygen environment such as that found 177
in first trimester placenta (Patel et al., 2010, Patel et al., 2012) when the requirement 178
for maternal TH is at its highest. The receptor for the TTR-TH complex has not yet 179
been identified but there is strong evidence that it is a member of the Lipoprotein 180
Receptor Related Protein (LRP) family since uptake of TTR-TH is sensitive to the 181
chaperone protein Receptor Associated protein (RAP) (Landers et al., 2013). 182
Incubation of human placental explants with fluorescently labelled TTR results in 183
accumulation of TTR in placental fetal capillaries (Mortimer et al., 2012) indicating 184
TTR is capable of transplacental passage; whether or not it is in a complex with TH 185
remains to be determined. 186
2.5 Proposed model of TH transfer across placenta 187
There is still much controversy surrounding the route of TH transfer across the 188
placenta. Several TH transporters are expressed by trophoblasts suggesting there is 189
some redundancy in the system; not surprising considering the importance of maternal 190
TH for fetal development. Given the high levels of D3 in placenta (Koopdonk-Kool et 191
al., 1996) and the protective effect of TTR binding (McKinnon et al., 2005), there is 192
strong evidence that TTR may chaperone TH across the placental barrier to the fetal 193
capillaries (Landers et al., 2013, Landers et al., 2009, McKinnon et al., 2005, 194
Mortimer et al., 2012) (Fig.1). 195
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3. Brain 198
Once in the fetal circulation, maternal THs must then traverse into the fetal brain. To 199
do this they must cross the Blood-Brain Barrier (BBB), the Blood-Cerebrospinal Fluid 200
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Barrier (BCSFB) or both (Fig.2). These barriers have two main functions; to impede 201
free diffusion between blood and brain fluids and to provide transport processes for 202
nutrients, ions and waste products (Redzic, 2011). 203
In adult rodents, the BBB is the primary route for TH to enter the brain, with a smaller 204
amount entering through the BCSFB (Dratman et al., 1991, Horn and Heuer, 2010). 205
However, there is evidence that the choroid plexuses (BCSFB) are the main route of 206
transfer from blood to brain in rat fetuses (Johansson et al., 2008). 207
In 1954, Grontoft (Grontoft, 1954) demonstrated that dye injected into the blood 208
stream did not enter the brain of human fetuses of 5 – 26cm long (approx. 10-20 209
weeks gestation) suggesting a functional barrier exists very early in development. 210
Additionally, some mechanisms present in embryos are not present in adults, e.g., 211
specific transport of plasma proteins across the blood–CSF barrier (Dziegielewska et 212
al., 1988) and embryo-specific intercellular junctions between neuroependymal cells 213
lining the ventricles (Saunders et al., 2012). For an excellent review of human brain 214
barrier mechanisms in developing brain see (Saunders et al., 2012). 215
There is very little known about the route of TH entry to the developing human brain 216
given the difficulty of conducting such studies, and much of our information is based 217
on conjecture from work with developing rodents and studies of adult human brain. 218
3.1 Blood-Brain Barrier 219
The BBB separates circulating blood from brain interstitial fluid and is localised to 220
the monolayer of endothelial cells lining brain capillaries (Fig. 2). Brain endothelial 221
cells have a specialised morphology in that they are connected to adjacent endothelial 222
cells via tight junctions (Vorbrodt and Dobrogowska, 2003). These tight junctions 223
restrict the paracellular passage of compounds in both directions (Anderson and Van 224
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Itallie, 2009, Wolburg and Lippoldt, 2002). Astrocytic end feet that line the basal side 225
of brain endothelial cells also provide a barrier function (Abbott et al., 2006). 226
3.1.1 Thyroid hormone transporters in the BBB 227
A number of thyroid hormone transporters have been identified in brain with species-228
specific expression and distribution (for a comprehensive review see (Wirth et al., 229
2014)). In both fetal and adult humans and adult rodents, MCT8 is expressed in 230
cerebral micro-vessels and in neurons (Roberts et al., 2008). In micro-vessels MCT8 231
is localised predominantly to the luminal (blood-facing) surface. OATP1C1 is also 232
expressed in cerebral micro-vessels of adult rodents and both fetal and adult humans, 233
however OATP1C1 in humans is present at comparatively lower levels (Roberts et al., 234
2008). OATP1C1 in micro-vessels is localised mainly to the abluminal (brain-facing) 235
surface with some staining overlapping with aquaporin 4, a marker of astrocytic end 236
feet (Roberts et al., 2008). 237
In MCT8 deficient mice, T4 is still transported to the brain, however mice deficient in 238
both MCT8 and OATP1C1 have diminished concentrations of T3 and T4 in brain 239
(Mayerl et al., 2014). The difference in OATP1C1 expression between species is most 240
likely the reason that human males with MCT8 mutations present with a severe X-241
linked neurological condition (Allan-Herndon-Dudley Syndrome), whilst Mct8 null 242
mice exhibit a normal neurological phenotype (Kersseboom and Visser, 2011, 243
Kersseboom and Visser, 2011). 244
LAT1 and LAT2 are both expressed in mouse neuron and astrocytic cells and both 245
transporters have been shown to be involved in T3 and T4 uptake into neurons and 246
astrocytes (Braun et al., 2011, Wirth et al., 2009). LAT2 is present in mouse neurons 247
at all stages of development; however, there is no expression of LAT2 in developing 248
neurons of humans (Braun et al., 2011, Wirth et al., 2009). LAT1 and to a lesser 249
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extent LAT2 are detected in human brain capillary endothelial cells (de Boer et al., 250
2003, Muller and Heuer, 2014). 251
3.1.2 TH metabolising enzymes in the BBB 252
In humans, D2 is present in the cerebral cortex during the first trimester of 253
development. T3 can also be detected in first trimester brain (Chan et al., 2002). D2 is 254
found almost exclusively in glial cells including the astrocytes (Guadano-Ferraz et al., 255
1997) that line the brain endothelial cells and provide part of the barrier function. D2 256
expression in fetal rat brain increases between gestational days 19 and 21 and 257
increases in response to low serum T4 levels (Ruiz de Ona et al., 1988). Neurons are 258
the only type of brain cell to demonstrate D3 expression in both mice and humans 259
(Galton, 2005) and human fetal cerebellum has high D3 activity (Kester et al., 2004). 260
To our knowledge there are no reports of TH sulfation or studies of sulfotransferase 261
expression specifically in human brain endothelium. 262
3.1.3 Proposed model for TH passage across BBB 263
The current proposed model for thyroid hormone crossing the BBB suggests that TH 264
is taken up primarily through MCT8 in brain endothelial cells (Fig.2). From the 265
endothelial cells T4 enters astrocytic end feet, possibly via OATP1C1, where it can be 266
locally converted to T3 by D2 and exported via an unknown transporter. MCT8 267
mediates T3 entry to neuronal cells where it binds thyroid receptors and regulates 268
transcription of specific genes, or T3 may be metabolised by D3 to T2. 269
270
3.2 Blood-Cerebrospinal Fluid Barrier 271
The BCSFB is localised to a monolayer of cuboidal epithelial cells of the choroid 272
plexus located in the lateral, third and fourth ventricles of the brain that separates 273
blood from the cerebrospinal fluid (CSF) (Fig.2). The choroid plexus is a villous 274
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structure attached to the ventricular ependyma, where ependymal cells and choroid 275
plexus epithelial cells form a continuous layer (Redzic and Segal, 2004). The 276
choroid plexus consists of a layer of CSF-facing epithelial cells that surround a core 277
of fenestrated capillaries and stromal cells. Choroid plexus epithelial cells are joined 278
together by tight junctions, providing the barrier between circulating blood and the 279
CSF (Redzic and Segal, 2004). The choroid plexus is a secretory epithelium that 280
produces 70% of CSF (Cserr, 1971) formed at a rate of ~0.4mL.min-1.g tissue-1. The 281
total volume of CSF in the entire human CNS amounts to 150mL, thus the CSF is 282
replaced three-four times per day (Cserr et al., 1992). 283
3.2.1 Thyroid hormone transporters in the BCSFB 284
Several thyroid hormone transporters have been localised to the choroid plexus 285
(Mayerl et al., 2012, Wirth et al., 2014). MCT8 is expressed in both apical and basal 286
membrane of human and mouse choroid plexus epithelial cells (Friesema et al., 2012, 287
Wirth et al., 2014). MCT8 is widely expressed in human fetal brain, including in the 288
epithelium of the choroid plexus and ependymal cells (Chan et al., 2014). 289
OATP1C1 is detected on both apical and basal membranes of human and rodent 290
choroid plexus epithelial cells, with a bias towards the basal surface (Grijota-Martinez 291
et al., 2011, Roberts et al., 2008). Expression of OATP1C1 is low in the human fetal 292
choroid plexus compared to adults and fetal rodents (Roberts et al., 2008). Expression 293
of MCT10 and LAT2 have also been described in human fetal choroid plexus (Chan 294
et al., 2011, Friesema et al., 2012). 295
3.2.2 TH metabolising enzymes in the BCSFB 296
D2 is expressed in chicken choroid plexus (Verhoelst et al., 2004) and human fetal 297
(13 – 20 weeks gestation) choroid plexus has the highest level of D2 activity 298
compared to other regions of the brain (Kester et al., 2004). Choroid plexus displays 299
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the highest level of TH sulfotransferase activity in human fetal brain and SULT1A1 300
protein has been localised to human fetal choroid plexus (Richard et al., 2001). Very 301
low levels of TH sulfatase activity is present in choroid plexus suggesting that it has 302
low capacity for recovery of sulphated THs and that they are not a major reservoir of 303
TH in the brain (Richard et al., 2001). 304
3.2.3 TH Distributor Proteins in the BCSFB 305
It has been shown in many species (Cavanagh et al., 1982, Ramey and Birge, 1979) 306
that, during the early stages of development, the brain is supported in CSF that 307
contains significantly higher levels of protein than are found in adult. Very high 308
expression of both TTR mRNA and protein have been demonstrated in second 309
trimester human fetal choroid plexus (Jacobsson, 1989) and TTR has been measured 310
in human fetal CSF as early as 12 weeks gestation suggesting an important role in 311
early brain development (Bell JE, 1991). There are no reports of humans that lack 312
TTR. Human fetuses and premature infants show levels of CSF protein which are 313
higher than those at term (Bell JE, 1991). Proteins in human fetal CSF include 314
albumin, TTR, α-1-antitrypsin, transferrin and alphafetoprotein (Bell JE, 1991). In the 315
CSF, 80% of T4 is bound to TTR (Chanoine et al., 1992). TTR is produced by the 316
choroid plexus epithelial cells and is secreted apically into the CSF where it 317
constitutes up to 20% of total CSF protein (Schreiber et al., 1990). TTR has been 318
postulated to move T4 against the free T4 gradient between blood and CSF (Chanoine 319
et al., 1992, Southwell et al., 1993), and assist in the distribution of thyroid hormone 320
throughout the rat brain (Chanoine et al., 1992). If synthesis of new TTR is blocked 321
then T4 cannot cross choroid plexus epithelial cells (Southwell et al., 1993). The 322
movement of T4 into the CSF is dependent on the binding capacity of TTR (Chanoine 323
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et al., 1992). If the TH binding capacity of TTR is disrupted then TH cannot cross the 324
choroid plexus. For a recent review see (Richardson et al., 2015). 325
From studies of TTR null mice, expression and localisation data suggests that thyroid 326
hormone may traverse the BCSFB by entering the basal side of choroid plexus 327
epithelial cells mediated by OATP1C1 and exiting apically into the CSF via MCT8 328
(Richardson et al., 2015). TTR null mice have 36% T4 levels in their brain compared 329
to wildtype mice (Palha et al., 1997). In rabbit choroid plexus epithelial cells T4 was 330
taken up and, following treatment with brefeldin A, accumulated in the epithelial cells 331
(Zibara et al., 2015). Brefeldin A also inhibits TTR secretion in placental cells 332
(Landers et al., 2009). This strongly suggests that TH binds to intracellular TTR and 333
the TTR-TH complex is exported to the CSF. 334
3.2.4 Specialised Ependymal Cells 335
As previously mentioned, the choroid plexus is attached to the ventricular ependyma. 336
Ependymal cells are glial cells that lack tight junctions and instead have gap junctions 337
allowing passage of larger solutes (Brightman and Reese, 1969) and may provide a 338
route of entry for thyroid hormones to enter nervous tissue (neuroglia and neurons) 339
from the CSF. In neonatal mouse a group of specialised ependymal cells called 340
tanycytes co-express MCT8 and D2 (Guadano-Ferraz et al., 1997, Roberts et al., 341
2008). MCT8 and OATP1C1 are both expressed in the tanycytes of second trimester 342
human fetal brain however only OATP1C1 expression is detected at term (Friesema et 343
al., 2012). Tanycytes have processes that penetrate into the hypothalamus of the brain 344
facilitating access of thyroid hormones to hypothalamic nuclei and neurons that 345
mediate release of thyrotrophin-releasing hormone (Bolborea and Dale, 2013) and 346
therefore are involved in the regulation of TH secretion from the thyroid gland. 347
3.2.5 Proposed model for TH passage across BCSFB 348
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The current proposed route for TH across the fetal BCSFB is that TH in the 349
bloodstream enters choroid plexus epithelial cells mainly through MCT8 (Fig.2). 350
Internalised THs bind with intracellular TTR and the TTR-TH complex is exported 351
through the apical choroid plexus cell membrane into the CSF. From the CSF, TH 352
may enter the brain through ependymal cells or tanycytes. The large amount of bound 353
thyroxine (TTR-T4) may be important in the distribution of thyroid hormone to other 354
areas of the brain (Chanoine et al., 1992). 355
356
4. Conclusion 357
TH is essential for normal human fetal brain development to occur but the human 358
fetal thyroid gland does not produce significant amounts of T4 until 18 weeks 359
gestation. Maternal TH must cross many complex biological barriers in order to reach 360
the developing fetal brain in an adequate and timely manner. The processes by which 361
TH crosses the human placental and brain barriers are complex and require further 362
study since most of our knowledge is based on animal studies. Understanding how TH 363
crosses human biological barriers at different stages of development poses a huge but 364
important challenge for researchers. 365
366
Acknowledgements 367
This work was funded by the Science Education and Research Trust Fund, Pathology 368
Queensland, Queensland Health and the Royal Brisbane and Womens Hospital 369
Research Foundation. 370
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Figure legends 374
Figure 1. Proposed route of TH transfer across placenta. Several transporters are 375
capable of transporting TH across placenta including MCT8, MCT10, LAT1, LAT2, 376
OATP1A2 and OATP4A1. However placental deiodinase 3 (D3) is expressed at high 377
levels and can convert T4 to rT3. Placenta synthesises and secretes transthyretin 378
(TTR) that can bind maternal TH. TTR is taken up by trophoblasts and may 379
chaperone T4 to the fetal capillaries. 380
381
Figure 2. Proposed model of TH transfer across the Blood-Brain (BBB) and 382
Blood-Cerebrospinal Fluid (BCSFB) Barriers 383
BBB - Brain endothelial cells take up T4 primarily through MCT8. T4 then enters 384
astrocytic end feet via OATP1C1, where it can be locally converted to T3 by D2 and 385
exported via an unknown transporter. MCT8 mediates T3 entry to neuronal cells. 386
BCSFB - T4 in the bloodstream enters choroid plexus epithelial cells through MCT8. 387
Internalised T4 binds with intracellular TTR and the TTR-T4 complex is exported 388
through the apical choroid plexus cell membrane into the CSF. From the CSF, TH 389
may enter the brain through ependymal cells or tanycytes. 390
391
392
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Highlights
• Fetal brain requires maternal thyroid hormone for normal development
• Maternal thyroid hormone must traverse complex biological barriers to
reach fetal brain
• Our understanding of biological barriers to thyroid hormone is limited
and requires further study