**2.2. By thyroid hormone-transporters (THTs) (Tables 2 & 3 and Figure 1)**

Membrane transporters mediate cellular uptake and efflux of TH [12,40,49]. The ability to transport TH has been described in members of different transporter groups including the monocarboxylate transporters (MCT), L-type amino acid transporters (LAT), Na+/Taurocholate cotransporting polypeptide (NTCP), and organic anion transporting polypeptides (OATP) [50]. With the exception of MCT8, these transporters do not exclusively transport TH and they all have slightly different affinities for specific forms of TH. To date six different THTs are known to be present in the placenta: MCT8, MCT10, LAT1, LAT2, OATP1A2 and OATP4A1 but their relative contributions to placental TH transport are unknown [50-55]. Also, their anatomical localization, ontogeny in the human placenta and relative affinity for the TH and thyronines are very complex. MCT8, MCT10, OATP1A2, OATP4A1 and LAT1 are expressed in villous syncytiotrophoblasts, and MCT8, MCT10 and OATP1A2 in cytotrophoblasts [50]. Although transporters in the apical syncytiotrophoblast membrane are well placed to maximize maternal cellular TH uptake early in gestation, the large numbers and variety of THTs are intriguing [51,53,55]. Moreover, the expression of MCT8 mRNA increased with advancing gestation [55] but there is limited information regarding the ontogeny of the other THTs. In addition, it is likely that the lower expression of MCT8, MCT10, OATP1A2 and LAT1 before 14 week compared to term, as well as the nadir in OATP4A1 expression in the late 1st and early 2nd trimester, may play a role in the necessary limitation of maternal-fetal TH transfer, particularly around the time of onset of endogenous fetal TH production in the early 2nd trimester [56]. Increased expression of THTs in late gestation is consistent with the proposal that there is continued/ increased maternal to fetal supply of TH in the 3rd trimester despite increasing fetal TH production [57]. It is also likely that increased expression of these transporters with gestation may also fulfil the increased need for other biological substances for fetal growth and development, such as amino acids. The most factors regulating the placental expression of these transporters are unknown until now. There are suggestions in rodents that the activity of system-L and the expression of MCT8 in non-placental tissues are influenced by thyroid status [58] suggesting that TH may be a regulator of its own transporters [50]. During the passage of THs from the maternal circulation to the fetal circulation, each THT is likely to have a specific role in each different plasma membrane layer, which might include cellular influx, efflux, or both [59]. To sum, THTs of the various placental cell types serve as channels that help to maintain the differences in the composition of THs and their metabolites between maternal and fetal circulations (figure1 [2,45-47] and tables 2 & 3 [51,52,55,59,60,61]). The relative contributions of these THTs to the transplacental transport of thyroid hormones are still a subject for research.

Maternal-Fetal Thyroid Interactions 131

Organic anion transporting polypeptides

Amphipathic organic compounds

Transporter family

Additional molecules transported

Localization in first and second trimestera

Localization in third trimesterb

transporter of T4.

of adult humans [13,65].

Km T4 (μM) 4.7c

Km rT3 (μM) 2.2c

Monocarboxylate transporters

N/A Aromatic

ST, CT, EVT

amino acids

Heterodimer N/A 4F2hc N/A

Km T3 (μM) 4.0c ≤4.0d 0.8 6.5 0.9

aOnly MCT8 has been localized in the placenta in all three trimesters of pregnancy. bLAT1 and OATP4A1 have been localized only at term. c These Km values were determined for the rat MCT8 protein expressed in Xenopus laevis oocytes. The other Km values shown are mainly from studies using the human gene expressed in X. laevis oocytes. dHuman MCT8 or MCT10 transporters expressed in COS1 cells both showed a greater preference for T3 than T4 uptake. Whereas MCT10 showed a greater capacity than MCT8 to transport T3, MCT8 was found to be a more active

Abbreviations: CT is cytotrophoblast cells, EVT is extravillous trophoblast cells, N/A is no data available, rT3 is reverse

Sulfation (S) appears to be an important pathway for the reversible inactivation of THs during fetal development [2,13,45-47]. Monique Kester and the group from Erasmus University have used a rat model to study the regulation of fetal TH status and have also extended their studies to human pregnancy [62]. The sulfotransferases catalyze the sulfation of the hydroxyl group of compounds, using 3'-phosphoadenosine-5'-phosphsulfate (PAPS) as the universal sulfate donor [63]. This co-factor PAPS is synthesized from two ATP molecules and inorganic sulfate. Neither the DII or DIII iodothyronines catalyze the deiodination of sulfated iodothyronines nor sulfation strongly facilitates the inner ring deiodination of T4 and T3 by DI, but blocks the outer ring deiodination of T4 (activation) [13,64]. The outer ring deiodination of rT3 by DI is not affected by sulfation [64]. Sulfation thus induces the irreversible degradation of TH. Thus, rapid inner ring deiodinations of T4S, T3S and out ring deiodination of rT3S lead to high concentrations of these sulfates in plasma

Km T2 (μM) N/A 7.9 N/A

T3, ST is syncytiotrophoblast layer and STap is predominantly at apical surface of the ST. **Table 3.** Expression of the thyroid hormone transporters in human placenta.

**2.3. By thyroid hormone-sulfotransferases (Figure 1)** 

System L amino acidtransporters

Large neutral amino acids

ST N/A STap N/A STap

N/A 12.5 N/A

>Km T3d 7.9 8.0 >Km T3

MCT8 MCT10 LAT1 LAT2 OATP1A2 OATP4A1

N/A


*<sup>a</sup>* The human protein symbol is presented, if TH transport has been demonstrated in different species including humans. *<sup>b</sup>* If a transporter only transports iodothyronine derivatives, specificity is high (+++). If fewer than five other ligands are known, specificity is moderate (++). If more than five ligands are known, the transporter is denoted as multispecific (+).

**Table 2.** Types of thyroid hormone transporters and their iodothyronine derivates.


aOnly MCT8 has been localized in the placenta in all three trimesters of pregnancy. bLAT1 and OATP4A1 have been localized only at term. c These Km values were determined for the rat MCT8 protein expressed in Xenopus laevis oocytes. The other Km values shown are mainly from studies using the human gene expressed in X. laevis oocytes. dHuman MCT8 or MCT10 transporters expressed in COS1 cells both showed a greater preference for T3 than T4 uptake. Whereas MCT10 showed a greater capacity than MCT8 to transport T3, MCT8 was found to be a more active transporter of T4.

Abbreviations: CT is cytotrophoblast cells, EVT is extravillous trophoblast cells, N/A is no data available, rT3 is reverse T3, ST is syncytiotrophoblast layer and STap is predominantly at apical surface of the ST.

**Table 3.** Expression of the thyroid hormone transporters in human placenta.
