**2.1. By thyroid hormone-deiodinases (Table 1 and Figure 1)**

The synthesis of THs is regulated through the hypothalamus–pituitary–thyroid (HPT) axis [28] and the follicular cells of the thyroid gland synthesize and secrete T4 and T3 [1,2,21]. This process is under the control of the circulating TH levels through negative feedback loops of this axis [28]. The availability of the active ligand T3 within tissues is locally determined by the action of the iodothyronine deiodinases (Ds) [29]. There are three selenocysteine monodeiodinase subtypes (DI, DII and DIII) [30]. Whilst T3 is generated by the activity of DI and DII, via 5'- reductive or outer ring deiodination (ORD) of the T4 [31], DIII activity (and to a lesser extent that of DI) convert T4 to 3,3',5'-tri-iodothyronine (reverse T3; rT3) and T3 into 3,3'-T2 via inner ring deiodination (IRD), in effect acting as a deactivating enzyme for THs [13,32].

Activities of all three iodothyronine deiodinase subtypes have been demonstrated in most rat placenta [33]. However, in contrast to man, rodent total serum T3 and T4 increase with gestation [34] and the predominant subtype expressed appears to be DIII [35], although DII is also present with significant activity [36]. Placental DIII activity is much greater (approx. 200 times) than DII activity; however, the activity and expression of both DII and DIII fall as gestation progresses [37-40]. Placental DII provides T3 for 'housekeeping' processes, and as indicated above, its activity is much less than that of D3 [40]. DII has been localized to the villous cytotrophoblasts in the first trimester and syncytiotrophoblasts in the third trimester, whereas DIII has been localized to the villous syncytiotrophoblasts in both the first and third trimesters of pregnancy [39]. Both DIII mRNA and activity are present at the implantation site in rodents, as early as gestational day 9 (GD 9), being expressed in mesometrial and antimesometrial decidual tissue [41]. Also, in rabbit [42] and pig [43], the placenta appears to express DIII activity predominantly. The positioning of the deiodinases, particularly DIII, suggests that they might regulate the amount of maternal TH reaching fetal circulation [40]. Interestingly, however, fetuses with total thyroid agenesis but with evidence of circulating maternal TH have normal placental DIII activity, suggesting that there might be other factors modulating T4 access to the deiodinases, such as intracellular protection of TH by THbinding protein (THBP) [40,44]. Collectively, express placental Ds (II, III) may play a critical role in delivery of TH to the fetus as summarized in figure1 [2,45-47] and table 1 [1,2,31,48].

126 Thyroid Hormone

In general, pregnancy is accompanied by profound alterations in the thyroidal economy (hypo- or hyper-thyroidism), resulting from a complex combination of factors specific to the pregnant state, which together concur to stimulate the maternal thyroid machinery [1,23]. Also, clinical studies showed that maternal TH deficiency during the first trimester of pregnancy can affect the outcome of human neurodevelopment [24,25]. Experiments in rats showed that early maternal TH deficiency affects neuronal migration in the cortex [26], while maternal hyperthyroidism too can disturb fetal brain development [27]. Experimental data on the mechanisms regulating intracellular TH availability and action prior to the onset of fetal TH secretion, however, remain scarce. Thus, in this chapter will be aware about the significant roles of THs, their metabolism by Ds and sulfotransferases, their transport by THTs and their binding to TRs from the mother via the placenta to the fetal compartment

The synthesis of THs is regulated through the hypothalamus–pituitary–thyroid (HPT) axis [28] and the follicular cells of the thyroid gland synthesize and secrete T4 and T3 [1,2,21]. This process is under the control of the circulating TH levels through negative feedback loops of this axis [28]. The availability of the active ligand T3 within tissues is locally determined by the action of the iodothyronine deiodinases (Ds) [29]. There are three selenocysteine monodeiodinase subtypes (DI, DII and DIII) [30]. Whilst T3 is generated by the activity of DI and DII, via 5'- reductive or outer ring deiodination (ORD) of the T4 [31], DIII activity (and to a lesser extent that of DI) convert T4 to 3,3',5'-tri-iodothyronine (reverse T3; rT3) and T3 into 3,3'-T2 via inner ring deiodination (IRD), in effect acting as a

Activities of all three iodothyronine deiodinase subtypes have been demonstrated in most rat placenta [33]. However, in contrast to man, rodent total serum T3 and T4 increase with gestation [34] and the predominant subtype expressed appears to be DIII [35], although DII is also present with significant activity [36]. Placental DIII activity is much greater (approx. 200 times) than DII activity; however, the activity and expression of both DII and DIII fall as gestation progresses [37-40]. Placental DII provides T3 for 'housekeeping' processes, and as indicated above, its activity is much less than that of D3 [40]. DII has been localized to the villous cytotrophoblasts in the first trimester and syncytiotrophoblasts in the third trimester, whereas DIII has been localized to the villous syncytiotrophoblasts in both the first and third trimesters of pregnancy [39]. Both DIII mRNA and activity are present at the implantation site in rodents, as early as gestational day 9 (GD 9), being expressed in mesometrial and antimesometrial decidual tissue [41]. Also, in rabbit [42] and pig [43], the placenta appears to express DIII activity predominantly. The positioning of the deiodinases, particularly DIII, suggests that they might regulate the amount of maternal TH reaching fetal circulation [40]. Interestingly,

especially during the gestation period in both human and animals.

**2.1. By thyroid hormone-deiodinases (Table 1 and Figure 1)** 

**2. Placental transport of thyroid hormones** 

deactivating enzyme for THs [13,32].

**Figure 1.** Summary about the interactions of maternal, placental and fetal thyroid metabolism. I, II and III denote deiodinases type 1 (DI), type two (DII) and type three (DIII). SO4 is a sulfation pathway and –SO4 is a desulfation pathway. CNS is central nervous system, TRH is thyroid releasing hormone, M-TRH is maternal thyroid releasing hormone, TSH is thyrotrophin, T2 is diiodothyronine, T3 is triiodothyronine, rT3 is reverse triiodothyronine, T4 is thyroxine, T2S is diiodothyronine sulfate, T3S is triiodothyronine sulfate, T4S is thyroxine sulfate, rT3S is reverse triiodothyronine sulfate, MCT8 is monocarboxylate transporter 8, OATP4A1 is organic anion transporter 4A1, TBG is thyroxin binding globulin, TTR is transthyretin, ACTH is adrenocorticotrophin and hCG is human chorionic gonadotrophin.


Maternal-Fetal Thyroid Interactions 129





++++ + +/-

++

Active site residues - Selenocysteine

Promoter elements - TRE, RXR, no CAAT

flavonoids + +++

**Table 1.** General characteristics of the iodothyronine deiodinases.

Human gene structure

and location

Propylthiouracil inhibitor

Aurothioglucose

X receptors and DDT is dithiols.

inhibitor

histidine and phenylalanine.

or TATA box.


Iopanoic acid inhibitor +++ ++++ +++ Thiouracils ++++ -/+ iodoacetate + ?

a Humans only. T2 is diiodothyronine, T3 is triiodothyronine, rT3 is reverse triiodothyronine, T4 is thyroxine, T2S is diiodothyronine sulfate, T3S is triiodothyronine sulfate, T4S is thyroxine sulfate, rT3S is reverse triiodothyronine sulfate, ORD is outer ring deiodination, IRD is inner ring deiodination, TRE is T3-responsive element, RXR is retinoid

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

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


a Humans only. T2 is diiodothyronine, T3 is triiodothyronine, rT3 is reverse triiodothyronine, T4 is thyroxine, T2S is diiodothyronine sulfate, T3S is triiodothyronine sulfate, T4S is thyroxine sulfate, rT3S is reverse triiodothyronine sulfate, ORD is outer ring deiodination, IRD is inner ring deiodination, TRE is T3-responsive element, RXR is retinoid X receptors and DDT is dithiols.

**Table 1.** General characteristics of the iodothyronine deiodinases.

128 Thyroid Hormone

*K*M

Activity in hypothyroidism

Activity in hyperthyroidism

Reaction catalyzed (Deiodination)

In vitro cofactor limiting

Selenocysteine present Homodimer Yes

Location - Liver, kidney,

Subcellular location - Liver: endoplasmic

Functions - Production serum

Characteristic DI DII DIII

Main form T4-T3, rT3- T2 - T4- rT3, T3- T2 - T4- rT3- T2

Substrate limiting *K*M 0.5 mM 1–2 nM 5–20 mM

5': rT3, rT3S>T2S>>T4

Molecular mass (kDa) 29 30 32

thyroid and pituitary.

reticulum. - kidney: basolateral plasma

T3 and the clearance of serum rT3.




Low-T3 syndrome - Decrease - No change


membrane

5 or 5' (ORD+IRD) 5' (ORD) 5 (IRD)

1–10 Mm DTT >10 mM DTT =70 mM DTT






of T3.

tissues.

tissues. - Increase in thyroida.

deiodination of T4 to T3 and is thus important for the local production



3,3'-T2.

deiodination of T4 to rT3 and of T3 to



musclea.

T4>rT3 T3>T4

Reaction kinetics Ping-pong Sequential

Sulfation of substrates Stimulation Inhibition

Substrate preference 5: T4S>T3S>>T3, T4
