**2.4. By thyroid hormone-genomic and non-genomic actions (Tables 4 & 5 and Figure 2)**

Although the thyroid gland predominantly secretes T4, T3 is the most active TH, since it has a higher affinity by the nuclear thyroid hormone receptors (TRs; α, β) (Figure 2A) [75], which mediate most actions of these hormones [72,73]. THs are released by the thyroid gland to the circulation where they are carried bound to proteins such as thyroxin binding globulin (TBG), transthyretin (TTR) or serum albumin (Table 4) [74]. The level of albumin, which has the lowest T4 affinity and enables a fast release of T4 [76], gradually decreases during pregnancy [77]. TBG is an active carrier and has a possibility to switch between the high-affinity and the low-affinity form [78]. TBG levels are the highest in the second and third trimester of pregnancy [79,80] and the same holds true for TH-binding ratio [81] and thyroid-binding capacity [82], which decreases as soon as 3-4 days after delivery.

**Figure 2)** 

High concentrations of the different iodothyronine sulfates, T4S (thyroxine sulfate), T3S (triiodothyronine sulfate), rT3S (reverse triiodothyronine sulfate) and T2S (diiodothyronine sulfate), have been documented in human fetal and neonatal plasma as well as in amniotic fluid [65,66], and similar findings have been reported for sheep [67]. This has classically been explained by the low hepatic DI expression in the human fetus until the postnatal period [68] and lack of hepatic DI expression until birth in rats [69]. Also, in the rat placenta, where there are insignificant sulfotransferases activities but high DIII activity, irreversible inactivation of DIII appears to be the predominant pathway of iodothyronine metabolism [13]. In the rat fetal liver, sulfotransferase activity is present from the end of the third trimester (GD 17), a time when DI activity is relatively absent [69]. The TH-sulfates may accumulate under such circumstances to form a 'reservoir' of inactive TH from which active hormone may be liberated, in a tissue specific and gestational dependent manner by the action of arylsulfases [13]. To date, six members of this family (ARSAeARSF) have been identified in humans [13,70]. It is interesting that DIII is abundantly expressed in the human placenta [39] and deiodinates T4 and T3 to 3,3'-T2 and rT3, respectively, thus providing substrates for these actions. In the human fetal circulation, T4S and in particular T3S, may represent a reservoir of inactive TH, from which active hormone may be liberated as required (vide supra) [13]. The iodothyronine sulfates in human fetal circulation and amniotic fluid may be derived, at least in part, from sulfation of THs by thermostabile phenol sulfotransferases in the uterus and placenta [13,45]. This may provide a route for the supply of maternal TH to the fetus in addition to placental transfer. Alternatively, iodothyronine sulfates may accumulate in the fetal circulation because of the absence of hepatic transporters which mediate their removal from plasma. It has been demonstrated recently that hepatic uptake of the different iodothyronine sulfates in rats is mediated at least in part through the NTCP and OATP families [71]. Thus, the TH-sulfation mechanism might be useful for non-invasive prenatal diagnostics of fetal thyroid function which is autonomously regulated. The overviews presented here are consistent with the evolving view that sulfation is a major chemical defense system in the maternal-fetal thyroid axis and

will hopefully provide a basis for understanding more about these enzymes.

thyroid-binding capacity [82], which decreases as soon as 3-4 days after delivery.

**2.4. By thyroid hormone-genomic and non-genomic actions (Tables 4 & 5 and** 

Although the thyroid gland predominantly secretes T4, T3 is the most active TH, since it has a higher affinity by the nuclear thyroid hormone receptors (TRs; α, β) (Figure 2A) [75], which mediate most actions of these hormones [72,73]. THs are released by the thyroid gland to the circulation where they are carried bound to proteins such as thyroxin binding globulin (TBG), transthyretin (TTR) or serum albumin (Table 4) [74]. The level of albumin, which has the lowest T4 affinity and enables a fast release of T4 [76], gradually decreases during pregnancy [77]. TBG is an active carrier and has a possibility to switch between the high-affinity and the low-affinity form [78]. TBG levels are the highest in the second and third trimester of pregnancy [79,80] and the same holds true for TH-binding ratio [81] and Abbreviations: T3 is triiodothyronine, T4 is thyroxine, TR is thyroid hormone receptor, RXR is retinoid X receptors, TRE is T3-responsive element, nTRE is none T3-responsive element, Ds is deiodonases, S is sulfotransferases, MCT is monocarboxylate transporter, OATP is organic anion transporter, MAPK/ERK1/2 is mitogen-activated protein kinase, P is phosphorylation and PI-3K is phosphatidylinositol 3-kinase.

**Figure 2.** (A) Schematic representation of major thyroid hormone receptors (TRα, β) domains and functional sub-regions. (B) General model for genomic and non-genomic actions of TH in both adult and fetus; Schematic representation of thyroid hormones (THs; T4 and T3) genomic actions, initiated at the nuclear receptors (TRβ), and non-genomic actions, initiated at cytoplasmatic receptors (TRβ, TRα) and at the plasma membrane on the membrane receptors, particularly integrin αvβ3 receptor. T4 binding (but not T3) to cytoplasmic TRα may cause a change of state of actin. T3 binding (but not T4) to cytoplasmic TRβ activates the phosphatidylinositol 3-kinase (PI-3K) pathway leading to alteration in membrane ion pumps and to transcription of specific genes. TH binding to the integrin receptor results in activation of mitogen-activated protein kinase (MAPK/ERK1/2). Phosphorylated MAPK (pMAPK) translocates to the nucleus where it phosphorylates transcription factors including thyroid receptors (TRβ), estrogen receptor (ER) and signal transducer activators of transcription (STAT). Generally, activity is regulated by an exchange of corepressor (CoR) and coactivator (CoA) complexes.


Maternal-Fetal Thyroid Interactions 135

Actions

repression

activation and repression

and altered transcriptional activity p53

activity

mediated transcription

expression

thermogenesis

phosphorylation and general transcriptional

mitochondrial gene

Increased oxidative phosphorylation

activation of phospholipase C (PLC) and D (PLD) [92-94]. Generally, binding of T3 to a subpopulation of receptors located outside the nuclei can also cause rapid "non-genomic" effects through interaction with adaptor proteins, leading to stimulation of signaling pathways. T4 can also bind to putative membrane receptors such as integrin receptor (αVβ3) inducing MAPK activity [18,73,95,96]. Thus, several observations suggest that the rapid nongenomic effects of TH are widespread and may be involved in multiple physiological processes in many different cell types [87]. However, no specific membrane associated TR isoform or thyroid hormone binding G protein-coupled receptors (GPCR) have been

partners

RXR and TRs

Associated factors or signalling pathways



Raf1/MEK/MAPK TR phosphorylation

MEK/STATs Increased STAT

Co-factors? Increased

identified or cloned and thus the area remains controversial.

Compare face Ligand Receptor Dimerization

T3 TRα and TRβ

T4/T3 Putative GPCR

Non-classical non-genomic actions (seconds to minutes)

T3 TRαp43 mtRXR and

T2 Cytochrome -*c* Va

nucleotide translocase and UCP is uncoupling protein. **Table 5.** General thyroid hormone actions.

mtPPAR

T3 TRαp28 ANT, UCPs Increased

Abbreviations: T4 is Thyroxine, T3 is triiodothyronine, T2 is diiodothyronine, RXR is retinoid X receptor, TR is thyroid hormone receptor, GPCR is G protein coupled receptor, mtRXR is mitochondrial retinoid X receptor α isoform, mtPPAR is mitochondrial peroxisome proliferator activator receptor γ2 isoform, NCoR is nuclear receptor corepressor, SMRT is silencing mediator of RAR and TR, SRC is steroid receptor cooactivator, TRAPs is thyroid receptor associated protein, Raf1 is Raf serine/threonine kinase, MEK is mitogen activated protein kinase kinase, MAPK is mitogen activated protein kinase, STAT is signal transducers and activators of transcription, ANT is adenine

Classical, genomic actions (hours to days)

Nuclear transcription

Cell surface receptor

Mitochondrial

transcription

Mitochondrial oxidation

gene
