*2.4.2. General non-genomic action (Table 5 and Figure 2)*

Although T3 is known to exert many of its actions through the classical genomic regulation of gene transcription, a number of T3 effects occur rapidly and are unaffected by inhibitors of transcription and protein synthesis [88,89]. However, the levels of circulating THs are tightly regulated and stable and thus rapidly mediated responses must involve regulation of pre-receptor ligand metabolism, ligand membrane transport or receptor availability leading to local cell type specific variation in thyroid hormone signaling [87]. Non-genomic actions of THs have been described at the plasma membrane, in the cytoplasm and in cellular organelles [15,21,83,90,91]. They have included the modulation of Na+, K+, Ca2+ and glucose transport, activation of protein kinase C (PKC), protein kinase A (PKA) and mitogenactivated protein kinase (ERK/MAPK) and regulation of phospholipid metabolism by 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 identified or cloned and thus the area remains controversial.


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 nucleotide translocase and UCP is uncoupling protein.

**Table 5.** General thyroid hormone actions.

134 Thyroid Hormone

T4-binding globulin Serum albumin Lipoproteins

Pyruvate kinase, subtype M1 Pyruvate kinase, subtype M2 Prolyl 4-hydroxylase, b-subunit Aldehyde dehydrogenase

**Table 4.** Types of thyroid hormone-binding proteins.

*2.4.1. General genomic action (Table 5 and Figure 2)* 

critical role in the cellular proliferations and differentiations.

*2.4.2. General non-genomic action (Table 5 and Figure 2)* 

TH-binding protein Cellular location

T4 and T3 enter the cell through transporter proteins such as MCT8 and 10 or OATPs. Inside the cells, deiodinases (DI, II) convert T4, the major form of thyroid hormone in the blood, to the more active form T3. DIII produces rT3 and T2 from T4 and T3, respectively [1,73,83]. T3 binds to nuclear TRs, TRα and TRβ, that activate transcription by binding, generally as heterodimers with the retinoid X receptor (RXR) (Table 5) [87], to thyroid hormone response elements (TREs) located in regulatory regions of target genes [84]. Activity is regulated by an exchange of corepressor (CoR) and coactivator (CoA) complexes. Negative TREs (nTRE) can mediate ligand-dependent transcriptional repression, although in this case the role of coactivators and corepressors is not well defined [73,85]. TRs can also regulate the activity of genes that do not contain a TRE through "cross-talk" with other transcription factors (TF) that stimulate target gene expression [28,86]. Both receptors and coregulators are targets for phosphorylation (P) by signal transduction pathways stimulated by hormones and growth factors [84,85]. Thus, the nuclear actions of T3 are sensitive to inhibitors of transcription and translation and have a latency of hours to days [9,73]. Thus, the genomic action will play a

Although T3 is known to exert many of its actions through the classical genomic regulation of gene transcription, a number of T3 effects occur rapidly and are unaffected by inhibitors of transcription and protein synthesis [88,89]. However, the levels of circulating THs are tightly regulated and stable and thus rapidly mediated responses must involve regulation of pre-receptor ligand metabolism, ligand membrane transport or receptor availability leading to local cell type specific variation in thyroid hormone signaling [87]. Non-genomic actions of THs have been described at the plasma membrane, in the cytoplasm and in cellular organelles [15,21,83,90,91]. They have included the modulation of Na+, K+, Ca2+ and glucose transport, activation of protein kinase C (PKC), protein kinase A (PKA) and mitogenactivated protein kinase (ERK/MAPK) and regulation of phospholipid metabolism by

Transthyretin Plasma

Myosin light chain kinase Cytoplasmic

There also are reports of nongenomic effects on cell structure proteins by THs. Actin depolymerization blocks DII inactivation by T4 in cAMP-stimulated glial cells, suggesting that an intact actin cytoskeleton is important for this downregulation of deiodinase activity [9,97]. Interestingly, T4, but not T3, can promote actin polymerization in astrocytes [98] and thus may influence the downregulation of DII activity by a secondary mechanism, perhaps by targeting to lysosomes [9,99]. Moreover, the regulation of actin polymerization and F-actin contents also could contribute to the effects of TH on arborization, axonal transport, and cell-cell contacts during brain development, where the regulation of these factors is fundamental for the organization of guidance molecules such as laminin on the astrocyte plasma membrane and modulates integrin–laminin interactions [3]. T4 was required for integrin clustering and attachment to laminin by integrin in astrocytes [100]. These data suggest that the non-genomic action may play an important role in promoting the normal development.

Maternal-Fetal Thyroid Interactions 137

Disturbance of these processes leads to abnormalities in the neuronal network and may result in mental retardation and other neurological defects, including impaired motor skills and visual processing [115]. If TH deficiency occurs at the perinatal stage, such as in congenital hypothyroidism, timely treatment may rescue most of the symptoms. A shortage of THs starting at the early stages of pregnancy, such as in cretinism, results in neurological

The role of THs in brain development has been studied most extensively in the cerebellum [23,116]. The cellular proliferation and migration processes are disturbed by TH deficiency as investigated predominantly in rodents, where most of cerebellar maturation occurs in the early postnatal period [2]. In the hypothyroid cerebellum, the number and length of Purkinje cell dendrites is severely reduced [1]. At the same time the granule cell parallel fiber growth is reduced, leading to a reduction in axodendritic connections between the Purkinje cells and the granule neurons [117]. Additionally, other cell types such as astrocytes, Golgi epithelial cells, basket cells, and oligodendrocytes show abnormalities under hypothyroid conditions [116]. Several TH target genes have been identified over the years, including genes coding for myelin proteins, cytoskeletal proteins, neurotrophins and their receptors, transcription factors, and intracellular signaling proteins [118] and recent transcriptome analyses continue to increase their number [119-121]. Some of these genes only respond to thyroid status for a short and specific period during development, a feature that is typical for many TH target genes in brain [122]. Interestingly, a reduction or absence of TH during brain maturation yields molecular, morphological and functional alterations in

Neonatal hyperthyroidism was described as a critical disease marked mainly by cardiac symptoms, poor weight gain and severe neurological manifestations [1,133-137]. Fetal thyrotoxicosis is the result of thyroid-stimulating antibody transfer to the fetus in the setting of maternal Grave's disease [2,138]. It may present with a variety of clinical features, which include persistent sinus tachycardia, fetal hydrops, intrauterine growth restriction, goiter and fetal demise [1,139]. The vast majority of cases of excessive serum TH concentration seen in pregnancy are due to the overproduction of THs (Graves' disease, toxic nodular goiter); in the postpartum period, thyrotoxicosis may be due to exacerbation of Graves' hyperthyroidism or to the release of thyroid hormone due to an acute autoimmune injury to

The management of hyperthyroidism in pregnancy, which most often is caused by Graves' disease, has been reviewed recently [141,142]. Hyperthyroidism occurs in about 0.2–0.4% of all pregnancies. Hyperthyroidism should be distinguished from gestational transient thyrotoxicosis, which is due to the TSH-receptor stimulating effects of hCG [143,144]. This hCGinduced hyperthyroidism is mostly mild and need not be treated. Only rare cases with extremely high hCG (i.e. due to a hydatidiform mole) might induce severe thyrotoxicosis [145]. The signs and symptoms of hyperthyroidism due to Graves' disease may aggravate in the first trimester and thereafter may become mild. Untreated hyperthyroidism is associated with severe

deficits that cannot be rescued by exogenous TH addition at later stages [25].

the cerebral cortex, hippocampus and cerebellum [123-132].

the thyroid tissue (postpartum thyroiditis-PPT) [2,140].

**5. Maternal-fetal thyroid in hyperthyroid state (Figure 3)** 
