1. Chapter 6 The Hypothalamus—Pituitary—Thyroid (HPT) Axis of Mammals
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Figure 6-1 The mammalian thyroid. The thyroid gland is located in the neck region. It consists of many hollow follicles, each of which is filled with a proteinaceous fluid called colloid which is secreted by the follicle cells. Thyroxine synthesized by the follicle cells is stored in the colloid. The C-cells or parafollicular cells are of ultimobranchial origin and secrete the calcium-regulating hormone, calcitonin (see Chapter 14). (Adapted with permission from McNabb, F.M.A., “Thyroid Hormones,” Prentice Hall, Upper Saddle River, NJ, 1993.)
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Figure 6-2A Thyroid and parathyroid glands. (A) Low magnification of compact parathyroid gland (above) embedded in the thyroid gland consisting of colloid-filled follicles (below). (B) High magnification of thyroid follicles with squamous epithelium surrounding colloid.
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Figure 6-2B Thyroid and parathyroid glands. (A) Low magnification of compact parathyroid gland (above) embedded in the thyroid gland consisting of colloid-filled follicles (below). (B) High magnification of thyroid follicles with squamous epithelium surrounding colloid.
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Figure 6-3 Thyroid hormone biosynthesis. The sodium iodide symporter (NIS) transports Na+ and I– across the basolateral plasma membrane of a follicular cell. The Na+/K+ ATPase maintains the sodium diffusion gradient required for operation of the NIS. The enzyme thyroid peroxidase (TPO) located at the apical surface is responsible for activating I–, for iodinating thyroglobulin (Tgb), and for coupling iodinated tyrosines to form T4. Release of thyroid hormones requires engulfing colloid (endocytosis) to form intracellular endosomes that merge with lysosomes to form an endolysosome. This results in degradation of Tgb and liberation of T4 into the cytosol, where a type-1 deiodinase (D1) converts some of it to T3 and rT3 (not shown). These products then pass from the basal surface of the cell into the blood.
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Figure 6-4 Worldwide location of iodide-poor regions. The shaded portions indicate the iodide-poor regions.
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Figure 6-5 The cassava root is an important dietary staple in tropical countries but is rich in thiocyanate which blocks iodide uptake by the thyroid gland.
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Figure 6-6 Some thyroid inhibitors. (A) Thiourea, thiouracil, propylthiouracil (PTU), carbimazole, and methimazole are all goitrogens that block iodide uptake and/or the iodination and coupling reactions. (B) Goitrin is a naturally occurring goitrogen that is made from the precursor progoitrin by the enzyme myrosinase. (C) Ipodate and amiodarone block liver deiodinases. PTU also blocks type-1 deiodinase activity.
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Figure 6-7 Some environmental thyroid disrupting contaminants. Dioxins (A) and polychlorinated biphenyls (PCBs) (B) arise from a number of diverse industrial sources and can alter normal thyroid hormone metabolism and action. Polybrominated diphenyl ethers (PBDEs) (C) are ubiquitous contaminants in the environment that arise mainly from fire-retardant materials. PBDEs have a striking structural resemblance to T4 and T3 and have been reported to alter plasma thyroid hormone levels and thyroid hormone metabolism. Chlorate (D) and perchlorate (E) anions potently block thyroid iodide transport and therefore inhibit thyroid hormone synthesis. They are found in the environment as a result of aerospace and military waste and agricultural use (chlorate is applied as a defoliant).
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Figure 6-8 Organic anion transport proteins that transport thyroid hormones across the blood–brain barrier (BBB) and into neurons. Monocarboxylic acid transporter 8 (MCT8), organic anion transporting polypeptide 1C1 (OATP1C1), and large neutral amino acid transporters 1 and 2 (LAT 1 and 2) transport T3 and T4 across the blood–brain barrier. Once transported across the bloodebrain barrier, T4 is deiodinated to T3 by neighboring astrocytes and then transported into neurons by MCT8. (Adapted with permission from Kinne, A. et al., Thyroid Research, 4(Suppl. 1), 1–10, 2011.)
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Figure 6-9 Thyroid hormones and development of the nervous system in humans. Note that many critical events in the nervous system are correlated with periods of thyroid hormones secretion. (Adapted with permission from Howdeshell, K.L., Environmental Health Perspectives, 110(Suppl. 3), 337–348, 2002.)
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Box Figure 6A-1 Secondary structure of the human sodium iodide symporter (NIS) protein. Each of the 13 transmembrane domains is labeled by a roman numeral. Mutations in the NIS known to cause iodide transport defects (ITDs) have led to a better understanding of the functional regions of the NIS protein as indicated. Adapted with permission from Spitzweg, C., Morris, J.C., Genetics and phenomics of hypothyroidism and goiter due to NIS mutations. Molecular and Cellular Endocrinology 322.,
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Box Figure 6B-1 Incidence of thyroid cancer following the Chernobyl nuclear plant disaster of (Adapted with permission from Demidchik, Y.E. et al., International Congress Series, 1299, 32–38, 2007 and Cardis, E. et al., Journal of Radiation Protection 26, 127–140, 2006.)
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Box Figure 6C-1 Formation of iodolipids by the thyroid gland. (A) Iodolactone is formed from iodination of arachidonate. (B) 2-Iodohexadecanal is synthesized by iodination of the phospholipid plasmenylethanolamine. Synthesis of both iodolipids by the thyroid gland requires
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Box Figure 6D-1 Alternative routes for decarboxylation (removal of COOH) and biosynthesis of thyronamines and dopamine. Recent studies indicate that an as of yet undiscovered “iodothyronine decarboxylase” enzyme (question mark) is responsible for the decarboxylation of T3 to 3-T1AM, the principle thyronamine and one of two thyronamines (TAMS) found in vivo. (Adapted with permission from Hoefig, C.S. et al., Molecular and Cellular Endocrinology, 349, 195–201, 2012.)
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Box Figure 6D-2 Theoretical model for the potential role of thyronamines modulating T3 action in a target cell. T3 and T4 are transported by various proteins (LAT2, MCT8, OATP14) into the target cell where they can interact with the thyroid hormone receptor (TR) to alter transcription and protein synthesis. Alternatively, T3 and T4 can interact with a domain on the extracellular portion of the integrin receptor to elicit effects through the protein kinase C and phospholipase signaling pathways. These effects can be blocked by an antagonist of the thyroid hormone membrane receptor tetraiodothyroacetic acid (TETRAC). Thyronamines (TAMs) are ligands for the G-protein-coupled receptor TAAR. TAMs can modulate cellular activity by activating this receptor and elevating intracellular cyclic AMP levels. Abbreviations: αβ3 integrin, vitronectin receptor; D1,2, type 1 and type 2 deiodinase; ERK1/2, extracellular-signal-regulated kinases; LAT2, L-type amino acid transporter 2; MCT8, monocarboxylate transporter 8; OATP14, organic anion transporter 14; PKC, protein kinase C; PLC, phospholipase C; RXR, retinoic acid X receptor; TAAR, trace amine associated receptor; TRα1 (TRα1), cytosolic variant of TR. (Adapted with permission from Piehl, S. et al., Endocrine Reviews, 32, 64–80, 2011.)
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