To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KE:425
Key Event Title
Decrease of Thyroidal iodide
|Level of Biological Organization|
|thyroid follicular cell|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|NIS inhibition and learning and memory impairment||KeyEvent||Arthur Author (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|NIS and Cognitive Dysfunction||KeyEvent||Evgeniia Kazymova (send email)||Under Development: Contributions and Comments Welcome|
|NIS inhib alters metamorphosis||KeyEvent||Arthur Author (send email)||Under Development: Contributions and Comments Welcome|
|IYD inhib alters metamorphosis||KeyEvent||Arthur Author (send email)||Under Development: Contributions and Comments Welcome|
|zebra fish||Danio rerio||High||NCBI|
|Xenopus (Silurana) n. sp. tetraploid-1||Xenopus (Silurana) sp. new tetraploid 1||Moderate||NCBI|
|African clawed frog||Xenopus laevis||NCBI|
|Birth to < 1 month||Moderate|
|During brain development||Moderate|
Key Event Description
Biological state: Iodine (I2) is a non-metallic chemical element which is required for the normal cellular metabolism. It is one of the essential components of the TH, comprising 65% and 58% of T4's and T3's weight, respectively and therefore it is crucial for the normal thyroid function. It is a trace element and a healthy human body contains 15-20 mg of iodine, most of which is concentrated in the thyroid gland (Dunn, 1998). Iodide (I-) that enters the thyroid gland remains in the free state only briefly and subsequently it bounds to the tyrosine residues of thyroglobulin to form the precursors of the thyroid hormones mono-iodinated tyrosine (MIT) or di-iodinated tyrosine (DIT) (Berson and Yalow, 1955). The bounding rate of iodide is 50-100% of the intra-thyroidal iodide pool, meaning that only a very small proportion of this element is free in the thyroid and this comes mainly by the deiodination of MIT and DIT.
The body is not able to produce or make iodine, thus the diet is the only source of this element. Iodine is found in nature in various forms, such as inorganic sodium and potassium salts (iodides and iodates), inorganic diatomic iodine and organic monoatomic iodine (Patrick, 2008). Thus, it is widely distributed in the environment but in many regions of the world the soil's iodine has been depleted due to different environmental phenomena. In these regions, the incidence of iodine deficiency is greatly increased (Ahad and Ganie, 2010).
The daily iodine intake of adult humans varies greatly due to the different dietary habits between the different regions on earth (Dunn, 1993). In any case, the ingested iodine is absorbed through the intestine and transported into the plasma to reach the thyroid gland. However, thyroid is not the only organ of the body that concentrates iodide. It has been shown that other tissues have also the ability of iodide concentration, such as the salivary glands, the gastric mucosa, the mammary glands and the choroid plexus, all of which express NIS, the iodine transporter protein (Jhiang et al., 1998; Cho et al., 2000).
Biological compartments: A sodium-iodide (Na/I) symporter pumps iodide (IO) actively into the cell, which previously has crossed the endothelium by largely unknown mechanisms. This iodide enters the follicular lumen from the cytoplasm by the transporter pendrin, in a purportedly passive manner. In the colloid, iodide (I−) is oxidized to iodine (I0) by an enzyme called thyroid peroxidase (TPO). IO is very reactive and iodinates the thyroglobulin at tyrosyl residues in its protein chain. In conjugation, adjacent tyrosyl residues are paired together. Thyroglobulin binds the megalin receptor for endocytosis back into the follicular cell. Proteolysis by various proteases liberates thyroxine (T4) and triiodothyronine molecules (T3), which enter the bloodstream where they are bound to thyroid hormone binding proteins, mainly thyroxin binding globulin (TBG) which accounts for about 75% of the bound hormone. The adult thyroid absorbs 60-80 μg of iodide per day to maintain the thyroid homeostasis (Degroot, 1966). Inadequate amount of iodide results to deficient production of thyroid hormones, which consequently leads to an increase of TSH secretion and goiter, as compensating effect (Delange, 2000). On the other hand, excess iodide could also inhibit TH synthesis (Wolff and Chaikoff, 1948). The proposed mechanism for this latter effect is the possible formation of 2-iodohexadecanal that inhibits the generation of H2O2 and the subsequent oxidation of iodide in the thyroid follicular cells. The lack of oxidized free radicals of iodide affects the reaction with the tyrosine residues of Thyroglobulin (Tg) (Panneels et al., 1994). During pregnancy, the organism of the mother is also supporting the needs of the foetus and therefore the iodide requirements are greatly increased (Glinoer, 1997). Additionally, small iodine concentrations have been found to have significant antioxidant effects that resembles to ascorbic acid (Smyth, 2003).
General role in biology: The most important role of iodine is the formation of the thyroid hormones (T4 and T3). The thyroid actively concentrates the circulating iodide through the basolateral membrane of the thyrocytes by the sodium/iodide symporter protein (NIS). The concentrated thyroid-iodine is oxidized in the follicular cells of the gland and consequently binds to tyrosines to form mono- or di-iodotyrosines (MIT and DIT respectively), being incorporated into thyroglobulin. This newly formed iodothyroglobulin forms one of the most important constituents of the colloid material, present in the follicle of the thyroid unit. If two di-iodotyrosine molecules couple together, the result is the formation of thyroxin (T4). If a di-iodotyrosine and a mono-iodotyrosine are coupled together, the result is the formation of tri-iodothyronine (T3). From the perspective of the formation of thyroid hormone, the major coupling reaction is the di-iodotyrosine coupling to produce T4.
How It Is Measured or Detected
The radioactive iodine uptake test, or RAIU test, is a type of scan used in the diagnosis of thyroid gland dysfunction (http://www.thyca.org/pap-fol/rai/; Kwee, et al., 2007). The patient swallows radioactive iodine in the form of capsule or fluid, and its absorption by the thyroid is studied after 4–6 hours and after 24 hours with the aid of a gamma scintillation counter. The percentage of RAIU 24 hours after the administration of radioiodide is the most useful, since this is the time when the thyroid gland has reached the plateau of isotope accumulation, and because it has been shown that at this time, the best separation between high, normal, and low uptake is obtained. The test does not measure hormone production and release but merely the avidity of the thyroid gland for iodide and its rate of clearance relative to the kidney.
Domain of Applicability
Various species express functional NIS encoded by the following genes: Human SLC5A5 (6528), Mouse Slc5a5 (114479), Rat Slc5a5 (114613), Zebrafish slc5a5 (561445), chicken SLC5A5 (431544), domestic cat SLC5A5 (101092587), dog SLC5A5 (484830), domestic guinea pig Slc5a5 (100714457), naked mole-rat Slc5a5 (101701995), cow SLC5A5 (505310), sheep SLC5A5 (101112315). The encoded protein is responsible for the uptake of iodine in tissues such as the thyroid and lactating breast tissue. The iodine taken up by the thyroid is incorporated into the metabolic regulators triiodothyronine (T3) and tetraiodothyronine (T4). Mutations in this gene are associated with thyroid dyshormonogenesis that significantly influences phenotypic expressions such as severity of hypothyroidism, goiter rates, and familial clustering demonstrating essentiality of NIS function to maintain TH status (Bakker et al., 2000; Spitzweg and Morris, 2010; Ramesh et al., 2016) . Animal studies have also proven that iodine normalizes elevated adrenal corticosteroid hormone secretion and has the ability to reverse the effects of hypothyroidism in the ovaries, testicles and thymus in thyroidectomized rats (Nolan et al., 2000).
Ahad F, Ganie SA. (2010). Iodine, iodine metabolism and iodine deficiency disorders revisited. Indian J Endocrinol Metab. 14: 13-17.
Bakker B, Bikker H, Vulsma T, de Randamie JS, Wiedijk BM, De Vijlder JJ. 2000. Two decades of screening for congenital hypothyroidism in The Netherlands: TPO gene mutations in total iodide organification defects (an update). The Journal of clinical endocrinology and metabolism. Oct;85:3708-3712.
Berson SA, Yalow RS. (1955). The iodide trapping and binding functions of the thyroid. J Clin Invest. 34: 186-204.
Cho JY, Leveille R, Kao R, Rousset B, Parlow AF, Burak WE Jr, Mazzaferri EL, Jhiang SM.(2000). Hormonal regulation of radioiodide uptake activity and Na+/I- symporter expression in mammary glands. J Clin Endocrinol Metab. 85:2936-2943.
Degroot LJ.(1966). Kinetic analysis of iodine metabolism. J Clin Endocrinol Metab. 26: 149-173.
Delange F. (2000). Iodine deficiency. In: Braverman L, Utiger R, editors. Werner and Ingbar's the thyroid: a fundamental and clinical text. Philadelphia: JD Lippincott. pp 295-316.
Dunn JT. (1993). Sources of dietary iodine in industrialized countries. In: Delange F, Dunn JT, Glinoer D, editors. Iodine deficiency in Europe. A continuing concern. New York: Plenum press. pp 17-21.
Dunn JT. (1998). What's happening to our iodine? J Clin Endocrinol Metab. 83: 3398-3400. Glinoer D. (1997). The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev. 18: 404-433.
http://www.thyca.org/pap-fol/rai/: Thyroid Cancer Survivors' Association, Inc.,Radioactive Iodine (RAI)
Jhiang SM, Cho JY, Ryu KY, DeYoung BR, Smanik PA, McGaughy VR, Fischer AH, Mazzaferri EL.(1998). An immunohistochemical study of Na+/I- symporter in human thyroid tissues and salivary gland tissues. Endocrinology. 139:4416-4419.
Kwee, Sandi A.; Coel, Marc N.; Fitz-Patrick, David (2007). Eary, Janet F.; Brenner, Winfried, eds. "Iodine-131 Radiotherapy for Benign Thyroid Disease". Nuclear Medicine Therapy. CRC Press: 172. ISBN 978-0-8247-2876-2.
Nolan LA, Windle RJ, Wood SA, Kershaw YM, Lunness HR, Lightman SL, Ingram CD, Levy A. (2000). Chronic iodine deprivation attenuates stress-induced and diurnal variation in corticosterone secretion in female Wistar rats. J Neuroendocrinol. 12:1149-1159.
Panneels V, Van den Bergen H, Jacoby C, Braekman JC, Van Sande J, Dumont JE, Boeynaems JM. (1994). Inhibition of H2O2 production by iodoaldehydes in cultured dog thyroid cells. Mol Cell Endocrinol. 102:167-176.
Patrick L. (2008).Iodine:Deficiency and therapeutic considerations. Altern MedRev. 13:166-127.
Ramesh BG, Bhargav PR, Rajesh BG, Devi NV, Vijayaraghavan R, Varma BA.(2016). Genotype‑phenotype correlations of dyshormonogenetic goiter in children and adolescents from South India . I J Endocrinol and Metab. 20: 816-824.
Smyth PA. (2003). Role of iodine in antioxidant defense in thyroid and breast disease. Biofactors. 19:121-130.
Spitzweg C, Morris JC. 2010. Genetics and phenomics of hypothyroidism and goiter due to NIS mutations. Molecular and cellular endocrinology. Jun 30;322:56-63.
Wolff J, Chaikoff IL. (1948). Plasma inorganic iodide as a homeostatic regulator of thyroid function. J Biol Chem. 174: 555-564.