- 1 Event Title
- 2 Key Event Overview
- 3 How this Key Event works
- 4 How it is Measured or Detected
- 5 Evidence Supporting Taxonomic Applicability
- 6 Evidence for Chemical Initiation of this Molecular Initiating Event
- 7 References
Key Event Overview
Please follow link to widget page to edit this section.
If you manually enter text in this section, it will get automatically altered or deleted in subsequent edits using the widgets.
AOPs Including This Key Event
The following are chemical initiators that operate directly through this Event:
|Xenopus laevis||Xenopus laevis||Moderate||NCBI|
Level of Biological Organization
How this Key Event works
Thyroid hormone (TH) synthesis is regulated by thyroid-stimulating hormone (TSH) binding to its receptor and thyroidal availability of iodine via the sodium iodide symporter (NIS). Other proteins contributing to TH production in the thyroid gland, including thyroperoxidase (TPO), dual oxidase enzymes (DUOX), and pendrin are also necessary for iodothyronine production (Zoeller et al., 2007). The production of THs in the thyroid gland and serum levels are controlled by an efficiently regulated feedback mechanism: the hypothalamus-pituitary-thyroid (HPT) axis. This regulatory system includes: 1) the hypothalamic secretion of the thyrotropin-releasing hormone (TRH); 2) the thyroid-stimulating hormone (TSH) secretion from the anterior pituitary; 3) hormonal transport by the plasma binding proteins; 4) cellular uptake mechanisms at the cell level; 5) intracellular control of TH concentration by deiodinating mechanisms; 6) transcriptional function of the nuclear TH receptor; and 7) in the fetus, the transplacental passage of T4 and T3 (Zoeller et al., 2007).
TRH and the TSH primarily regulate the production of pro-hormone T4, and to a lesser extent of T3, the biologically active TH. Most of the hormone released into circulation is is in the form of T4, while peripheral deiodination of T4 is responsible for the majority of circulating T3. Outer ring deiodination of T4 is conducted by activation of the deiodinating enzymes D1 and D2 (Bianco et al., 2006), takes place mainly in liver and kidney, but also in other target organs such as in the brain, the anterior pituitary, brown adipose tissue, thyroid and skeletal muscle (Gereben et al., 2008; Larsen, 2009).
The majority of evidence for the ontogeny of TH synthesis comes from measurements of serum hormone concentrations. And, importantly, the impact of xenobiotics on fetal hormones must include the influence of the maternal compartment since a majority of fetal THs are derived from maternal blood, especially early in fetal life. In humans, THs can be found in the fetus as early as gestational weeks 10-12, and concentations rise continuously until birth. At term fetal T4 is similar to maternal levels, but T3 remains 2-3 fold lower than maternal levels. In rats, THs can be detected in the fetus as early as the second gestational week, but fetal synthesis does not start until around the third week of gestation. (see Howdeshell, 2002; Santisteban and Bernal, 2005 for review).
Decreased TH synthesis in the thyroid gland may result from one or a combination of a set of possible molecular-initiating events (MIEs) including: 1) Inhibition of TPO, inhibition of the NIS, or dietary iodine insufficiency. Theoretically, decreased synthesis of Tg could also affect TH production (Kessler et al., 2008; Yi et al., 1997). 2) Decreased TH synthesis in cases of clinical hypothyroidism may be due to Hashimoto's thyroiditis or other forms of thyroiditis, or physical destruction of the thyroid gland as in radioablation or surgical treatment of thyroid lymphoma. 3) It is possible that TH synthesis may also be reduced subsequent to disruption of the negative feedback mechanism governing TH homeostasis, e.g. pituitary gland dysfunction may result in a decreased TSH signal with concomitant T3 and T4 decreases. 4) More rarely, hypothalamic dysfunction can result in decreased TH synthesis.
It should be noted that different species and different lifestages store different amounts of TH precursor and iodine within the thyroid gland. Thus, decreased TH synthesis via transient iodine insufficiency or inhibition of TPO may not affect TH release from the thyroid gland until depletion of stored iodinated Tg. Adult humans may store Tg-DIT residues to supply for several months to a year of TH demand (Greer et al., 2002). Neonates and infants have a much more limited supply of less than a week.
How it is Measured or Detected
Decreased TH synthesis is often implied by measurement of TPO and NIS inhibition measured clinically and in laboratory models asthese enzymes are essential for TH synthesis. Rarely is decreased TH synthesis measured directly, but rather the impact of chemicals onthe quantity of T4 released from the thyroid gland is assessed (e.g., Romaldini et al., 1988). Methods used include, use of radiolabel tracer compounds, radioimmunoassay, ELISA, and analytical detection.
Recently, amphibian thyroid explant cultures have been used to demonstrate direct effects of chemicals on TH synthesis, as this model contains all of the necessary synthesis enzymes including TPO and NIS (Hornung et al., 2010). For this work TH was measured by HPLC/ICP-mass spectometry. Decreased TH synthesis and release, using T4 release as the endpoint, has been shown for thiouracil antihyperthyroidism drugs including MMI, PTU, and the NIS inhibitor perchlorate (Hornung et al., 2010).
Evidence Supporting Taxonomic Applicability
Decreased TH synthesis resulting from TPO or NIS inhibition is conserved across taxa, with in vivo evidence from humans, rats, amphibians, and birds, and in vitro evidence from rat and porcine microsomes. Indeed, TPO and NIS mutations result in congenital hypothyroidism in humans (Bakker et al., 2000; Spitzweg and Morris, 2010), demonstrating the essentiality of TPO and NIS function toward maintaining euthyroid status.
Typically decreased serum thyroxine (T4) is used as a surrogate measure to indicate chemical-mediated decreases in TH synthesis. However, clinical and veterinary management of hyperthyroidism and Grave's disease involves administration of drugs including propylthiouracil and methimazole, known to decrease TH synthesis, indicating strong medical evidence for chemical initiation of this event (Zoeller and Crofton, 2005).
Evidence for Chemical Initiation of this Molecular Initiating Event
Typically decreased serum thyroxine (T4) is used as a surrogate measure to indicate chemical-mediated decreases in thyroid hormone synthesis. However, clinical and veterinary management of hyperthyroidism and Grave's disease involves administration of drugs including propylthiouracil and methimazole, known to decrease TH synthesis, indicating strong medical evidence for chemical initiation of this event.
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.
Bianco AC, Kim BW. (2006). Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest. 116: 2571–2579.
Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, Zeöld A, Bianco AC. (2008). Cellular and molecular basis of deiodinase-regulated thyroid hormone signalling. Endocr Rev. 29:898–938.
Greer MA, Goodman G, Pleus RC, Greer SE. 2002. Health effects assessment for environmental perchlorate contamination: the dose response for inhibition of thyroidal radioiodine uptake in humans. Environmental health perspectives. Sep;110:927-937.
Howdeshell KL. 2002. A model of the development of the brain as a construct of the thyroid system. Environ Health Perspect. 110 Suppl 3:337-48.
Hornung MW, Degitz SJ, Korte LM, Olson JM, Kosian PA, Linnum AL, Tietge JE. 2010. Inhibition of thyroid hormone release from cultured amphibian thyroid glands by methimazole, 6-propylthiouracil, and perchlorate. Toxicological Sciences Nov;118:42-51.
Kessler J, Obinger C, Eales G. Factors influencing the study of peroxidase-generated iodine species and implications for thyroglobulin synthesis. Thyroid. 2008 Jul;18(7):769-74. doi: 10.1089/thy.2007.0310
Larsen PR. (2009).Type 2 iodothyronine deiodinase in human skeletal muscle: new insights into its physiological role and regulation. J Clin Endocrinol Metab. 94:1893-1895.
Romaldini JH, Farah CS, Werner RS, Dall'Antonia Júnior RP, Camargo RS. 1988. "In vitro" study on release of cyclic AMP and thyroid hormone in autonomously functioning thyroid nodules. Horm Metab Res.20:510-2.
Santisteban P, Bernal J. Thyroid development and effect on the nervous system. Rev Endocr Metab Disord. 2005 Aug;6(3):217-28.
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.
Yi X, Yamamoto K, Shu L, Katoh R, Kawaoi A. Effects of Propylthiouracil (PTU) Administration on the Synthesis and Secretion of Thyroglobulin in the Rat Thyroid Gland: A Quantitative Immuno-electron Microscopic Study Using Immunogold Technique. Endocr Pathol. 1997 Winter;8(4):315-325.
Zoeller RT, Crofton KM. 2005 Mode of action: developmental thyroid hormone insufficiency--neurological abnormalities resulting from exposure to propylthiouracil. Crit Rev Toxicol. 35:771-81
Zoeller RT, Tan SW, Tyl RW. 2007. General background on the hypothalamic-pituitary-thyroid (HPT) axis. Critical reviews in toxicology. Jan-Feb;37:11-53.