Increase, Hypertrophy and proliferation (follicular cell)

51-52-5

KNAHARQHSZJURB-UHFFFAOYSA-N

6-Propyl-2-thiouracil

6-Propyl-2 thiouracil (PTU) 4(1H)-Pyrimidinone, 2,3-dihydro-6-propyl-2-thioxo- 2,3-Dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone 2-Mercapto-4-hydroxy-6-n-propylpyrimidine 2-Mercapto-4-hydroxy-6-propylpyrimidine 2-Mercapto-6-propylpyrimidin-4-ol 2-Thio-4-oxo-6-propyl-1,3-pyrimidine 2-Thio-6-propyl-1,3-pyrimidin-4-one 6-n-Propyl-2-thiouracil 6-n-Propylthiouracil 6-Propyl-2-thio-2,4(1H,3H)pyrimidinedione 6-Propylthiouracil NSC 6498 NSC 70461 Procasil Propacil propiltiouracilo Propycil Propyl-Thiorist Propylthiorit propylthiouracil Propylthiouracile Propyl-Thyracil Prothiucil Prothiurone Prothycil Prothyran Protiural Thiuragyl Thyreostat II URACIL, 4-PROPYL-2-THIO- Uracil, 6-propyl-2-thio-

DTXSID5021209

60-56-0

PMRYVIKBURPHAH-UHFFFAOYSA-N

Methimazole

2H-Imidazole-2-thione, 1,3-dihydro-1-methyl- 1,3-Dihydro-1-methyl-2H-imidazole-2-thione 1-Methyl-1,3-dihydroimidazole-2-thione 1-Methyl-1H-imidazole-2-thiol 1-Methyl-2-mercapto-1H-imidazole 1-Methyl-2-mercaptoimidazole 1-Methyl-4-imidazoline-2-thione 1-Methylimidazole-2(3H)-thione 1-Methylimidazole-2-thiol 1-Methylimidazole-2-thione 2-Mercapto-1-methyl-1H-imidazole 2-Mercapto-1-methylimidazole 2-Mercapto-N-methylimidazole 4-Imidazoline-2-thione, 1-methyl- Basolan Danantizol Favistan Frentirox Imidazole-2-thiol, 1-methyl- Mercaptazole Mercazole Mercazolyl Metazolo Methimazol Methylmercaptoimidazole Metothyrin Metothyrine Metotirin N-Methyl-2-mercaptoimidazole N-Methylimidazolethiol NSC 38608 Strumazol Tapazole Thacapzol Thiamazol thiamazole Thycapzol Thymidazol Thymidazole tiamazol

DTXSID4020820

14797-73-0

VLTRZXGMWDSKGL-UHFFFAOYSA-M

Perchlorate

Perchlorate ion Perchlorate ion (ClO41-) Perchlorate ion(1-) Perchlorate(1-) Perchloric acid, ion(1-)

DTXSID6024252

14797-55-8

NHNBFGGVMKEFGY-UHFFFAOYSA-N

Nitrate

Nitrate (NO3-) Nitrate ion Nitrate ion (NO3-) Nitrate ion(1-) Nitrate(1-) Nitrates/nitrites Nitrato Nitric acid, ion(1-)

DTXSID5024217

302-04-5

ZMZDMBWJUHKJPS-UHFFFAOYSA-M

Thiocyanate

Thiocyanates Isothiocyanic acid, ion(1-) Rhodanide Thiocyanate (NCS1-) Thiocyanate anion Thiocyanate ion Thiocyanic acid, ion(1-) Thiocyanide

DTXSID8047763

CL:0002258

CL thyroid follicular cell

D000236

MESH Adenoma

D002277

MESH Carcinoma

CHEBI:60311

CHEBI thyroid hormone

CHEBI:30660

CHEBI thyroxine

CHEBI:81567

CHEBI Thyroid stimulating hormone

PR:000015171

PR sodium/iodide cotransporter

GO:0008283

GO cell proliferation

D006984

MESH hypertrophy

D006965

MESH hyperplasia

GO:0006590

GO thyroid hormone generation

MP:0005475

MP abnormal circulating thyroxine level

GO:0008507

GO sodium:iodide symporter activity

WIKI increased

WIKI decreased

Propylthiouracil

2016-11-29T18:42:22

Methimazole

2016-11-29T18:42:19

Perchlorate

2016-11-29T18:42:26

Nitrate

2016-11-29T18:42:26

Thiocyanate

2016-11-29T18:42:26

Dysidenin

2016-11-29T18:42:26

Aryltrifluoroborates

2016-11-29T18:42:26

Econazole

2016-12-07T11:06:26

5-(N,N-hexamethylene) amiloride (HMA)

2016-12-07T11:06:59

Small molecules: ITB3, ITB4, ITB5, ITB9

2016-12-07T11:16:09

10116

NCBI rat

10090

NCBI mouse

WCS_9606

common toxicological species human

WCS_8355

common ecological species Xenopus laevis

WCS_7955

common ecological species zebrafish

WCS_90988

common ecological species fathead minnow

9823

NCBI Sus scrofa

WCS_9031

common ecological species chicken

WCS_8355

common ecological species African clawed frog

10118

NCBI Rattus sp.

WikiUser_24

Wikiuser:Migration Pig

7955

NCBI zebra fish

224340

NCBI Xenopus (Silurana) epitropicalis

10116

NCBI Rattus norvegicus

10090

NCBI Mus musculus

Increase, Hypertrophy and proliferation (follicular cell)

Cellular

CL:0002258

CL thyroid follicular cell

Not Specified Not Specified

AOPWiki 2016-11-29T18:41:26

2017-09-16T10:16:07

Increase, Hyperplasia (follicular cells)

Cellular

CL:0002258

CL thyroid follicular cell

Not Specified Not Specified

AOPWiki 2016-11-29T18:41:26

2017-09-16T10:16:07

Increase, Adenomas/carcinomas (follicular cell)

Tissue

UBERON:0002046

UBERON thyroid gland

Not Specified Not Specified

AOPWiki 2016-11-29T18:41:26

2017-09-16T10:16:08

Thyroid hormone synthesis, Decreased

TH synthesis, Decreased

Cellular

The thyroid hormones (TH), triiodothyronine (T3) and thyroxine (T4) are thyrosine-based hormones. Synthesis of THs 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 the transport protein pendrin are also necessary for iodothyronine production (Zoeller et al., 2007). The production of THs in the thyroid gland and resulting serum concentrations are controlled by a negatively regulated feedback mechanism. Decreased T4 and T3 serum concentrations activates the hypothalamus-pituitary-thyroid (HPT) axis which upregulates thyroid-stimulating hormone (TSH) that acts to increase production of additional THs (Zoeller and Tan, 2007). 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 tissue level; 5) intracellular control of TH concentrations 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 T4, often considered a “pro-hormone,” and to a lesser extent of T3, the transcriptionally active TH. Most of the hormone released from the thyroid gland into circulation is in the form of T4, while peripheral deiodination of T4 is responsible for the majority of circulating T3. Outer ring deiodination of T4 to T3 is catalyzed by the deiodinases 1 and 2 (DIO1 and DIO2), with DIO1 expressed mainly in liver and kidney, and DIO2 expressed in several tissues including the brain (Bianco et al., 2006). Conversion of T4 to T3 takes place mainly in the 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).  In mammals, most 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 early in fetal life, with a transition during mid-late gestation to fetal production of THs that is still supplemented by maternal THs. 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 gestational day 17 with birth at gestational day 22-23. Maternal THs continue to supplement fetal production until parturition. (see Howdeshell, 2002; Santisteban and Bernal, 2005 for review). Due to the maternal factor, the life stage specific impact of TPO inhibition after exposure to environmental chemicals is complex (Ramhoj et al., 2022). Decreased TH synthesis in the thyroid gland may result from several possible molecular-initiating events (MIEs) including: 1) Disruption of key catalytic enzymes or cofactors needed for TH synthesis, including TPO, NIS, or dietary iodine insufficiency. Theoretically, decreased synthesis of Tg could also affect TH production (Kessler et al., 2008; Yi et al., 1997). Mutations in genes that encode requisite proteins in the thyroid may also lead to impaired TH synthesis, including mutations in pendrin associated with Pendred Syndrome (Dossena et al., 2011), mutations in TPO and Tg (Huang and Jap 2015), and mutations in NIS (Spitzweg and Morris, 2010). 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.  Increased fetal TH levels are also possible. Maternal Graves disease, which results in fetal thyrotoxicosis (hyperthyroidism and increased serum T4 levels), has been successfully treated by maternal administration of TPO inhibitors (c.f., Sato et al., 2014).   It should be noted that different species and different life stages store different amounts of TH precursors 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 sufficient Tg-DIT residues to serve for several months to a year of TH demand (Greer et al., 2002; Zoeller, 2004). Neonates and infants have a much more limited supply of less than a week. While the TH system is highly conserved across vertebrates, there are some taxon-specific considerations. Zebrafish and fathead minnows are oviparous fish species in which maternal THs are transferred to the eggs and regulate early embryonic developmental processes during external (versus intra-uterine in mammals) development (Power et al., 2001; Campinho et al., 2014; Ruuskanen and Hsu, 2018) until embryonic TH synthesis is initiated. Maternal transfer of THs to the eggs has been demonstrated in zebrafish (Walpita et al., 2007; Chang et al., 2012) and fathead minnows (Crane et al., 2004; Nelson et al., 2016). Decreases in TH synthesis can only occur after initiation of embryonic TH synthesis. The components of the TH system responsible for TH synthesis are highly conserved across vertebrates and therefore interference with the same molecular targets compared to mammals can lead to decreased TH synthesis (TPO, NIS, etc.) in fish. Endogenous transcription profiles of thyroid-related genes in zebrafish and fathead minnow showed that mRNA coding for these genes is also maternally transferred and increasing expression of most transcripts during hatching and embryo-larval transition indicates a fully functional HPT axis in larvae (Vergauwen et al., 2018). Although the HPT axis is highly conserved, there are some differences between fish and mammals (Blanton and Specker, 2007; Deal and Volkoff, 2020). For example, in fish, corticotropin releasing hormone (CRH) often plays a more important role in regulating thyrotropin (TSH) secretion by the pituitary and thus TH synthesis compared to TSH-releasing hormone (TRH). Also, in most fish species thyroid follicles are more diffusely located in the pharyngeal region rather than encapsulated in a gland.

Decreased TH synthesis is often implied by measurement of TPO and NIS inhibition measured clinically and in laboratory models as these enzymes are essential for TH synthesis. Rarely is decreased TH synthesis measured directly, but rather the impact of chemicals on the quantity of T4 produced in the thyroid gland, or the amount of T4 present in serum is used as a marker of decreased T4 release from the thyroid gland (e.g., Romaldini et al., 1988). Methods used to assess TH synthesis include, incorporation of radiolabeled 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 necessary synthesis enzymes including TPO and NIS (Hornung et al., 2010). For this work THs 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). Techniques for in vivo analysis of TH system disruption among other drug-related effects in fish were reviewed by Raldua and Piña (2014). TIQDT (Thyroxine-immunofluorescence quantitative disruption test) is a method that provides an immunofluorescent based estimate of thyroxine in the gland of zebrafish (Raldua and Babin, 2009; Thienpont et al., 2011; Jomaa et al., 2014; Rehberger et al., 2018).  Thienpont used this method with ~25 xenobiotics (e.g., amitrole, perchlorate, methimazole, PTU, DDT, PCBs). The method detected changes for all chemicals known to directly impact TH synthesis in the thyroid gland (e.g., NIS and TPO inhibitors), but not those that upregulate hepatic catabolism of T4. Rehberger et al. (2018) updated the method to enable simultaneous semi-quantitative visualization of intrafollicular T3 and T4 levels. Most often, whole body TH level measurements in fish early life stages are used as indirect evidence of decreased TH synthesis (Nelson et al., 2016; Stinckens et al., 2016; Stinckens et al., 2020). Analytical determination of TH levels by LC-MS is becoming increasingly available (Hornung et al., 2015). More recently, transgenic zebrafish with fluorescent thyroid follicles are being used to visualize the compensatory proliferation of the thyroid follicles following inhibition of TH synthesis among others (Opitz et al., 2012).

Taxonomic: This KE is plausibly applicable across vertebrates. Decreased TH synthesis resulting from TPO or NIS inhibition is conserved across vertebrate taxa, with in vivo evidence from humans, rats, amphibians, some fish species, 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. Though decreased serum T4 is used as a surrogate measure to indicate chemical-mediated decreases in TH synthesis, clinical and veterinary management of hyperthyroidism and Graves’ disease using propylthiouracil and methimazole, known to decrease TH synthesis, indicates strong evidence for chemical inhibition of TPO (Zoeller and Crofton, 2005). Life stage: Applicability to certain life stages may depend on the species and their dependence on maternally transferred THs during the earliest phases of development. The earliest life stages of teleost fish (e.g., fathead minnow, zebrafish) rely on maternally transferred THs to regulate certain developmental processes until embryonic TH synthesis is active (Power et al., 2001). In externally developing fish species, decreases in TH synthesis can only occur after initiation of embryonic TH synthesis. In zebrafish, Opitz et al. (2011) showed the formation of a first thyroid follicle at 55 hours post fertilization (hpf), Chang et al. (2012) showed a first significant TH increase at 120 hpf and Walter et al. (2019) showed clear TH production already at 72 hpf but did not analyse time points between 24 and 72 hpf. TPO inhibition in a homozygous knockout line abolished the T4 production in thyroid follicles of mutant zebrafish with phenotypic abnormalities occurring from 20 dpf onwards but not before 10 dpf (Fang et al., 2022). Therefore, it is still uncertain when exactly embryonic TH synthesis is activated and thus when exactly this process becomes sensitive to disruption. In fathead minnows, a significant increase of whole body TH levels was already observed between 1 and 2 dpf, which corresponds to the appearance of the thyroid anlage at 35 hpf prior to the first observation of thyroid follicles at 58 hpf (Wabuke-Bunoti and Firling, 1983). It currently remains unclear when exactly embryonic TH production is initiated in zebrafish. Sex: The KE is plausibly applicable to both sexes. THs are essential in both sexes and the components of the HPT-axis are identical in both sexes. There can however be sex-dependent differences in the sensitivity to the disruption of TH levels and the magnitude of the response. In humans, females appear more susceptible to hypothyroidism compared to males when exposed to certain halogenated chemicals (Hernandez‐Mariano et al., 2017; Webster et al., 2014). In adult zebrafish, Liu et al. (2019) showed sex-dependent changes in TH levels and mRNA expression of regulatory genes including corticotropin releasing hormone (crh), thyroid stimulating hormone (tsh) and deiodinase 2 after exposure to organophosphate flame retardants. The underlying mechanism of any sex-related differences remains unclear.

UBERON:0002046

UBERON thyroid gland

CL:0002258

CL thyroid follicular cell

High Male High Female

High

All life stages

High High Moderate High Moderate High

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.  85:3708-3712. Bianco AC, Kim BW. (2006). Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest. 116: 2571–2579. Blanton ML, Specker JL. 2007. The hypothalamic-pituitary-thyroid (hpt) axis in fish and its role in fish development and reproduction. Crit Rev Toxicol. 37(1-2):97-115. Campinho MA, Saraiva J, Florindo C, Power DM. 2014. Maternal thyroid hormones are essential for neural development in zebrafish. Molecular Endocrinology. 28(7):1136-1149. Chang J, Wang M, Gui W, Zhao Y, Yu L, Zhu G. 2012. Changes in thyroid hormone levels during zebrafish development. Zoological Science. 29(3):181-184. Crane HM, Pickford DB, Hutchinson TH, Brown JA. 2004. Developmental changes of thyroid hormones in the fathead minnow, pimephales promelas. General and Comparative Endocrinology. 139(1):55-60. Deal CK, Volkoff H. 2020. The role of the thyroid axis in fish. Frontiers in Endocrinology. 11. Dossena S, Nofziger C, Brownstein Z, Kanaan M, Avraham KB, Paulmichl M. (2011). Functional characterization of pendrin mutations found in the Israeli and Palestinian populations. Cell Physiol Biochem. 28: 477-484.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. Fang, Y., Wan, J. P., Zhang, R. J., Sun, F., Yang, L., Zhao, S. X., Dong, M., & Song, H. D. (2022). Tpo knockout in zebrafish partially recapitulates clinical manifestations of congenital hypothyroidism and reveals the involvement of TH in proper development of glucose homeostasis. General and Comparative Endocrinology, 323–324. https://doi.org/10.1016/j.ygcen.2022.114033 Gereben B, Zeöld A, Dentice M, Salvatore D, Bianco AC.  Activation and inactivation of thyroid hormone by deiodinases: local action with general consequences.  Cell Mol Life Sci. 2008 Feb;65(4):570-90 Greer MA, Goodman G, Pleus RC, Greer SE. Health effects assessment for environmental perchlorate contamination: the dose response for inhibition of thyroidal radioiodine uptake in humans. Environ Health Perspect. 2002. 110:927-937. Hernandez-Mariano JA, Torres-Sanchez L, Bassol-Mayagoitia S, Escamilla-Nunez M, Cebrian ME, Villeda-Gutierrez EA, Lopez-Rodriguez G, Felix-Arellano EE, Blanco-Munoz J. 2017. Effect of exposure to p,p '-dde during the first half of pregnancy in the maternal thyroid profile of female residents in a mexican floriculture area. Environmental Research. 156:597-604. 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. Toxicol Sci 118:42-51. Hornung MW, Kosian PA, Haselman JT, Korte JJ, Challis K, Macherla C, Nevalainen E, Degitz SJ. 2015. In vitro, ex vivo, and in vivo determination of thyroid hormone modulating activity of benzothiazoles. Toxicological Sciences. 146(2):254-264. 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. Huang CJ and Jap TS. 2015. A systematic review of genetic studies of thyroid disorders in Taiwan. J Chin Med Assoc. 78: 145-153. Jomaa B, Hermsen SAB, Kessels MY, van den Berg JHJ, Peijnenburg AACM, Aarts JMMJG, Piersma AH, Rietjens IMCM. 2014. Developmental toxicity of thyroid-active compounds in a zebrafish embryotoxicity test. Altex-Alternatives to Animal Experimentation. 31(3):303-317. 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. Liu XS, Cai Y, Wang Y, Xu SH, Ji K, Choi K. 2019. Effects of tris(1,3-dichloro-2-propyl) phosphate (tdcpp) and triphenyl phosphate (tpp) on sex-dependent alterations of thyroid hormones in adult zebrafish. Ecotoxicology and Environmental Safety. 170:25-32. Nelson K, Schroeder A, Ankley G, Blackwell B, Blanksma C, Degitz S, Flynn K, Jensen K, Johnson R, Kahl M et al. 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part i: Fathead minnow. Aquatic Toxicology. 173:192-203. Opitz R, Maquet E, Huisken J, Antonica F, Trubiroha A, Pottier G, Janssens V, Costagliola S. 2012. Transgenic zebrafish illuminate the dynamics of thyroid morphogenesis and its relationship to cardiovascular development. Developmental Biology. 372(2):203-216. Opitz R, Maquet E, Zoenen M, Dadhich R, Costagliola S. 2011. Tsh receptor function is required for normal thyroid differentiation in zebrafish. Molecular Endocrinology. 25(9):1579-1599. Power DM, Llewellyn L, Faustino M, Nowell MA, Bjornsson BT, Einarsdottir IE, Canario AV, Sweeney GE. 2001. Thyroid hormones in growth and development of fish. Comp Biochem Physiol C Toxicol Pharmacol. 130(4):447-459. Raldua D, Babin PJ. 2009. Simple, rapid zebrafish larva bioassay for assessing the potential of chemical pollutants and drugs to disrupt thyroid gland function. Environmental Science & Technology. 43(17):6844-6850. Raldua D, Pina B. 2014. In vivo zebrafish assays for analyzing drug toxicity. Expert Opinion on Drug Metabolism & Toxicology. 10(5):685-697. Ramhoj, L., Svingen, T., Fradrich, C., Rijntjes, E., Wirth, E.K., Pedersen, K., Kohrle, J., Axelstad, M., 2022. Perinatal exposure to the thyroperoxidase inhibitors methimazole and amitrole perturbs thyroid hormone system signaling and alters motor activity in rat offspring. Toxicology Letters 354, 44-55. Rehberger K, Baumann L, Hecker M, Braunbeck T. 2018. Intrafollicular thyroid hormone staining in whole-mount zebrafish (danio rerio) embryos for the detection of thyroid hormone synthesis disruption. Fish Physiology and Biochemistry. 44(3):997-1010. 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. Ruuskanen S, Hsu BY. 2018. Maternal thyroid hormones: An unexplored mechanism underlying maternal effects in an ecological framework. Physiological and Biochemical Zoology. 91(3):904-916. 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. 322:56-63. Stinckens E, Vergauwen L, Blackwell BR, Anldey GT, Villeneuve DL, Knapen D. 2020. Effect of thyroperoxidase and deiodinase inhibition on anterior swim bladder inflation in the zebrafish. Environmental Science & Technology. 54(10):6213-6223. Stinckens E, Vergauwen L, Schroeder A, Maho W, Blackwell B, Witters H, Blust R, Ankley G, Covaci A, Villeneuve D et al. 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part ii: Zebrafish. Aquatic Toxicology. 173:204-217. Thienpont B, Tingaud-Sequeira A, Prats E, Barata C, Babin PJ, Raldúa D.  Zebrafish eleutheroembryos provide a suitable vertebrate model for screening chemicals that impair thyroid hormone synthesis.  Environ Sci Technol. 2011. 45(17):7525-32. Vergauwen L, Cavallin JE, Ankley GT, Bars C, Gabriels IJ, Michiels EDG, Fitzpatrick KR, Periz-Stanacev J, Randolph EC, Robinson SL et al. 2018. Gene transcription ontogeny of hypothalamic-pituitary-thyroid axis development in early-life stage fathead minnow and zebrafish. General and Comparative Endocrinology. 266:87-100. Wabukebunoti MAN, Firling CE. 1983. The prehatching development of the thyroid-gland of the fathead minnow, pimephales-promelas (rafinesque). General and Comparative Endocrinology. 49(2):320-331. Walpita CN, Van der Geyten S, Rurangwa E, Darras VM. 2007. The effect of 3,5,3'-triiodothyronine supplementation on zebrafish (danio rerio) embryonic development and expression of iodothyronine deiodinases and thyroid hormone receptors. Gen Comp Endocrinol. 152(2-3):206-214. Walter KM, Miller GW, Chen XP, Yaghoobi B, Puschner B, Lein PJ. 2019. Effects of thyroid hormone disruption on the ontogenetic expression of thyroid hormone signaling genes in developing zebrafish (danio rerio). General and Comparative Endocrinology. 272:20-32. Webster GM, Venners SA, Mattman A, Martin JW. 2014. Associations between perfluoroalkyl acids (pfass) and maternal thyroid hormones in early pregnancy: A population-based cohort study. Environmental Research. 133:338-347. Yi X, Yamamoto K, Shu L, Katoh R, Kawaoi A. Effects of Propyithiouracil (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.  37:11-53. Zoeller RT.  Interspecies differences in susceptibility to perturbation of thyroid hormone homeostasis requires a definition of "sensitivity" that is informative for risk analysis. Regul Toxicol Pharmacol. 2004 Dec;40(3):380.   AOPWiki 2016-11-29T18:41:23

2022-11-04T09:25:39

Thyroxine (T4) in serum, Decreased

T4 in serum, Decreased

Tissue

All iodothyronines are derived from the modification of tyrosine molecules (Taurog, 2000). There are two biologically active thyroid hormones (THs) in serum, triiodothyronine (T3) and T4, and a few less active iodothyronines, reverse T3 (rT3),  and 3,3'-Diiodothyronine (3,5-T2). T4 is the predominant TH in circulation, comprising approximately 80% of the TH excreted from the thyroid gland in mammals and is the pool from which the majority of T3 in serum is generated (Zoeller et al., 2007). As such, serum T4 changes usually precede changes in other serum THs. Decreased thyroxine (T4) in serum results from one or more MIEs upstream and is considered a key biomarker of altered TH homeostasis (DeVito et al., 1999). Serum T4 is used as a biomarker of TH status because the circulatory system serves as the major transport and delivery system for TH delivery to tissues. The majority of THs in the blood are bound to transport proteins (Bartalena and Robbins, 1993). In serum, it is the unbound, or ‘free’ form of the hormone that is thought to be available for transport into tissues. Free hormones are approximately 0.03 and 0.3 percent for T4 and T3, respectively. There are major species differences in the predominant binding proteins and their affinities for THs (see below). However, there is broad agreement that changes in serum concentrations of THs is diagnostic of thyroid disease or chemical-induced disruption of thyroid homeostasis across vertebrates (DeVito et al., 1999; Miller et al., 2009; Zoeller et al., 2007; Carr and Patiño, 2011). Normal serum T4 reference ranges can be species and lifestage specific. In rodents, serum THs are low in the fetal circulation, increasing as the fetal thyroid gland becomes functional on gestational day 17, just a few days prior to birth. After birth serum hormones increase steadily, peaking at two weeks, and falling slightly to adult levels by postnatal day 21 (Walker et al., 1980; Harris et al., 1978; Goldey et al., 1995; Lau et al., 2003). Similarly, in humans, adult reference ranges for THs do not reflect the normal ranges for children at different developmental stages, with TH concentrations highest in infants, still increased in childhood, prior to a decline to adult levels coincident with pubertal development (Corcoran et al. 1977; Kapelari et al., 2008). In some frog species, there is an analogous peak in THs in tadpoles that starts around embryonic NF stage 56, peaks at stage 62 and the declines to lower levels by stage 56 (Sternberg et al., 2011; Leloup and Buscaglia, 1977).  Additionally, ample evidence is available from studies investigating responses to inhibitors of TH synthesis in fish. For example, Stinckens et al. (2020) showed reduced whole body T4 concentrations in zebrafish larvae exposed to 50 or 100 mg/L methimazole, a potent TPO inhibitor, from immediately after fertilization until 21 or 32 days of age. Exposure to 37 or 111 mg/L propylthiouracil also reduced T4 levels after exposure up to 14, 21 and 32 days in the same study. Walter et al. (2019) showed that propylthiouracil had no effect on T4 levels in 24h old zebrafish, but decreased T4 levels of 72h old zebrafish. This difference is probably due to the onset of embryonic TH production between the age of 24 and 72 hours (Opitz et al., 2011). Stinckens et al. (2016) showed that exposure to 2-mercaptobenzothiazole (MBT), an environmentally relevant TPO inhibitor, decreased whole body T4 levels in continuously exposed 5 and 32 day old zebrafish larvae. A high concentration of MBT also decreased whole body T4 levels in 6 day old fathead minnows, but recovery was observed at the age of 21 days although the fish were kept in the exposure medium (Nelson et al., 2016). Crane et al. (2006) showed decreased T4 levels in 28 day old fathead minnows continuously exposed to 32 or 100 µg/L methimazole.

Serum T3 and T4 can be measured as free (unbound) or total (bound + unbound). Free hormone concentrations are clinically considered more direct indicators of T4 and T3 activities in the body, but in animal studies, total T3 and T4 are typically measured. Historically, the most widely used method in toxicology is the radioimmunoassay (RIA). The method is routinely used in rodent endocrine and toxicity studies. The ELISA method is commonly used as a human clinical test method. Analytical determination of iodothyronines (T3, T4, rT3, T2) and their conjugates, through methods employing HPLC, liquid chromatography, immuno luminescence, and mass spectrometry are less common, but are becoming increasingly available (Hornung et al., 2015; DeVito et al., 1999; Baret and Fert, 1989; Spencer, 2013; Samanidou V.F et al., 2000; Rathmann D. et al., 2015 ). In fish early life stages most evidence for the ontogeny of thyroid hormone synthesis comes from measurements of whole body thyroid hormone levels using LC-MS techniques (Hornung et al., 2015) which are increasingly used to accurately quantify whole body thyroid hormone levels as a proxy for serum thyroid hormone levels (Nelson et al., 2016; Stinckens et al., 2016; Stinckens et al., 2020). It is important to note that thyroid hormones concentrations can be influenced by a number of intrinsic and extrinsic factors (e.g., circadian rhythms, stress, food intake, housing, noise) (see for example, Döhler et al., 1979). Any of these measurements should be evaluated for the relationship to the actual endpoint of interest, repeatability, reproducibility, and lower limits of quantification using a fit-for-purpose approach. This is of particular significance when assessing the very low levels of TH present in fetal serum. Detection limits of the assay must be compatible with the levels in the biological sample. All three of the methods summarized above would be fit-for-purpose, depending on the number of samples to be evaluated and the associated costs of each method. Both RIA and ELISA measure THs by an indirect methodology, whereas analytical determination is the most direct measurement available. All these methods, particularly RIA, are repeatable and reproducible.

Taxonomic: This KE is plausibly applicable across vertebrates and the overall evidence supporting taxonomic applicability is strong. THs are evolutionarily conserved molecules present in all vertebrate species (Hulbert, 2000; Yen, 2001). Moreover, their crucial role in zebrafish development, embryo-to-larval transition and larval-to-juvenile transition (Thienpont et al., 2011; Liu and Chan, 2002), and amphibian and lamprey metamorphoses is well established (Manzon and Youson, 1997; Yaoita and Brown, 1990; Furlow and Neff, 2006). Their role as environmental messenger via exogenous routes in echinoderms confirms the hypothesis that these molecules are widely distributed among the living organisms (Heyland and Hodin, 2004). However, the role of THs in the different species depends on the expression and function of specific proteins (e.g receptors or enzymes) under TH control and may vary across species and tissues. As such, extrapolation regarding TH action across species and developmental stages should be done with caution. With few exceptions, vertebrate species have circulating T4 (and T3) that are bound to transport proteins in blood. Clear species differences exist in serum transport proteins (Dohler et al., 1979; Yamauchi and Isihara, 2009). There are three major transport proteins in mammals; thyroid binding globulin (TBG), transthyretin (TTR), and albumin. In adult humans, the percent bound to these proteins is about 75, 15 and 10 percent, respectively (Schussler 2000).  In contrast, in adult rats the majority of THs are bound to TTR. Thyroid- binding proteins are developmentally regulated in rats. TBG is expressed in rats until approximately postnatal day (PND) 60, with peak expression occurring during weaning (Savu et al., 1989). However, low levels of TBG persist into adult ages in rats and can be experimentally induced by hypothyroidism, malnutrition, or caloric restriction (Rouaze-Romet et al., 1992). While these species differences impact TH half-life (Capen, 1997) and possibly regulatory feedback mechanisms, there is little information on quantitative dose-response relationships of binding proteins and serum hormones during development across different species. Serum THs are still regarded as the most robust measurable key event causally linked to downstream adverse outcomes. Life stage: The earliest life stages of teleost fish rely on maternally transferred THs to regulate certain developmental processes until embryonic TH synthesis is active (Power et al., 2001). As a result, T4 levels are not expected to decrease in response to exposure to inhibitors of TH synthesis during these earliest stages of development. In zebrafish, Opitz et al. (2011) showed the formation of a first thyroid follicle at 55 hours post fertilization (hpf), Chang et al. (2012) showed a first significant TH increase at 120 hpf and Walter et al. (2019) showed clear TH production already at 72 hpf but did not analyse time points between 24 and 72 hpf. In fathead minnows, a significant increase of whole body TH levels was already observed between 1 and 2 dpf, which corresponds to the appearance of the thyroid anlage at 35 hpf prior to the first observation of thyroid follicles at 58 hpf (Wabuke-Bunoti and Firling, 1983). It is still uncertain when exactly embryonic TH synthesis is activated and how this determines sensitivity to TH system disruptors. Sex: The KE is plausibly applicable to both sexes. THs are essential in both sexes and the components of the HPT-axis are identical in both sexes. There can however be sex-dependent differences in the sensitivity to the disruption of TH levels and the magnitude of the response. In humans, females appear more susceptible to hypothyroidism compared to males when exposed to certain halogenated chemicals (Hernandez‐Mariano et al., 2017; Webster et al., 2014). In adult zebrafish, Liu et al. (2019) showed sex-dependent changes in TH levels and mRNA expression of regulatory genes including corticotropin releasing hormone (crh), thyroid stimulating hormone (tsh) and deiodinase 2 after exposure to organophosphate flame retardants. The underlying mechanism of any sex-related differences remains unclear.

UBERON:0001977

UBERON serum

High Female High Male

High

All life stages

High High High Moderate Moderate High High High

Axelrad DA, Baetcke K, Dockins C, Griffiths CW, Hill RN, Murphy PA, Owens N, Simon NB, Teuschler LK. Risk assessment for benefits analysis: framework for analysis of a thyroid-disrupting chemical. J Toxicol Environ Health A. 2005 68(11-12):837-55. Baret A. and Fert V.  T4 and ultrasensitive TSH immunoassays using luminescent enhanced xanthine oxidase assay. J Biolumin Chemilumin. 1989. 4(1):149-153 Bartalena L, Robbins J. Thyroid hormone transport proteins. Clin Lab Med. 1993 Sep;13(3):583-98. Bassett JH, Harvey CB, Williams GR. (2003). Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions. Mol Cell Endocrinol. 213:1-11. Capen CC. Mechanistic data and risk assessment of selected toxic end points of the thyroid gland. Toxicol Pathol. 1997 25(1):39-48. Carr JA, Patino R. 2011. The hypothalamus-pituitary-thyroid axis in teleosts and amphibians: Endocrine disruption and its consequences to natural populations. General and Comparative Endocrinology. 170(2):299-312. Chang J, Wang M, Gui W, Zhao Y, Yu L, Zhu G. 2012. Changes in thyroid hormone levels during zebrafish development. Zoological Science. 29(3):181-184. Cope RB, Kacew S, Dourson M. A reproductive, developmental and neurobehavioral study following oral exposure of tetrabromobisphenol A on Sprague-Dawley rats. Toxicology. 2015 329:49-59. Corcoran JM, Eastman CJ, Carter JN, Lazarus L. (1977). Circulating thyroid hormone levels in children. Arch Dis Child. 52: 716-720. Crane HM, Pickford DB, Hutchinson TH, Brown JA. 2006. The effects of methimazole on development of the fathead minnow, pimephales promelas, from embryo to adult. Toxicological Sciences. 93(2):278-285. Crofton KM. Developmental disruption of thyroid hormone: correlations with hearing dysfunction in rats. Risk Anal. 2004 Dec;24(6):1665-71. DeVito M, Biegel L, Brouwer A, Brown S, Brucker-Davis F, Cheek AO, Christensen R, Colborn T, Cooke P, Crissman J, Crofton K, Doerge D, Gray E, Hauser P, Hurley P, Kohn M, Lazar J, McMaster S, McClain M, McConnell E, Meier C, Miller R, Tietge J, Tyl R. (1999). Screening methods for thyroid hormone disruptors. Environ Health Perspect. 107:407-415. Döhler KD, Wong CC, von zur Mühlen A (1979).   The rat as model for the study of drug effects on thyroid function: consideration of methodological problems.  Pharmacol Ther B. 5:305-18. Eales JG. (1997). Iodine metabolism and thyroid related functions in organisms lacking thyroid follicles: Are thyroid hormones also vitaminsProc Soc Exp Biol Med. 214:302-317. Furlow JD, Neff ES. (2006). A developmental switch induced by thyroid hormone: Xenopus laevis metamorphosis. Trends Endocrinol Metab. 17:40–47. Goldey ES, Crofton KM. Thyroxine replacement attenuates hypothyroxinemia, hearing loss, and motor deficits following developmental exposure to Aroclor 1254 in rats. Toxicol Sci. 1998 45(1):94-10 Goldey ES, Kehn LS, Lau C, Rehnberg GL, Crofton KM.  Developmental exposure to polychlorinated biphenyls (Aroclor 1254) reduces circulating thyroid hormone concentrations and causes hearing deficits in rats. Tox Appl Pharmacol. 1995 135(1):77-88. Harris AR, Fang SL, Prosky J, Braverman LE, Vagenakis AG.  Decreased outer ring monodeiodination of thyroxine and reverse triiodothyronine in the fetal and neonatal rat.  Endocrinology. 1978 Dec;103(6):2216-22 Hernandez-Mariano JA, Torres-Sanchez L, Bassol-Mayagoitia S, Escamilla-Nunez M, Cebrian ME, Villeda-Gutierrez EA, Lopez-Rodriguez G, Felix-Arellano EE, Blanco-Munoz J. 2017. Effect of exposure to p,p '-dde during the first half of pregnancy in the maternal thyroid profile of female residents in a mexican floriculture area. Environmental Research. 156:597-604. Heyland A, Hodin J. (2004). Heterochronic developmental shift caused by thyroid hormone in larval sand dollars and its implications for phenotypic plasticity and the evolution of non-feeding development. Evolution. 58: 524-538. Heyland A, Moroz LL. (2005). Cross-kingdom hormonal signaling: an insight from thyroid hormone functions in marine larvae. J Exp Biol. 208:4355-4361. Hill RN, Crisp TM, Hurley PM, Rosenthal SL, Singh DV. Risk assessment of thyroid follicular cell tumors.  Environ Health Perspect. 1998 Aug;106(8):447-57. Hornung MW, Kosian P, Haselman J, Korte J, Challis K, Macherla C, Nevalainen E, Degitz S (2015) In vitro, ex vivo and in vivo determination of thyroid hormone modulating activity of benzothiazoles. Toxicol Sci 146:254-264. Hulbert AJ. Thyroid hormones and their effects: a new perspective. Biol Rev Camb Philos Soc. 2000 Nov;75(4):519-631. Review. Kapelari K, Kirchlechner C, Högler W, Schweitzer K, Virgolini I, Moncayo R. 2008. Pediatric reference intervals for thyroid hormone levels from birth to adulthood: a retrospective study. BMC Endocr Disord. 8: 15. Lau C, Thibodeaux JR, Hanson RG, Rogers JM, Grey BE, Stanton ME, Butenhoff JL, Stevenson LA.  Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. II: postnatal evaluation.  Toxicol Sci. 2003 Aug;74(2):382-92. Leloup, J., and M. Buscaglia. La triiodothyronine: hormone de la métamorphose des amphibiens. CR Acad Sci 284 (1977): 2261-2263. Liu J, Liu Y, Barter RA, Klaassen CD.: Alteration of thyroid homeostasis by UDP-glucuronosyltransferase inducers in rats: a dose-response study. J Pharmacol Exp Ther 273, 977-85, 1994 Liu XS, Cai Y, Wang Y, Xu SH, Ji K, Choi K. 2019. Effects of tris(1,3-dichloro-2-propyl) phosphate (tdcpp) and triphenyl phosphate (tpp) on sex-dependent alterations of thyroid hormones in adult zebrafish. Ecotoxicology and Environmental Safety. 170:25-32. Liu YW, Chan WK. 2002. Thyroid hormones are important for embryonic to larval transitory phase in zebrafish. Differentiation. 70(1):36-45. Manzon RG, Youson JH. (1997). The effects of exogenous thyroxine (T4) or triiodothyronine (T3), in the presence and absence of potassium perchlorate, on the incidence of metamorphosis and on serum T4 and T3 concentrations in larval sea lampreys (Petromyzon marinus L.). Gen Comp Endocrinol. 106:211-220.  McClain RM. Mechanistic considerations for the relevance of animal data on thyroid neoplasia to human risk assessment. Mutat Res. 1995 Dec;333(1-2):131-42 Miller MD, Crofton KM, Rice DC, Zoeller RT.  Thyroid-disrupting chemicals: interpreting upstream biomarkers of adverse outcomes. Environ Health Perspect. 2009 117(7):1033-41 Morse DC, Wehler EK, Wesseling W, Koeman JH, Brouwer A. Alterations in rat brain thyroid hormone status following pre- and postnatal exposure to polychlorinated biphenyls (Aroclor 1254). Toxicol Appl Pharmacol. 1996 Feb;136(2):269-79. Nelson K, Schroeder A, Ankley G, Blackwell B, Blanksma C, Degitz S, Flynn K, Jensen K, Johnson R, Kahl M et al. 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part i: Fathead minnow. Aquatic Toxicology. 173:192-203. NTP National Toxicology Program.: NTP toxicology and carcinogenesis studies of 3,3'-dimethylbenzidine dihydrochloride (CAS no. 612-82-8) in F344/N rats (drinking water studies). Natl Toxicol Program Tech Rep Ser 390, 1-238, 1991. O'Connor, J. C., J. C. Cook, et al. (1998). "An ongoing validation of a Tier I screening battery for detecting endocrine-active compounds (EACs)." Toxicol Sci 46(1): 45-60. O'Connor, J. C., L. G. Davis, et al. (2000). "Detection of dopaminergic modulators in a tier I screening battery for identifying endocrine-active compounds (EACs)." Reprod Toxicol 14(3): 193-205. Opitz R, Maquet E, Zoenen M, Dadhich R, Costagliola S. 2011. Tsh receptor function is required for normal thyroid differentiation in zebrafish. Molecular Endocrinology. 25(9):1579-1599. Power DM, Llewellyn L, Faustino M, Nowell MA, Bjornsson BT, Einarsdottir IE, Canario AV, Sweeney GE. 2001. Thyroid hormones in growth and development of fish. Comp Biochem Physiol C Toxicol Pharmacol. 130(4):447-459. Rathmann D, Rijntjes E, Lietzow J, Köhrle J. (2015) Quantitative Analysis of Thyroid Hormone Metabolites in Cell Culture Samples Using LC-MS/MS. Eur Thyroid J. Sep;4(Suppl 1):51-8. Rouaze-Romet M, Savu L, Vranckx R, Bleiberg-Daniel F, Le Moullac B, Gouache P, Nunez EA. 1992. Reexpression of thyroxine-binding globulin in postweaning rats during protein or energy malnutrition. Acta Endocrinol (Copenh).127:441-448. Samanidou VF, Kourti PV. (2009) Rapid HPLC method for the simultaneous monitoring of duloxetine, venlaflaxine, fluoxetine and paroxetine in biofluids. Bioanalysis. 2009 Aug;1(5):905-17. Savu L, Vranckx R, Maya M, Gripois D, Blouquit MF, Nunez EA. 1989. Thyroxine-binding globulin and thyroxinebinding prealbumin in hypothyroid and hyperthyroid developing rats. BiochimBiophys Acta. 992:379-384. Schneider S, Kaufmann W, Strauss V, van Ravenzwaay B.    Vinclozolin: a feasibility and sensitivity study of the ILSI-HESI F1-extended one-generation rat reproduction protocol. Regul Toxicol Pharmacol. 2011 Feb;59(1):91-100. Schussler, G.C. (2000). The thyroxine-binding proteins. Thyroid 10:141–149. Spencer, CA. (2013). Assay of thyroid hormone and related substances. In De Groot, LJ et al. (Eds). Endotext. South Dartmouth, MA Sternberg RM, Thoemke KR, Korte JJ, Moen SM, Olson JM, Korte L, Tietge JE, Degitz SJ Jr. Control of pituitary thyroid-stimulating hormone synthesis and secretion by thyroid hormones during Xenopus metamorphosis. Gen Comp Endocrinol. 2011. 173(3):428-37 Stinckens E, Vergauwen L, Blackwell BR, Anldey GT, Villeneuve DL, Knapen D. 2020. Effect of thyroperoxidase and deiodinase inhibition on anterior swim bladder inflation in the zebrafish. Environmental Science & Technology. 54(10):6213-6223. Stinckens E, Vergauwen L, Schroeder A, Maho W, Blackwell B, Witters H, Blust R, Ankley G, Covaci A, Villeneuve D et al. 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part ii: Zebrafish. Aquatic Toxicology. 173:204-217. Taurog A. 2005. Hormone synthesis. In: Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text (Braverman LE, Utiger RD, eds). Philadelphia:Lippincott, Williams and Wilkins, 47–81Walker P, Dubois JD, Dussault JH.  Free thyroid hormone concentrations during postnatal development in the rat.  Pediatr Res. 1980 Mar;14(3):247-9. Thienpont B, Tingaud-Sequeira A, Prats E, Barata C, Babin PJ, Raldúa D. Zebrafish eleutheroembryos provide a suitable vertebrate model for screening chemicals that impair thyroid hormone synthesis. Environ Sci Technol. 2011 Sep 1;45(17):7525-32. Wabukebunoti MAN, Firling CE. 1983. The prehatching development of the thyroid-gland of the fathead minnow, pimephales-promelas (rafinesque). General and Comparative Endocrinology. 49(2):320-331. Walter KM, Miller GW, Chen XP, Yaghoobi B, Puschner B, Lein PJ. 2019. Effects of thyroid hormone disruption on the ontogenetic expression of thyroid hormone signaling genes in developing zebrafish (danio rerio). General and Comparative Endocrinology. 272:20-32. Webster GM, Venners SA, Mattman A, Martin JW. 2014. Associations between perfluoroalkyl acids (pfass) and maternal thyroid hormones in early pregnancy: A population-based cohort study. Environmental Research. 133:338-347. Yamauchi K1, Ishihara A. Evolutionary changes to transthyretin: developmentally regulated and tissue-specific gene expression. FEBS J. 2009. 276(19):5357-66. Yaoita Y, Brown DD. (1990). A correlation of thyroid hormone receptor gene expression with amphibian metamorphosis. Genes Dev. 4:1917-1924. Yen PM. (2001). Physiological and molecular basis of thyroid hormone action. Physiol Rev. 81:1097-1142. Zoeller RT, Tan SW, Tyl RW. General background on the hypothalamic-pituitary-thyroid (HPT) axis. Crit Rev Toxicol. 2007 Jan-Feb;37(1-2):11-53 Zoeller, R. T., R. Bansal, et al. (2005). "Bisphenol-A, an environmental contaminant that acts as a thyroid hormone receptor antagonist in vitro, increases serum thyroxine, and alters RC3/neurogranin expression in the developing rat brain." Endocrinology 146(2): 607-612. AOPWiki 2016-11-29T18:41:23

2022-10-10T08:52:30

Increased, Thyroid-stimulating hormone (TSH)

Tissue

UBERON:0001977

UBERON serum

Not Specified Not Specified Not Specified

AOPWiki 2016-11-29T18:41:28

2017-09-16T10:17:01

Inhibition, Na+/I- symporter (NIS)

Molecular

<h4>Evidence for Perturbation by Stressor</h4> <h5>Overview for Molecular Initiating Event</h5> Thyroid Disrupting Chemicals (TDCs) are defined as the xenobiotics that interfere with the thyroid axis with different outcomes for the organism. A very well-studied mechanism of action of the TDCs is the reduction of the circulating levels of THs by inhibiting hormone synthesis in the thyroid gland. For example, perchlorate is a very potent inhibitor of iodide uptake through the sodium/iodide symporter (Tonacchera et al., 2004). Perchlorate has been detected in human breast milk ranging from 1.4 to 92.2 mg μl–1 (10.5 μg l–1 mean) in 18 US states (Kirk et al. 2005), and 1.3 to 411 μg l–1 (9.1 μg l–1 median) in the Boston area, United States (Pearce et al. 2007). Perchlorate has also been detected in human colostrum of 46 women in the Boston area (from < 0.05 to 187.2 μmol l–1 (Leung et al. 2009)). The mechanism of perchlorate action is quite simple, as it is believed to be mediated only by the NIS inhibition (Dohan et al., 2007; Wolff, 1998). Additionally, thiocyanate and nitrate are two known inhibitors that have been found to reduce circulating TH levels (Blount et al., 2006; Steinhaus et al., 2007), but they are both less potent than perchlorate (Tonacchera et al., 2004). However, there are also contradictory results from other studies that showed no correlation between thyroid parameters and perchlorate levels in humans (Pearce et al., 2010; Amitai et al., 2007; Tellez et al., 2005). Co-occurrence of perchlorate, nitrate, and thiocyanate can alter thyroid function in pregnant women. Horton et al. (2015) have shown positive associations between the weighted sum of urinary concentrations of these three analytes and increased TSH, with perchlorate showing the largest weight in the index. Interestingly, De Groef et al. 2006 showed that nitrate and thiocyanate, acquired through drinking water or food, account for a much larger proportion of iodine uptake inhibition than perchlorate, suggesting that NIS inhibition and any potential downstream effect by perchlorate are highly dependent on the presence of other environmental NIS inhibitors and iodine intake itself (Leung et al., 2010). In particular, Tonacchera et al. (2004) showed that the relative potency of perchlorate to inhibit radioactive I− uptake by NIS is 15, 30 and 240 times that of thiocyanate, iodide, and nitrate respectively on a molar concentration basis. These data are in line with earlier studies in rats (Alexander and Wolff, 1996; Greer et al. 1966). Contradictory findings in these studies may therefore be a result of the confounding mixtures in the environment, masking the primary effect of perchlorate. Decreased iodine intake can decrease TH production, and therefore exposure to perchlorate might be particularly detrimental in iodine-deficient individuals (Leung et al. 2010). Moreover, biologically based dose-response modeling of the relationships among iodide status (e.g., dietary iodine levels), perchlorate dose, and TH production in pregnant women has shown that iodide intake has a profound effect on the likelihood that exposure to goitrogens will produce hypothyroxinemia (Lewandowski et al. 2015). During pregnancy TH requirements increase, particularly during the first trimester (Alexander et al. 2004; Leung et al. 2010), due to higher concentrations of thyroxine-binding globulin, placental T4 inner-ring deiodination leading to the inactive reverse T3 (rT3), and transfer of small amounts of T4 to the foetus (during the first trimester foetal thyroid function is absent). Moreover, glomerular filtration rate and clearance of proteins and other molecules are both increased during pregnancy, possibly causing increased renal iodide clearance and a decreased of circulating plasma iodine (Glinoer, 1997). Thus, even though the foetal thyroid can trap iodide by about 12 week of gestation (Fisher and Klein, 1981), high concentrations of maternal perchlorate may potentially decrease thyroidal iodine available to the foetus by inhibiting placental NIS (Leung et al. 2010). Consequences of TH deficiency depend on the developmental timing of the deficiency (Zoeller and Rovet, 2004). For instance, if the TH deficiency occurs during early pregnancy, offspring show visual attention, visual processing and gross motor skills deficits, while if it occurs later, offspring may show subnormal visual and visuospatial skills, along with slower response speeds and motor deficits. If TH insufficiency occurs after birth, language and memory skills are most predominantly affected (Zoeller and Rovet, 2004). Along this line, age and developmental stage are crucial in determining sensitivity to NIS inhibitors (e.g., perchlorate, thiocyanate, and nitrate). In this regard, McMullen et al. (2017) have shown that adolescent boys and girls, more than adults, represent vulnerable subpopulations to NIS symporter inhibitors. Altogether these studies indicate that age, gender, developmental stage, and dietary iodine levels can affect the impact of NIS inhibitors. Finally, ten more small simple-structured molecules were identified in a large screening study (Lecat-Guillet et al., 2008b) that could block iodide uptake by specifically disrupting NIS in a dose-dependent manner. These molecules were named Iodide Transport Blockers (ITBs). There are few organic molecules that lead to NIS inhibition but no direct interaction with NIS has been determined (Gerard et al., 1994; Kaminsky et al., 1991, Lindenthal et al., 2009). Up to date, only dysidenin, a toxin isolated from the marine sponge Dysidea herbacea, has been reported to specifically inhibit NIS (Van Sande et al., 2003). Finally, the aryltrifluoroborates were found to inhibit iodide uptake with an IC50 value of 0.4 μM on rat-derived thyroid cells (Lecat-Guillet et al., 2008a). The biological activity is rationalized by the presence of the BF3− ion as a minimal binding motif for substrate recognition at the iodide binding site. It has been also shown that many anions, such as ClO3-, SCN-, NO3-, ReO4-, TcO4- and in a lower extent Br- and BF4-, are also acting as NIS substrates and they enter the cell by the same transporter mechanism (Van Sande et al., 2003). It has been also shown that ClO4- is transferred by NIS with high affinity and is considered as one of its most potent inhibitors (Dohan et al., 2007). Most recently, the aryltrifluoroborates were also shown to inhibit NIS function (Lecat-Guillet et al., 2008a). A library of 17,020 compounds was tested by a radioactive screening method with high specificity using transfected mammalian cells (Lecat-Guillet et al., 2008b; 2007) for NIS inhibition evaluation. Further studies with the most powerful iodide transport blockers showed a high diversity in their structure and mode of action (Lindenthal et al., 2009). Apart from the human, functional NIS protein has been also identified in different species, including the rat (Dai et al., 1996), the mouse (Perron et al., 2001), the pig (Selmi-Ruby et al., 2003), zebrafish (Thienpont et al., 2011) and xenopus (amphibian) (Lindenthal et al., 2009). Mouse and rat NIS proteins contain 618 amino acid residues, while the human and pig variants contain 643. There are several NIS variants that produce three active proteins in the pig due to alternative splicing at mRNA sites that are not present on the other species (Selmi-Ruby et al., 2003). NIS orthologs are discussed in the review by Darrouzet's group (Darrouzet et al., 2014). Interestingly, functional differences have been identified between mouse or rat NIS (mNIS or rNIS, respectively) and human NIS (hNIS). The rat and themouse orthologs were shown to accumulate radioisotopes more efficiently than the human protein (Dayem et al., 2008; Heltemes et al., 2003). The molecular basis of these functional differences could be helpful for further characterization of NIS. Zhang and collaborators showed that rNIS is localized in a higher proportion at the plasma membrane than hNIS and the N-terminal region up to putative transmembrane helix TM7 appears to be involved in this difference (Zhang et al., 2005). These authors also reported differences in the kinetics of the Na+ binding, implicating the region spanning from TM4 to TM6 and Ser200 of hNIS. They, thus, proposed that this region could be involved in sodium binding (Zhang et al., 2005). In our laboratory, it was shown that the Vmax of the mouse protein is four times higher than the Vmax of the human protein when expressed in the same cell line (HEK-293) (Dayem et al., 2008; Darrouzet et al., 2014). The KmI value determined for hNIS (9.0 ± 0.8 μM) was significantly lower than the KmI for the mouse protein (26.4 ± 3.5 μM) whereas the KmNa values were not significantly different indicating that mNIS has a lower iodide affinity than hNIS. Similarly to the rat protein, mNIS is predominantly localized in the plasma membrane whereas the human ortholog is detected intracellularly in 40% of the cells in which it is expressed (Darrouzet et al., 2014). However, the difference in the Vmax values does not only seem to be related to the higher intracellular localization of hNIS. Using chimeric proteins between human and mouse NIS, we showed that the N-terminal region up to TM8 is most probably involved in iodide binding, and that the region from TM5 to the C terminus could play an important role in targeting the protein to the plasma membrane (Dayem et al., 2008). One of the long-term goals of these studies is the engineering of a chimeric NIS protein most suitable for gene therapy, i.e. preserving regions responsible for the high turnover rate and the efficient plasma membrane localization of the mouse proteinwhile replacing the immunogenic extracellular regions with those of the human ortholog. The porcine NIS gene gives rise to splice variants leading to three active NIS proteins with differences in their C-terminal extremities [4]. However, it is not known if these differences lead to distinct properties (Darrouzet et al., 2014). There is evidence that the MIE (NIS inhibition) is of relevance also for fish as an expression of the slc5a5 transcript (sodium/iodide co-transporter) has been described by various publications for the zebrafish embryo (see <a href="http://www.zfin.org/">www.zfin.org</a>). It has been demonstrated that NIS inhibitors in zebra fish lead also to a strong repression of thyroid hormone levels (Thienpont et al., 2011) and in xenopus (amphibian) to  inhibition of the iodide-induced current  (Lindenthal et al., 2009). Biological state: Sodium/Iodide symporter (NIS) is a key protein in the thyroid function and its role has been thoroughly investigated after the determination of its molecular identity a few decades ago (Dai et al., 1996). NIS is an intrinsic membrane glycoprotein and it belongs to the superfamily of sodium /solute symporters (SSS) and to the family of human transporters SLC5 (De La Vieja, 2000; Jung, 2002). Its molecular weight is 87 kDa and it contains 13 transmembrane domains that transport 2 sodium cations (Na+) for each iodide anion (I-) into the follicular thyroid cell (Dohan et al., 2003). The regulation of NIS protein function is usually cell- and tissue-specific (Hingorani et al., 2010) and it is done at the transcriptional and posttranslational levels, including epigenetic regulation (Darrouzet et al., 2014; Russo et al., 2011a). One of the major NIS regulators is the thyroid stimulating hormone (TSH), which has been shown to enhance NIS mRNA and protein expression, therefore it can contribute to restore and maintain iodide uptake activity (Saito et al., 1997; Kogai et al., 2000). At the posttranslational level TSH also contributes to NIS regulation but the specific mechanisms that underlie these effects are still under investigation (Riedel et al., 2001). Biological compartments: NIS protein is mainly found at the basolateral plasma membrane of the thyroid follicular cells (Dai et al., 1996), where it actively mediates the accumulation of iodide that is the main component of thyroid hormone synthesis and therefore is considered as a major regulator of thyroid homeostasis. NIS also mediates active I- transport in extrathyroidal tissues but it is commonly agreed that is regulated and processed differently in each tissue. Functional NIS protein has been found in salivary gland ductal cells (Jhiang et al., 1998; La Perle et al., 2013), in the mammary gland during lactation (Perron et al., 2001; Cho et al., 2000), lung epithelial cells (Fragoso et la., 2004), intestinal enterocytes (Nicola et al., 2009), stomach cells (Kotani et al., 1998), placenta (Bidart et al., 2000) and testicular cells (Russo et al. 2011b). Additionally, contradictory results have been obtained regarding the NIS expression in human kidney tissue (Lacroix et al., 2001; Spitzweg et al., 2001). In the case of the lactating breast, it is suggested that NIS serves the transfer of iodide in the cells and its subsequent accumulation in the milk, thereby supplying newborns with this component during this sensitive developmental period (Tazebay et al., 2000). Additionally, NIS mRNA has been detected in various other tissues, such as colon, ovaries, uterus, and spleen (Perron et al., 2001; Spitzweg et al., 1998; Vayre et al., 1999), but the functional NIS protein and the site of its localization has not been verified. General role in biology: The NIS is known in the field of thyroidology because of its ability to mediate the active transport of I- into the thyrocytes, which is the first and most crucial step for T3 and T4 biosynthesis (Dohan et al., 2000). NIS is located on the basolateral membrane of the thyrocytes and co-transports 2 sodium ions along with 1 iodide (2:1 stoichiometry). The electrochemical gradient of sodium serves as the driving force for iodide uptake and it is generated and maintained by the Na+/K+ ATPase pump, which is located in the same membrane of the thyrocytes. The iodide molecules, after their active transport in the cytoplasm, are passively translocated in the follicular lumen via the transporter protein pendrin and possibly other unknown efflux proteins that are located on the apical membrane (Bizhanova and Kopp, 2009). Subsequently, the thyroid hormones are synthesized in the follicular lumen by incorporating the accumulated iodide, a process which is significantly suppressed in case of NIS dysfunction or inhibition (reviewed in Spitzweg and Morris, 2010). NIS is the last thyroid-related component to be expressed during development at the 10th gestational week, which temporaly coincides with the onset of thyroid function and hormonogenesis (Szinnai et al., 2007). Albeit the localization of NIS is not fully completed at this stage, the iodide accumulation has already started. Mutations of NIS gene (SLCA5A) cause expression of non-functional NIS molecule leading to inability of the thyrocyte to accumulate iodide (Matsuda and Koshugi, 1997; Pohlenz et al., 1998), a condition called iodide transport defect (ITD). This is a rear autosomic recessive disease, which if not properly treated is clinically identified by congenital hypothyroidism, goiter, low I- uptake, low saliva/plasma I- ratio and mental impairment of varying degrees (Dohan et al., 2003). Up to date 13 mutations have been described in the NIS gene (Spitzweg and Morris, 2010) and each one of them produces mutants with different structure but in all cases non-functional. The extensive study after NIS molecular characterization and the numerous findings have convinced the scientists that is one of the most crucial components of the entire thyroid system. Additionally, after the realization that NIS could be also used as diagnostic and therapeutic tool for thyroid and non-thyroid cancers (Portulano et al., 2013) a new research activity concerning this specific mechanism has been initiated.

There are several methods that are used nowadays to detect the functionality of NIS but none of these methods is OECD validated (OECD Scoping document, 2017). The most well established methods are the following: 1. Measurement of radioiodide uptake (125I-) in NIS expressing cells. For this method the FRTL5 cell line is the most commonly used, as it endogenously express the NIS protein, but also NIS transfected cell lines have been successfully implemented in many cases (Lecat-Guillet et al., 2007; 2008b; Lindenthal et al., 2009). Once inhibitory activity is identified for a compound then further tests are performed in order to verify that the observed effect is specific due to NIS inhibition. This method has been also adapted in a high throughput format and has been already used for the screening of a chemical library of 17.020 compounds (Lecat-Guillet et al., 2008b). 2. More recently a non-radioactive method has been developed, which has been also adapted in a high throughput format (Waltz et al., 2010). It is a simple spectrophotometric assay for the determination of iodide uptake  using  rat thyroid-derived cells (FRTL5) based on the catalytic effect of iodide on the reduction of yellow cerium(IV) to colorless cerium(III) in the presence of arsenious acid (Sandell-Kolthoff reaction). The assay is fast, highly reproducible and equally sensitive with the radioiodine detection method. 3. A fluorescence-based method has been developed, which uses the variant  YFP-H148Q/I152L of the Yellow Fluorescent Protein (YFP) in order to detect the efflux of iodide into the rat FRTL5 cells. As a positive control perchlorate is used  as it is a well known  competitive inhibitor of iodide transport by NIS. Fluorescence of recombinant YFP-H148Q/I152L is  suppressed by perchlorate and iodide with similar affinities. Fluorescence changes in FRTL-5 cells are  Na+-dependent, consistent with the Na+-dependence of NIS activity.   It is supposed to be an innovative approach to detect the cellular uptake of perchlorate and characterize the kinetics of transport by NIS. This method needs further optimization, as YFP is not specific for iodide and thus binding of other ionic molecules could affect the results of the assay (Cianchetta et al., 2010; Rhoden et al., 2008; Di Bernarde et al., 2011). 4. In vivo 125I uptake assays is based on  immunofluorescence analyses of thyroid glands after the treatment of rat with excess I−,  injected with Ci Na125I  as previously described by Ferreira et al., 2005. Then the thyroid glands are  removed and weighed, and the amount of 125I in the thyroid gland is  measured in a γ-counter (PerkinElmer; model Wizard). The counts per minute in the thyroid gland are used to calculate the percentage of 125I in the thyroid gland, having in account that 100% corresponded to the counts per minute injected I− into the rat (Arriagada et al., 2015). 5. The U.S. EPA's Endocrine Disruptor Screening Program aims to use high-throughput assays and computational toxicology models to screen and prioritize chemicals that may disrupt the thyroid signaling pathway. Thyroid hormone biosynthesis requires active iodide uptake mediated by the sodium/iodide symporter (NIS). Monovalent anions, such as the environmental contaminant perchlorate, are competitive inhibitors of NIS, yet limited information exists for more structurally diverse chemicals. A novel cell line expressing human NIS, hNIS-HEK293TEPA, was used in a radioactive iodide uptake (RAIU) assay to identify inhibitors of NIS-mediated iodide uptake. The RAIU assay was optimized and performance evaluated with 12 reference chemicals comprising known NIS inhibitors and inactive compounds. An additional 39 chemicals including environmental contaminants were evaluated, with 28 inhibiting RAIU over 20% of that observed for solvent controls. Cell viability assays were performed to assess any confounding effects of cytotoxicity. RAIU and cytotoxic responses were used to calculate selectivity scores to group chemicals based on their potential to affect NIS. RAIU IC50 values were also determined for chemicals that displayed concentration-dependent inhibition of RAIU (≥50%) without cytotoxicity. Strong assay performance and highly reproducible results support the utilization of this approach to screen large chemical libraries for inhibitors of NIS-mediated iodide uptake (Hallinger et al., 2017). 6. This study (Wang et al., 2018) applied a previously validated high-throughput approach to screen for NIS inhibitors in the ToxCast phase I library, representing 293 important environmental chemicals. Here 310 blinded samples were screened in a tiered-approach using an initial single-concentration (100 μM) radioactive-iodide uptake (RAIU) assay, followed by 169 samples further evaluated in multi-concentration (0.001 μM−100 μM) testing in parallel RAIU and cell viability assays. A novel chemical ranking system that incorporates multi-concentration RAIU and cytotoxicity responses was also developed as a standardized method for chemical prioritization in current and future screenings. Representative chemical responses and thyroid effects of high-ranking chemicals are further discussed. This study significantly expands current knowledge of NIS inhibition potential in environmental chemicals and provides critical support to U.S. EPA’s Endocrine Disruptor Screening Program (EDSP) initiative to expand coverage of thyroid molecular targets, as well as the development of thyroid adverse outcome pathways (AOPs).

Apart from the human, functional NIS protein has been also identified in different species, including  the rat (Dai et al., 1996), the mouse (Perron et al., 2001), the pig (Selmi-Ruby et al., 2003), zebrafish (Thienpont et al., 2011) and in xenopus (amphibian)  (Lindenthal et al., 2009). Mouse and rat contain 618 amino acid residues, while the human and pig contain 643. There are several NIS variants that produce three active proteins in the pig due to alternative splicing at mRNA sites that are not present on the other species (Selmi-Ruby et al., 2003). NIS orthologs are discussed in the review by Darrouzet's group ( Darrouzet et al., 2014). Interestingly, functional differences have been identified between mouse or rat NIS (mNIS or rNIS, respectively) and human NIS (hNIS). The rat and themouse orthologs were shown to accumulate radioisotopes more efficiently than the human protein (Dayem et al., 2008; Heltemes et al., 2003). The molecular basis of these functional differences could be helpful for further characterization of NIS. Zhang and collaborators showed that rNIS is localized in a higher proportion at the plasma membrane than hNIS and the N-terminal region up to putative TM7 appears to be involved in this difference (Zhang et al., 2005). These authors also reported differences in the kinetics of the Na+ binding, implicating the region spanning from TM4 to TM6 and Ser200 of hNIS. They, thus, proposed that this region could be involved in sodium binding (Zhang et al., 2005). In our laboratory, it was shown that the Vmax of the mouse protein is four times higher than the Vmax of the human protein when expressed in the same cell line (HEK-293) (Dayem et al., 2008; Darrouzet et al., 2014). The KmI value determined for hNIS (9.0 ± 0.8 μM) was significantly lower than the KmI for the mouse protein (26.4 ± 3.5 μM) whereas the KmNa values were not significantly different. Similarly to the rat protein, mNIS is predominantly localized in the plasma membrane whereas the human ortholog is detected intracellularly in 40% of the cells in which it is expressed (Darrouzet et al., 2014). However, the difference in the Vmax values does not only seem to be related to the higher intracellular localization of hNIS. Using chimeric proteins between human and mouse NIS, we showed that the N-terminal region up to TM8 is most probably involved in iodide binding, and that the region from TM5 to the C terminus could play an important role in targeting the protein to the plasma membrane (Dayem et al., 2008). One of the long-term goals of these studies is the engineering of a chimeric NIS protein most suitable for gene therapy, i.e. preserving regions responsible for the high turnover rate and the efficient plasma membrane localization of the mouse proteinwhile replacing the immunogenic extracellular regions with those of the human ortholog. The porcine NIS gene gives rise to splice variants leading to three active NIS proteins with differences in their C-terminal extremities [4]. However, it is not known if these differences lead to distinct properties (Darrouzet et al., 2014). There is evidence that the MIE (NIS inhibition) is of relevance also for fish as an expression of the slc5a5 transcript (sodium/iodide co-transporter) has been described by various publications for the zebrafish embryo (see <a href="http://www.zfin.org">www.zfin.org</a>). It has been demonstrated that NIS inhibitors in zebra fish lead also to a strong repression of thyroid hormone levels (Thienpont et al., 2011) and in xenopus (amphibian) to  inhibition of the iodide-induced current  (Lindenthal et al., 2009).

CL:0002258

CL thyroid follicular cell

High Mixed

High

Pregnancy

High

Birth to < 1 month

High

During brain development

High High High High High Moderate Not Specified

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Fluorescence quantitation of thyrocyte iodide accumulation with the yellow fluorescent protein variant YFP-H148Q/I152L. Analyt Biochem. 373:239-246. Riedel C, Levy O, Carrasco N. (2001). Post-transcriptional regulation of the sodium/iodide symporter by thyrotropin. J Biol Chem 276:21458–21463. Russo D, Damante G, Puxeddu E, Durante C, Filetti S. (2011a). Epigenetics of thyroid cancer and novel therapeutic targets. J Mol Endocrinol 46:R73–R81. Russo D, Scipioni A, Durante C, Ferretti E, Gandini L, Maggisano V, Paoli D, Verrienti A, Costante G, Lenzi A, Filetti S. (2011b). Expression and localization of the sodium/iodide symporter (NIS) in testicular cells. Endocrine 40:35–40. Saito T, Endo T, Kawaguchi A, Ikeda M, Nakazato M, Kogai T, Onaya T. (1997). Increased expression of the Na+/I− symporter in cultured human thyroid cells exposed to thyrotropin and in Graves’thyroid tissue. J Clin Endocrinol Metab 82:3331–3336. Selmi-Ruby S, Watrin C, Trouttet-Masson S, Bernier-Valentin F, Flachon V, Munari-Silem Y, Rousset B. (2003). The porcine sodium/iodide symporter gene exhibits an uncommon expression pattern related to the use of alternative splice sites not present in the human or murine species. Endocrinology. 144:1074–1085. Spitzweg C, Dutton CM, Castro MR, Bergert ER, Goellner JR, Heufelder AE, Morris JC. (2001). Expression of the sodium iodide symporter in human kidney. Kidney Int 59:1013-1023. Spitzweg C, Joba W, Eisenmenger W, Heufelder AE. (1998). Analysis of human sodium iodide symporter gene expression in extrathyroidal tissues and cloning of its complementary deoxyribonucleic acids from salivary gland, mammary gland, and gastric mucosa. J Clin Endocrinol Metab. 83:1746–1751. Spitzweg C, Morris JC. (2010). Genetics and phenomics of hypothyroidism and goiter due to NIS mutations. Mol Cell Endocrinol 322: 56-63. Steinmaus C, Miller MD, Howd R. (2007). Impact of smoking and thiocyanate on perchlorate and thyroid hormone associations in the 2001-2002 National Health and Nutrition Examination Survey. Env Health Persp. 115:1333-1338. Szinnai G, Lacroix L, Carré A, Guimiot F, Talbot M, Martinovic J, Delezoide AL, Vekemans M, Michiels S, Caillou B, Schlumberger M, Bidart JM, Polak M. (2007). Sodium/iodide symporter (NIS) gene expression is the limiting step for the onset of thyroid function in the human fetus. J Clin Endocrinol Metab. 92:70–76. Tazebay UH, Wapnir IL, Levy O, Dohan O, Zuckier LS, Hua Zhao Q, Fu Deng H, Amenta PS, Fineberg S, Pestell RG, Carrasco N. (2000). The mammary gland iodide transporter is expressed during lactation and in breast cancer. Nat. Med. 6:871–878. Tellez RT, Chacon PM, Abarca CR, Blount BC, Van Landingham CB, Crump KS, Gibbs JP. (2005). Long-term environmental exposure to perchlorate through drinking water and thyroid function during pregnancy and the neonatal period. Thyroid. 15:963-975. Thienpont B, Tingaud-Sequeira A, Prats E, Barat, C., Babin P.J, Raldua D, 2011. Zebrafish eleutheroembryos provide a suitable vertebrate model for screening chemicals that impair thyroid hormone synthesis. Environ Sci Technol 45, 7525-7532.) Tonacchera M, Pinchera A, Dimida A, Ferrarini E, Agretti P, Vitti P, Santini F, Crump K, Gibbs J. (2004). Relative potencies and additivity of perchlorate, thiocyanate, nitrate and iodide on the inhibition of radioactive iodide uptake by the human sodium iodide symporter. Thyroid. 14:1012-1019. Van Sande J, Massart C, Beauwens R, Schoutens A, Costagliola S, Dumont JE, Wolff J. (2003). Anion selectivity by the sodium iodide symporter. Endocrinology 144:247–252. Vayre L, Sabourin JC, Caillou B, Ducreux M, Schlumberger M, Bidart JM. (1999). Immunohistochemical analysis of Na-/I- symporter distribution in human extra-thyroidal tissues. Eur J Endocrinol. 141:382–386. Waltz F, Pillette L, Ambroise Y. (2010). A nonradioactive iodide uptake assay for sodium iodide symporter function. Analytic Biochem. 396:91-95. Wolff J. (1998). Perchlorate and the thyroid gland. Pharmacol Rev. 50:89-105. Wang J, Hallinger DR, Murr AS, Buckalew AR, Simmons SO, Laws SC, Stoker TE (2018). High-Throughput Screening and Quantitative Chemical Ranking for Sodium-Iodide Symporter Inhibitors in ToxCast Phase I Chemical Library. Environ Sci Technol. 2018 May 1;52(9):5417-5426. Zhang Z, Liu YY, Jhiang SM. (2005). Cell surface targeting accounts for the difference in iodide uptake activity between human Na+/I− symporter and rat Na+/I− symporter. J Clin Endocrinol Metab. 90:6131–6140. Zoeller RT, Rovet J (2004). Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings. J Neuroendocrinol. Oct;16(10):809-18. AOPWiki 2016-11-29T18:41:24

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<upstream-id>b72ab8e5-5bf8-4b1c-aca8-d627ee76774c</upstream-id> <downstream-id>6c35a2a9-0487-4905-8b48-e913748a218c</downstream-id>

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43137e3c78> AOPWiki 2016-11-29T18:41:34

2016-12-03T16:37:58

<upstream-id>6c35a2a9-0487-4905-8b48-e913748a218c</upstream-id> <downstream-id>79cc1b52-121b-4007-8387-b5a840afb744</downstream-id> Thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3) are synthesized by NIS and TPO in the thyroid gland as iodinated thyroglobulin (Tg) and stored in the colloid of thyroid follicles across vertebrates. Secretion from the follicle into serum is a multi-step process. The first involves thyroid stimulating hormone (TSH) stimulation of the separation of the peptide linkage between Tg and TH. The next steps involve endocytosis of colloid, fusion of the endosome with the basolateral membrane of the thyrocyte, and finally release of TH into blood. More detailed descriptions of this process can be found in reviews by Braverman and Utiger (2012) and Zoeller et al. (2007).

The weight of evidence linking these two KEs of decreased TH synthesis and decreased T4 in serum is strong. It is commonly accepted dogma that decreased synthesis in the thyroid gland will result in decreased circulating TH (serum T4).

The biological relationship between two KEs in this KER is well understood and documented fact within the scientific community.

It is widely accepted that TPO inhibition leads to declines in serum T4 levels in adult mammals. This is due to the fact that the sole source for circulating T4 derives from hormone synthesis in the thyroid gland. Indeed, it has been known for decades that insufficient dietary iodine will lead to decreased serum TH concentrations due to inadequate synthesis. Strong qualitative and quantitative relationships exist between reduced TH synthesis and reduced serum T4 (Ekerot et al., 2013; Degon et al., 2008; Cooper et al., 1982; 1983; Leonard et al., 2016; Zoeller and Tan, 2007).  There is more limited evidence supporting the relationship between decreased TH synthesis and lowered circulating hormone levels during development.  Lu and Anderson (1994) followed the time course of TH synthesis, measured as thyroxine secretion rate, in non-treated pregnant rats and correlated it with serum T4 levels. Modeling of TH in the rat fetus demonstrates the quantitative relationship between TH synthesis and serum T4 concentrations (Hassan et al., 2017, 2020; Handa et al., 2021). Furthermore, a wide variety of drugs and chemicals that inhibit TPO are known to result in decreased release of TH from the thyroid gland, as well as decreased circulating TH concentrations. This is evidenced by a very large number of studies that employed a wide variety of techniques, including thyroid gland explant cultures, tracing organification of 131-I and in vivo treatment of a variety of animal species with known TPO inhibitors (King and May,1984; Atterwill et al., 1990; Brown et al., 1986; Brucker-Davis, 1998; Haselman et al., 2020; Hornung et al., 2010; Hurley et al., 1998; Kohrle, 2008; Tietge et al., 2010). Additionally, evidence is available from studies investigating responses to TPO inhibitors in fish. For example, Stinckens et al. (2020) showed reduced whole body T4 concentrations in zebrafish larvae exposed to 50 or 100 mg/L methimazole, a potent TPO inhibitor, from immediately after fertilization until 21 or 32 days of age. Exposure to 37 or 111 mg/L propylthiouracil also reduced T4 levels after exposure up to 14, 21 and 32 days in the same study. Walter et al. (2019) showed that propylthiouracil had no effect on T4 levels in 24h old zebrafish, but decreased T4 levels of 72h old zebrafish. This difference is probably due to the onset of embryonic TH production between the age of 24 and 72 hours (Opitz et al., 2011). Stinckens et al. (2016) showed that exposure to 2-mercaptobenzothiazole (MBT), an environmentally relevant TPO inhibitor, decreased whole body T4 levels in continuously exposed 5 and 32 day old zebrafish larvae. Several other studies have also shown that chemically induced Inhibition of TPO results in reduced TH synthesis in zebrafish (Van der Ven et al., 2006; Raldua and Babin, 2009; Liu et al., 2011; Thienpont et al., 2011; Rehberger et al., 2018). A high concentration of MBT also decreased whole body T4 levels in 6 day old fathead minnows, but recovery was observed at the age of 21 days although the fish were kept in the exposure medium (Nelson et al., 2016). Crane et al. (2006) showed decreased T4 levels in 28 day old fathead minnows continuously exposed to 32 or 100 µg/L methimazole. Temporal Evidence: In mammals, the temporal nature of this KER is applicable to all life stages, including development (Seed et al., 2005).  There are currently no studies that measured both TPO synthesis and TH production during development. However, the impact of decreased TH synthesis on serum hormones is similar across all ages in mammals. Good evidence for the temporal relationship comes from thyroid system modeling of the impacts of iodine deficiency and NIS inhibition (e.g., Degon et al., 2008; Fisher et al., 2013). In addition, recovery experiments have demonstrated that serum thyroid hormones recovered in athyroid mice following grafting of in-vitro derived follicles (Antonica et al., 2012). In Xenopus, it has been shown that depression of TH synthesis in the thyroid gland precedes depression of circulating TH within 7 days of exposure during pro-metamorphosis (Haselman et al., 2020).    In oviparous fish such as zebrafish and fathead minnow, the nature of this KER depends on the life stage since the earliest stages of embryonic development rely on maternal THs transferred to the eggs. Embryonic TH synthesis is activated later during embryo-larval development. (See Domain of applicability) Dose-response Evidence: Dose-response data is lacking from studies that include concurrent measures of both TH synthesis and serum TH concentrations. However, data is available demonstrating correlations between thyroidal TH and serum TH concentrations during gestation and lactation during development (Gilbert et al., 2013). This data was used to develop a rat quantitative biologically-based dose-response model for iodine deficiency (Fisher et al., 2013). In Xenopus, dose-responses were demonstrated in both thyroidal T4 and circulating T4 following exposure to three TPO inhibitors (Haselman et al., 2020).

There are no inconsistencies in this KER, but there are some uncertainties. The first uncertainty stems from the paucity of data for quantitative modeling of the relationship between the degree of synthesis decrease and resulting changes in circulating T4 concentrations. In addition, most of the data supporting this KER comes from inhibition of TPO, and there are a number of other processes (e.g., endocytosis, lysosomal fusion, basolateral fusion and release) that are not as well studied. For example, Kim et al. (2015) investigated the adverse effects of Triphenyl phosphate (TPP), a substance that disrupts the thyroid system. Therefore, Rat pituitary (GH3) and thyroid follicular cell lines (FRTL-5) were studied. In the GH3 cells, TPP led to an upregulation of the expression of important thyroid genes (tsh, tr alpha and tr beta) while T3, a positive control, downregulated the expression of these genes. In FRTL-5 cells, the expression of nis and tpo genes was significantly upregulated, suggesting that TPP stimulates TH synthesis in the thyroid gland. In zebrafish larvae at the age of 7 days post-fertilisation (dpf), TPP exposure resulted in a significant increase in T3 and T4 concentrations and the expression of genes involved in thyroid hormone synthesis. Exposure to TPP also significantly regulated the expression of genes involved in the metabolism (dio1), transport (ttr) and excretion (ugt1ab) of THs. The down-regulation of the crh and tsh genes in the zebrafish larvae suggests the activation of a central regulatory feedback mechanism that is triggered by the increased T3 levels in vivo. Taken together, these observations indicate that TPP increases TH concentrations in early life stages of zebrafish by disrupting central regulatory and hormone synthesis pathways.

During Xenopus metamorphosis, circulating T4 steadily increases to peak levels at metamorphic climax. Therefore, during Xenopus metamorphosis, this KER is operable at an increased rate as compared to a system that is maintaining steady circulating T4 levels through homeostatic control. In this case, developmental status is a modulating factor for the rates and trajectories of these KEs.

In rats, Hassan et al. (2020) demonstrated in vitro: ex vivo correlations of TPO inhibition using PTU and MMI and constructed a quantitative model relating level of TPO inhibition with changes in circulating T4 levels. They determined that 30% inhibition of TPO was sufficient to decrease circulating T4 levels by 20%. This is further supported by studies of Hassan et al. (2017) and Handa et al. (2021) In Xenopus, Haselman et al. (2020) collected temporal and dose-response data for both thyroidal and circulating T4 which showed strong qualitative concordance of the response-response relationship. A quantitative relationship exists there in, but is yet to be demonstrated mathematically in this species.

Fisher et al. (2013) published a quantitative biologically-based dose-response model for iodine deficiency in the rat. This model provides quantitative relationships for thyroidal T4 synthesis (iodine organification) and predictions of serum T4 concentrations in developing rats. There are other computational models that include thyroid hormone synthesis. Ekerot et al. (2012) modeled TPO, T3, T4 and TSH in dogs and humans based on exposure to myeloperoxidase inhibitors that also inhibit TPO.  This model was recently adapted for rats(Leonard et al., 2016) and Hassan et al (2017) have extended it to include the pregnant rat dam in response to TPO inhibition induced by PTU. While the original model predicted serum TH and TSH levels as a function of oral dose, it was not used to explicitly predict the relationship between serum hormones and TPO inhibition, or TH synthesis. Leonard et al. (2016) recently incorporated TPO inhibition into the model. Degon et al (2008) developed a human thyroid model that includes TPO, but does not make quantitative prediction of organification changes due to inhibition of the TPO enzyme. Further empirical support for the response-response relationship has been demonstrated in the amphibian model, Xenopus laevis, exposed to TPO inhibitors during pro-metamorphosis (Haselman et al., 2020) wherein temporal profiles were measured for both thyroidal and circulating T4.

Given that the thyroid gland contains follicular lumen space filled with stored thyroglobulin/T4, complete inhibition of thyroid hormone synthesis at a given point in time will not result in an instantaneous decrease in circulating T4. The system will be capable of maintaining sufficient circulating T4 levels until the gland stores are depleted. The time it takes to deplete stored hormone will greatly depend on species, developmental status and numerous other factors. In Xenopus, Haselman et al. (2020) demonstrated an approximately 5 day difference between a significant decrease in thyroidal T4 preceding a significant decrease in circulating T4 while exposed to a potent TPO inhibitor (MMI) continuously during pro-metamorphosis.

This KER is entirely influenced by the feedback loop between circulating T4 originating from the thyroid gland and circulating TSH originating from the pituitary. Intermediate biochemical processes exist within the hypothalamus to affirm feedback and coordinately release TSH from the pituitary. However, quantitative representations of these feedback processes are limited to models discussed previously. In Xenopus, circulating levels of T4 increase through pro-metamorphosis indicating a "release" of feedback to allow circulating levels of T4 to increase and drive metamorphic changes (Sternberg et al., 2011). This provides evidence that homeostatic control of feedback can be developmentally dependent, and likely species dependent.

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4313b229e8> AOPWiki 2016-11-29T18:41:35

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Inhibition of iodide pump activity leading to follicular cell adenomas and carcinomas (in rat and mouse)

Iodide pump inhibition- follicular adenoma/carcinoma

Allie Always

Cancer AOP group. National Health and Environmental Effects Research Laboratory, Office of Research and Development, Integrated Systems Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC. Corresponding author for wiki entry (wood.charles@epa.gov)

BY-SA

1.29

1.0

This putative adverse outcome pathway (AOP) outlines potential key events leading to a tumor outcome in standard carcinogenicity models. This information is based largely on modes of action described previously in cited literature sources and is intended as a resource template for AOP development and data organization. Presentation in this Wiki does not indicate EPA acceptance of a particular pathway for a given reference agent, only that the information has been proposed in some manner. In addition, this putative AOP relates to the model species indicated and does not directly address issues of human relevance

Thyroid Disrupting Chemicals (TDCs) are defined as the xenobiotics that interfere with the thyroid axis with different outcomes for the organism. A very well-studied mechanism of action of the TDCs is the reduction of the circulating levels of THs by inhibiting hormone synthesis in the thyroid gland. For example, perchlorate is a very potent inhibitor of iodide uptake through the sodium/iodide symporter (Tonacchera et al., 2004). Perchlorate has been detected in human breast milk ranging from 1.4 to 92.2 mg μl–1 (10.5 μg l–1 mean) in 18 US states (Kirk et al. 2005), and 1.3 to 411 μg l–1 (9.1 μg l–1 median) in the Boston area, United States (Pearce et al. 2007). Perchlorate has also been detected in human colostrum of 46 women in the Boston area (from < 0.05 to 187.2 μmol l–1 (Leung et al. 2009)). The mechanism of perchlorate action is quite simple, as it is believed to be mediated only by the NIS inhibition (Dohan et al., 2007; Wolff, 1998). Additionally, thiocyanate and nitrate are two known inhibitors that have been found to reduce circulating TH levels (Blount et al., 2006; Steinhaus et al., 2007), but they are both less potent than perchlorate (Tonacchera et al., 2004). However, there are also contradictory results from other studies that showed no correlation between thyroid parameters and perchlorate levels in humans (Pearce et al., 2010; Amitai et al., 2007; Tellez et al., 2005). Co-occurrence of perchlorate, nitrate, and thiocyanate can alter thyroid function in pregnant women. Horton et al. (2015) have shown positive associations between the weighted sum of urinary concentrations of these three analytes and increased TSH, with perchlorate showing the largest weight in the index. Interestingly, De Groef et al. 2006 showed that nitrate and thiocyanate, acquired through drinking water or food, account for a much larger proportion of iodine uptake inhibition than perchlorate, suggesting that NIS inhibition and any potential downstream effect by perchlorate are highly dependent on the presence of other environmental NIS inhibitors and iodine intake itself (Leung et al., 2010). In particular, Tonacchera et al. (2004) showed that the relative potency of perchlorate to inhibit radioactive I− uptake by NIS is 15, 30 and 240 times that of thiocyanate, iodide, and nitrate respectively on a molar concentration basis. These data are in line with earlier studies in rats (Alexander and Wolff, 1996; Greer et al. 1966). Contradictory findings in these studies may therefore be a result of the confounding mixtures in the environment, masking the primary effect of perchlorate. Decreased iodine intake can decrease TH production, and therefore exposure to perchlorate might be particularly detrimental in iodine-deficient individuals (Leung et al. 2010). Moreover, biologically based dose-response modeling of the relationships among iodide status (e.g., dietary iodine levels), perchlorate dose, and TH production in pregnant women has shown that iodide intake has a profound effect on the likelihood that exposure to goitrogens will produce hypothyroxinemia (Lewandowski et al. 2015). During pregnancy TH requirements increase, particularly during the first trimester (Alexander et al. 2004; Leung et al. 2010), due to higher concentrations of thyroxine-binding globulin, placental T4 inner-ring deiodination leading to the inactive reverse T3 (rT3), and transfer of small amounts of T4 to the foetus (during the first trimester foetal thyroid function is absent). Moreover, glomerular filtration rate and clearance of proteins and other molecules are both increased during pregnancy, possibly causing increased renal iodide clearance and a decreased of circulating plasma iodine (Glinoer, 1997). Thus, even though the foetal thyroid can trap iodide by about 12 week of gestation (Fisher and Klein, 1981), high concentrations of maternal perchlorate may potentially decrease thyroidal iodine available to the foetus by inhibiting placental NIS (Leung et al. 2010). Consequences of TH deficiency depend on the developmental timing of the deficiency (Zoeller and Rovet, 2004). For instance, if the TH deficiency occurs during early pregnancy, offspring show visual attention, visual processing and gross motor skills deficits, while if it occurs later, offspring may show subnormal visual and visuospatial skills, along with slower response speeds and motor deficits. If TH insufficiency occurs after birth, language and memory skills are most predominantly affected (Zoeller and Rovet, 2004). Along this line, age and developmental stage are crucial in determining sensitivity to NIS inhibitors (e.g., perchlorate, thiocyanate, and nitrate). In this regard, McMullen et al. (2017) have shown that adolescent boys and girls, more than adults, represent vulnerable subpopulations to NIS symporter inhibitors. Altogether these studies indicate that age, gender, developmental stage, and dietary iodine levels can affect the impact of NIS inhibitors. Finally, ten more small simple-structured molecules were identified in a large screening study (Lecat-Guillet et al., 2008b) that could block iodide uptake by specifically disrupting NIS in a dose-dependent manner. These molecules were named Iodide Transport Blockers (ITBs). There are few organic molecules that lead to NIS inhibition but no direct interaction with NIS has been determined (Gerard et al., 1994; Kaminsky et al., 1991). Up to date, only dysidenin, a toxin isolated from the marine sponge Dysidea herbacea, has been reported to specifically inhibit NIS (Van Sande et al., 2003). Finally, the aryltrifluoroborates were found to inhibit iodide uptake with an IC50 value of 0.4 μM on rat-derived thyroid cells (Lecat-Guillet et al., 2008a). The biological activity is rationalized by the presence of the BF3− ion as a minimal binding motif for substrate recognition at the iodide binding site. It has been also shown that many anions, such as ClO3-, SCN-, NO3-, ReO4-, TcO4- and in a lower extent Br- and BF4-, are also acting as NIS substrates and they enter the cell by the same transporter mechanism (Van Sande et al., 2003). It has been also shown that ClO4- is transferred by NIS with high affinity and is considered as one of its most potent inhibitors (Dohan et al., 2007). Most recently, the aryltrifluoroborates were also shown to inhibit NIS function (Lecat-Guillet et al., 2008a). A library of 17,020 compounds was tested by a radioactive screening method with high specificity using transfected mammalian cells (Lecat-Guillet et al., 2008b; 2007) for NIS inhibition evaluation. Further studies with the most powerful inhibitors showed a high diversity in their structure and mode of action (Lindenthal et al., 2009).

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Dellarco, V. L., McGregor, D., Berry, S. C., Cohen, S. M., & Boobis, A. R. (2006). Thiazopyr and thyroid disruption: case study within the context of the 2006 IPCS Human Relevance Framework for analysis of a cancer mode of action. Crit Rev Toxicol, 36(10), 793-801. doi: 10.1080/10408440600975242 U.S. Environmental Protection Agency, R. A. F. (Mar. 1998). Assessment of Thyroid Follicular Cell Tumors. Washington, DC. Hurley, P. M. (1998). Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents. Environ Health Perspect, 106(8), 437-445. Wolff, J. (1998). Perchlorate and the thyroid gland. Pharmacol Rev, 50(1), 89-105. AOPWiki 2016-11-29T18:41:16

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