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Thyroidal Iodide, Decreased leads to TH synthesis, Decreased
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||adjacent||High||High||Evgeniia Kazymova (send email)||Under Development: Contributions and Comments Welcome|
|Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment||adjacent||High||High||Arthur Author (send email)||Open for citation & comment||TFHA/WNT Endorsed|
|Sodium Iodide Symporter (NIS) Inhibition leading to altered amphibian metamorphosis||adjacent||High||Moderate||Arthur Author (send email)||Under Development: Contributions and Comments Welcome|
|Iodotyrosine deiodinase (IYD) inhibition leading to altered amphibian metamorphosis||adjacent||High||Moderate||Arthur Author (send email)||Under Development: Contributions and Comments Welcome|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
Thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3) are synthesized in the thyroid gland in the presence of functional NIS and thyroid peroxidase (TPO) as iodinated thyroglobulin (Tg), and stored in the colloid of thyroid follicles. NIS is a membrane bound glycoprotein whose main physiological function is to transport one iodide ion along with two sodium ions across the basolateral membrane of thyroid follicular cells. Extensive studies on NIS protein have identified 14 different mutations and each one of them is related to Iodine Transport Deficiencies (ITD) (Spitzweg and Morris, 2010). Once inside the follicular cells, the iodide diffuses to the apical membrane, where it is metabolically oxidized through the action of TPO to iodinium (I+), which in turn iodinates tyrosine residues of the Tg proteins in the follicle colloid. Therefore, NIS is essential for the synthesis of thyroid hormones (T3 and T4). TPO is a heme-containing apical membrane protein within the follicular lumen of thyrocytes that acts as the enzymatic catalyst for TH synthesis (Taurog, 2005). Propylthiouracil (PTU) and methimazole (MMI), are thioureylene drugs that are known to inhibit the ability of TPO to: a) activate iodine and transfer it to thyroglobulin (Tg) (Davidson et al., 1978) and, b) couple thyroglobulin (Tg)-bound iodotyrosyls to produce Tg-bound T3 and T4 (Taurog, 2005). PTU and MMI have been found to decrease also the expression of NIS mRNA and consequently iodide accumulation, as shown in FRTL-5 cells (Spitzweg et al. 1999).
Other compounds, such as triclosan, triclocarban, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), and bisphenol A (BPA) have been reported to decrease thyroid hormone (TH) levels by inducing an inhibition of NIS-mediated iodide uptake and altering the expression of genes involved in TH synthesis in rat thyroid follicular FRTL-5 cells, and on the activity of thyroid peroxidase (TPO), using rat thyroid microsomes (Wu Y et al. 2016).
Perchlorate, thiocyanate, nitrate, and iodide, which are competitive inhibitors of iodide uptake, have been shown to inhibit radioactive iodide uptake by NIS (Tonacchera et al. 2004), consequentially resulting in inhibition of TH synthesis. In particular, perchlorate blocks iodide uptake into the thyroid through NIS inhibition and decreases the production of TH (Steinmaus, 2016a). More recent evidence also suggests that young children, pregnant women, foetuses, and people co-exposed to similarly acting agents may be especially susceptible to perchlorate-induced toxicity (Steinmaus et al., 2016b).
Concern about environmental perchlorate exposure is focused on its inhibition of iodide uptake into the thyroid (MIE). Decreased iodine intake may decrease thyroid hormone production. Perchlorate exposure, therefore, might be particularly detrimental in iodine-deficient individuals. Median urinary iodine levels are used instead and reflect dietary iodine sufficiency across populations (International Council for the Control of Iodine Deficiency Disorders (ICCIDD); available from: www.iccidd.org). According to ICCIDD report Iodine deficiency continues to be an important global public health issue, with an estimated 2.2 million people (38% of the world's population) living in iodine-deficient areas. In 1990, the United Nations World Summit for Children set forth the goal of eliminating iodine deficiency worldwide (UNICEF World Summit for Children. Available from: http://www.unicef.org/wsc/declare.htm; 1990). Considerable progress has been achieved by programmes of universal salt iodisation (USI) in various countries, in line with the recommendations of the World Health Organization (WHO) (WHO, UNICEF, ICCIDD. A guide for programme managers. World Health Organization; Geneva: 2007. Assessment of the iodine deficiency disorders and monitoring their elimination.WHO/NHD/01.1). However, many countries remain iodine deficient (de Benoist et al., 2013; Lazarus and Delange, 2004). In the U.S., data from large population studies have shown that median urinary iodine levels decreased by approximately 50% between the early 1970s and the early 1990s, although the population overall remained iodine sufficient (Hollowell et al., 1998). Subsequent studies have shown that this decrease has stabilised (Caldwell et al., 2005). The WHO still considers iodine deficiency, which leads to hypothyroidism, the single most important preventable cause of brain damage worldwide (WHO/UNICEF/ICCIDD, 2007). The most vulnerable groups are pregnant and lactating women and their developing fetuses and neonates, given the crucial importance of iodine to ensure adequate levels of thyroid hormones for brain maturation. Iodine deficiency in pregnancy is a prevailing problem not only in developing countries, but also in western industrialized nations and other countries classified as free of iodine deficiency, and solution may be found in dietary changes (Moog et al., 2017).
Evidence Supporting this KER
The association between these two KEs is strong, and supported by in vitro, in vivo and epidemiological studies. Blocking iodide uptake into the thyroid follicular cells as a consequence of NIS inhibition or functional impairment, leads to reduced TH synthesis. Compounds that have been shown to inhibit NIS function (e.g., perchlorate, thiocyanate, nitrate, and iodide), has also been proven to decrease TH synthesis by inducing a downregulation of TPO gene expression and/or increase of TSH level, which are both indicative of a reduce TH biosynthesis. TSH receptor controls transcription and posttranslational modification of NIS (Dai et al., 1996). Stimulation of TSH receptor increases T3 and T4 production and secretion (Szkudlinski et al., 2002). NIS gene expression is suppressed by growth factors such as IGF-1 and TGF-β (the latter is induced by the BRAF-V600E oncogene), which prevent NIS to localize in the basolateral membrane (Riesco-Eizaguirre et al., 2009). The BRAF-V600E oncogene is also associated with downregulation TSH receptor (Kleiman et al. 2013). Altogether these studies support the association between NIS inhibition-induced decreased iodide uptake (KE up) and reduced TH synthesis (KE down).
Uncertainties and Inconsistencies
Some studies have highlighted contradictory results in relation to response to chemicals. For instance, PTU and MMI have been shown to inhibit the activity of TPO in rats (Davidson et al., 1978), while inducing an increase of cellular TPO activity and TPO mRNA in cultured porcine thyroid follicles (Sugawara et al., 1999). PTU was also found to increase NIS gene expression, and the accumulation of 125I, as shown in in rat thyroid FRTL-5 cells, while MMI had no effect (Sue et al., 2012).
Moreover, despite the well described effects of perchlorate, thiocyanate, nitrate, and iodide on iodide uptake into the thyroid, occupational and clinical dosing studies have not identified clear adverse effects, particularly in the case of perchlorate (Tarone et al. 2010). For instance, a longitudinal epidemiologic Chilean study found that there were no increases of thyroglobulin (Tg) or thyrotropin (TSH) levels, and no decreases of free T4 levels among either women during early pregnancy, late pregnancy, or the neonates at birth related to perchlorate in drinking water, suggesting that perchlorate in drinking water at 114 microg/L did not cause changes in neonatal thyroid function or fetal growth retardation (Téllez Téllez et al., 2005). Similarly, no associations between urine perchlorate concentrations and serum TSH or free T4 were found in individual euthyroid or hypothyroid/hypothyroxinemic cohorts of 261 hypothyroid/hypothyroxinemic and 526 euthyroid women from Turin and 374 hypothyroid/hypothyroxinemic and 480 euthyroid women from Cardiff (Pearce et al., 2010), suggesting that log perchlorate may not be a predictor of serum free T4 or TSH. However, it should be considered that these studies may be limited by short study durations, and the inclusion of mostly healthy adults (Steinmaus, 2016b).
Charnley's (2008) review examines several studies pointing out a number of inconsistent conclusions regarding link between TH serum levels, urinary iodine concentrations, and environmental perchlorate exposure (Charnley et al. 2008). For instance, no correlations were found between TH serum levels and urinary iodine concentrations among women exposed to perchlorate participating in the 2000-2001 National Health and Nutrition Examination Survey (NHANES). Available evidence does not support a causal relationship between changes in TH levels and current environmental levels of perchlorate exposure, but does support the conclusion that the US EPA's reference dose (RfD) for perchlorate is conservatively health-protective. However, potential perchlorate risks are unlikely to be distinguishable from the ubiquitous background of naturally occurring substances present at much higher exposures that can affect the thyroid via the same biological mode of action as perchlorate, such as nitrate and thiocyanate. Therefore, risk management approaches that account for both aggregate and cumulative exposures and that consider the larger public health context in which exposures are occurring are desirable.
In a cross-sectional analysis, McMullen et al. (2017) evaluated the exposure to perchlorate, thiocyanate, and nitrate in 3151 participants aged 12 to 80, to assess whether sensitivity to perchlorate, thiocyanate, and nitrate (NIS inhibitors) could be a factor of age and sex. These results indicate that adolescent boys and girls represent the most vulnerable subpopulations to NIS symporter inhibitors. Therefore, discrepancies in results described in epidemiological studies may be due to difference in age of study participants.
Apart from age, relative source contribution of perchlorate exposure plays an important role in determining a significant reduction of serum TH levels. For instance, Lumen and George (2017) showed that there was no significant difference in geometric mean estimates of free T4 when perchlorate exposure from food only was compared to no perchlorate exposure in pregnant women. The reduction in maternal free T4 levels reached statistical significance when an added contribution from drinking water was assumed in addition to the 90th percentile of food intake for pregnant women. In particular, a daily intake of 0.45- 0.50μg/kg/day of perchlorate was necessary to produce results that were significantly different than those obtained from no perchlorate exposure. The authors comment that 'these modelling results can explain why findings from observational studies present inconsistent outcomes regarding the relationship between perchlorate exposure and thyroid hormone levels'."
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Empirical evidence comes from in vivo studies in rats (Wu F et al., 2012; Davidson et al., 1978), in vitro studies using thyroid follicular rat cells (Spitzweg et al., 1999; Sue et al., 2012) and porcine thyroid follicles (Sugawara et al., 1999), and human epidemiological studies (Steinmaus et al., 2016b; Horton et al., 2015; Brechner et al., 2000)
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Caldwell KL, Jones R, Hollowell JG. (2005). Urinary iodine concentration: United States National Health and Nutrition Examination Survey 2001-2002. Thyroid., 15:692–699.
Charnley G. (2008) Perchlorate: overview of risks and regulation. Food Chem Toxicol. 46(7):2307-15 (Review).
Charatcharoenwitthaya N, Ongphiphadhanakul B, Pearce EN, Somprasit C, Chanthasenanont A, He X, Chailurkit L, Braverman LE (2014). The association between perchlorate and thiocyanate exposure and thyroid function in first-trimester pregnant Thai women. J Clin Endocrinol Metab. Jul;99(7):2365-71.
Dai G, Levy O, Carrasco N. (1996). Cloning and characterization of the thyroid iodide transporter. Nature;379:458–460.
Davidson, B., Soodak, M., Neary, J.T., Strout, H.V., and Kieffer, J.D. (1978). The irreversible inactivation of thyroid peroxidase by methylmercaptoimidazole, thiouracil, and propylthiouracil in vitro and its relationship to in vivo findings. Endocrinology 103:871–882.
de Benoist B, Andersson M, Takkouche B, et al. (2003).Prevalence of iodine deficiency worldwide. Lancet, 362:1859–1860.
De Groef B, Decallonne BR, Van der Geyten S, Darras VM, Bouillon R. (2006). Perchlorate versus other environmental sodium/iodide symporter inhibitors: potential thyroid-related health effects. Europ J Endocr. 155:17-25.
Gilbert ME, McLanahan ED, Hedge J, Crofton KM, Fisher JW, Valentín-Blasini L, Blount BC (2011). Marginal iodide deficiency and thyroid function: dose-response analysis for quantitative pharmacokinetic modeling. Toxicology. Apr 28;283(1):41-8.
Hollowell JG, Staehling NW, Hannon WH, et al.(1998). Iodine nutrition in the United States. Trend and public health implications: iodine excretion data from National Health and Nutrition Examination Survey I and III (1971-1974 and 1988-1994). The Journal of Clinical Endocrinology and Metabolism., 83:3401–3408.
Horton MK, Blount BC, Valentin-Blasini L, Wapner R, Whyatt R, Gennings C, Factor-Litvak P. (2015). CO-occurring exposure to perchlorate, nitrate and thiocyanate alters thyroid function in healthy pregnant women. Environ Res. Nov;143(Pt A):1-9.
Jones PA, Pendlington RU, Earl LK, Sharma RK, Barrat MD. (1996). In vitro investigations of the direct effects of complex anions on thyroidal iodide uptake: identification of novel inhibitors. Toxicol. In Vitro. 10: 149-160.
Kleiman DA, Buitrago D, Crowley MJ, Beninato T, Veach AJ, Zanzonico PB, Jin M, Fahey TJ 3rd, Zarnegar R. (2013). Thyroid stimulating hormone increases iodine uptake by thyroid cancer cells during BRAF silencing. J Surg Res. Jun 1;182(1):85-93.
Lazarus JH, Delange F. (2004). Prevalence of iodine deficiency worldwide. Lancet, 363:901-910.
Lumen A, George NI (2017). Evaluation of the risk of perchlorate exposure in a population of late-gestation pregnant women in the United States: Application of probabilistic biologically-based dose response modeling. Toxicol Appl Pharmacol. 2017 May 1;322:9-14.
McMullen J, Ghassabian A, Kohn B, Trasande L (2017). Identifying Subpopulations Vulnerable to the Thyroid-Blocking Effects of Perchlorate and Thiocyanate. J Clin Endocrinol Metab. Jul 1;102(7):2637-2645.
Moog N.K., Entringer S., Heim Ch., Wadhwa PD., Kathmann N., Buss C. (2017). Influence of maternal thyroid hormones during gestation on fetal brain development. Neuroscience, 342: 68–100.
Pearce EN, Lazarus JH, Smyth PP, He X, Dall'amico D, Parkes AB, Burns R, Smith DF, Maina A, Bestwick JP, Jooman M, Leung AM, Braverman LE. (2010). Perchlorate and thiocyanate exposure and thyroid function in first-trimester pregnant women. J Clin Endocrinol Metab. Jul;95(7):3207-15.
Riesco-Eizaguirre G, Rodríguez I, De la Vieja A, Costamagna E, Carrasco N, Nistal M, Santisteban P. (2009). The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. Cancer Res. Nov 1;69(21):8317-25.
Spitzweg C, Morris JC. (2010). Genetics and phenomics of hypothyroidism and goiter due to NIS mutations. Mol Cell Endocrinol. 322: 56-63.
Spitzweg C, Joba W, Morris JC, Heufelder AE. (1999). Regulation of sodium iodide symporter gene expression in FRTL-5 rat thyroid cells. Thyroid. Aug;9(8):821-30.
Steinmaus CM. (2016a). Perchlorate in Water Supplies: Sources, Exposures, and Health Effects. Curr Environ Health Rep. Jun;3(2):136-43.
Steinmaus C, Pearl M, Kharrazi M, Blount BC, Miller MD, Pearce EN, Valentin-Blasini L, DeLorenze G, Hoofnagle AN, Liaw J. (2016b). Thyroid Hormones and Moderate Exposure to Perchlorate during Pregnancy in Women in Southern California. Environ Health Perspect. Jun;124(6):861-7.
Sue M, Akama T, Kawashima A, Nakamura H, Hara T, Tanigawa K, Wu H, Yoshihara A, Ishido Y, Hiroi N, Yoshino G, Kohn LD, Ishii N, Suzuki K.(2012). Propylthiouracil increases sodium/iodide symporter gene expression and iodide uptake in rat thyroid cells in the absence of TSH. Thyroid. 2012 Aug;22(8):844-52.
Sugawara M, Sugawara Y, Wen K. (1999). Methimazole and propylthiouracil increase cellular thyroid peroxidase activity and thyroid peroxidase mRNA in cultured porcine thyroid follicles. Thyroid. May;9(5):513-8.
Szkudlinski MW, Fremont V, Ronin C, Weintraub BD. (2002). Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. Physiological Reviews. 82 (2): 473–502.
Tarone RE, Lipworth L, McLaughlin JK. (2010). The epidemiology of environmental perchlorate exposure and thyroid function: a comprehensive review. J Occup Environ Med. Jun;52(6):653-60.
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, 47–81.
Téllez Téllez R, Michaud Chacón P, Reyes Abarca C, 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, Sep;15(9):963-75.
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, Dec;14(12):1012-9.
Waltz F, Pillette L, Ambroise Y. (2010). A nonradioactive iodide uptake assay for sodium iodide symporter function. Anal Biochem. 396:91-95.
Wu F, Zhou X, Zhang R, Pan M, Peng KL. (2012). The effects of ammonium perchlorate on thyroid homeostasis and thyroid-specific gene expression in rat. Environ Toxicol. Aug;27(8):445-52.
Wu Y, Beland FA1, Fang JL. (2016). Effect of triclosan, triclocarban, 2,2',4,4'-tetrabromodiphenyl ether, and bisphenol A on the iodide uptake, thyroid peroxidase activity, and expression of genes involved in thyroid hormone synthesis. Toxicol In Vitro. Apr;32:310-9.