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Inhibition, Na+/I- symporter (NIS) leads to Thyroidal Iodide, 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||Mary Gilbert (send email)||Under Development: Contributions and Comments Welcome|
|Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment||adjacent||High||High||Anna Price (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|Sodium Iodide Symporter (NIS) Inhibition leading to altered amphibian metamorphosis||adjacent||High||Moderate||Jonathan Haselman (send email)||Under Development: Contributions and Comments Welcome|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
NIS is a membrane protein implicated in iodide uptake into the follicular cells of the thyroid. Other large anions can be also bound by NIS and inhibit accumulation of iodide into the thyroid by competing binding with iodide (Wolff, 1964).
Evidence Collection Strategy
Evidence Supporting this KER
NIS is a membrane bound glycoprotein and its main physiological function is to transport one iodide ion along with two sodium ions across the basolateral membrane of thyroid follicular cells. It uses the sodium gradient generated by the Na+/K+ ATPase for the active transport of iodide into the thyrocytes (Eskandari et al., 1997). Extensive studies on NIS protein have identified 14 different mutations and each one of them is related to Iodine Transport Deficiencies (ITD) (reviewed in Spitzweg and Morris, 2010). Most of these mutations have been characterized and it is well known that they even lead to the synthesis of truncated protein (Pohlenz et al., 1997; Pohlenz et al., 1998), partial deletions (Kosugi et al., 2002; Tonacchera et al., 2003; Montanelli et al., 2009) or substitutions of amino acids (Matsuda and Kosugi, 1997; Kosugi et al., 1999; Szinnai et al., 2006) that eventually result in total or partial NIS dysfunction. While most of the NIS mutants have been further investigated and the functional relationship between the NIS dysfunction and ITD is well established (reviewed in Darrouzet et al., 2014; Portulano et al., 2014), the exact structural relationship between mutated NIS and ITD still needs to be elucidated and the molecular modelling of the protein would greatly benefit these studies. At the same time, causative link between iodide deficiency, thyroid hormones, and neurodevelopment deffects is well documented (Gilbert et al., 2009).
Recent revision of the affinity constant for perchlorate binding to the NIS symporter based on in vitro and human in vivo data, performed by refitting published in vitro data, in which perchlorate-induced inhibition of iodide uptake via the NIS was measured, yielding a Michaelis-Menten kinetic constant (Km) of 1.5 μm, showed that a 60% lower value for the Km, equal to 0.59 μm. Substituting this value into the PBPK model for an average adult human significantly improved model agreement with the human RAIU data for exposures <100 μg kg-1 day-1 (Schlosser PM, 2016).
The effects of maternal hypothyroidism could also contribute to this KER. 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).
There are limited data regarding low-level environmental perchlorate exposure and maternal thyroid function during pregnancy. A Chilean study found no increases in TSH or decreases in free thyroxine or urinary iodine concentrations in pregnant women living in three areas (all of which had more than adequate mean urinary iodine levels) with long-term environmental perchlorate exposure (Téllez Téllez et al. 2005). A follow-up analysis of this cohort also confirmed the lack of association between individual urinary iodide or perchlorate concentrations and thyroid function in the pregnant women (Gibbs and Van Landingham, 2008). Studies of large cohorts of first-trimester pregnant women from the U.S., Europe and Argentina found that environmental perchlorate exposure did not affect maternal thyroid function (Pearce et al. 2009).
Uncertainties and Inconsistencies
The thyroid system is quite complex and therefore some inconsistent results have been produced by recent studies. For example, it has been observed in healthy volunteers that a 6-month exposure to perchlorate at doses up to 3 mg/d (low doses) had no effect on thyroid function, including inhibition of thyroid iodide uptake as well as serum levels of thyroid hormones, TSH, and Tg (Braverman et al., 2006). However, this study was limited by the small sample size and is obviously underpowered.
The review by Charnley (2008) examines a number of studies where association between perchlorate environmental (low) exposure and thyroid effects were analysed and many inconsistent conclusions have been drawn. 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 Environmental Protection Agency'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.
Additionally, a more comprehensive study by Pearce et al. (2010) conducted during 2002-2006 on 22,000 women at less than 16-week gestation showed that while low-level perchlorate exposure was ubiquitous in these women (with a median urinary perchlorate concentration of 5 µg/liter in the Turin cohort and 2 µg/liter in the Cardiff cohort), no associations between urine perchlorate concentrations and serum TSH or free T4 in the individual euthyroid or hypothyroid/hypothyroxinemic cohorts were found.
The data assessing the effect of maternal perchlorate exposure in neonates and children and thyroid function remain unclear (Leung et al., 2010).
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).
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 problems in visual attention, visual processing and gross motor skills, while if it occurs later, offspring may show subnormal visual and visuospatial skills, slower response speeds and motor deficits. If TH insufficiency occurs after birth, language and memory skills are most predominantly affected (Zoeller and Rovet, 2004). Altogether these studies indicate that factors, such as age, gender, developmental stage, and iodide status can affect the impact of perchlorate and other NIS inhibitors. All these variables should be taken into account to explain possible inconsistencies in study findings.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Empirical evidence comes from in vitro works using rat follicular cells (Cianchetta et al., 2010; Waltz et al., 2010; Lecat-Guillet et al., 2007; 2008; Lecat-Guillet et al., 2008b), human in vitro cell models (Wen et al., 2016) and in vivo data (Arriagada et al. 2015), as well as Xenopus oocytes (Lindenthal et al., 2009) and Zebrafish (Thienpont et al., 2011).
Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR (2004). Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med. 2004 Jul 15;351(3):241-9.
Arriagada AA, Albornoz E, Opazo MC, Becerra A, Vidal G, Fardella C, Michea L, Carrasco N, Simon F, Elorza AA, Bueno SM, Kalergis AM, Riedel CA. (2015). Excess iodide induces an acute inhibition of the sodium/iodide symporter in thyroid male rat cells by increasing reactive oxygen species. Endocrinology. Apr;156(4):1540-51.
Braverman LE, Pearce EN, He X, Pino S, Seeley M, Beck B, Magnani B, Blount BC, Firek A. (2006). Effects of six months of daily low-dose perchlorate exposure on thyroid function in healthy volunteers. J Clin Endocrinol Metab. 91:2721-2724.
Charnley G. (2008) Perchlorate: overview of risks and regulation. Food Chem Toxicol. 46(7):2307-15 (Review).
Cianchetta S, di Bernardo J, Romeo G, Rhoden KJ (2010). Perchlorate transport and inhibition of the sodium iodide symporter measured with the yellow fluorescent protein variant YFP-H148Q/I152L. Toxicol Appl Pharmacol. 243:372-380.
Darrouzet E, Lindenthal S, Marcellin D, Pellequer JL, Pourcher T. (2014). The sodium/iodide symporter: state of the art of its molecular characterization. Biocim Biophys Acta. 1838:244-253.
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.
Eskandari S, Loo DD, Dai G, Levy O, Wright M, Carrasco N. (1997). Thyroid Na+/I- symporter: mechanism, stoichiometry, and specificity. J Biol Chem 272: 27230-27238.
Fisher DA, Klein AH (1981). Thyroid development and disorders of thyroid function in the newborn. N Engl J Med. 1981 Mar 19;304(12):702-12.
Gibbs JP, Van Landingham C (2008). Urinary perchlorate excretion does not predict thyroid function among pregnant women. Thyroid. Jul; 18(7):807-8.
Gilbert ME, Hedge J, Grant K, Lyke D, Gitata I, Anderson W, et al. (2009) Marginal iodide deficiency, thyroid hormones, and neurodevelopment: developing a model. Toxicol Sci., 108 (S-1):32.
Glinoer D (1997). The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev. Jun;18(3):404-33.
Greer MA, Goodman G, Pleus RC, Greer SE. (2002). Health effects assessment for environmental perchlorate contamination: the dose response for inhibition of thyroidal radioiodine uptake in humans. Environm Health Persp. 110: 927-937.
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.
Kosugi S, Bhayana S, Dean HJ. (1999). A novel mutation in the sodium/iodide symporter gene in the largest family with iodide transport defect. J Clin Endocrinol Metab. 84: 3248-3253.
Kosugi S, Okamoto H, Tamada A, Sanchez-Franco F. (2002). A novel peculiar mutation in the sodium/iodide symporter gene in Spanish siblings with iodide transport defect. J Clin Endocrinol Metab. 87: 3830–3836.
Lecat-Guillet N, Merer G, Lopez R, Pourcher T, Rousseau B, Ambroise Y. (2008a). Small-molecule inhibitors of sodium iodide symporter function. Chembiochem 9:889–895.
Lecat-Guillet N, Ambroise Y. (2008b). Discovery of aryltrifluoroborates as potent sodium/iodide symporter (NIS) inhibitors. Chem Med Chem 3:1207–1209.
Lecat-Guillet N, Merer G, Lopez R, Pourcher T, Rousseau B, Ambroise Y. (2007). A 96-well automated radioiodide uptake assay for sodium/iodide symporter inhibitors. Assay Drug Dev Technol 5:535-540.
Leung AM, Pearce EN, Braverman LE (2010). Perchlorate, iodine and the thyroid. Best Pract Res Clin Endocrinol Metab. Feb;24(1):133-41.
Lewandowski TA, Peterson MK2, Charnley G (2015). Iodine supplementation and drinking-water perchlorate mitigation. Food Chem Toxicol. Jun;80:261-70.
Lindenthal S, Lecat-Guillet N, Ondo-Mendez A, Ambroise Y, Rousseau B, Pourcher T. (2009). Characterization of small-molecule inhibitors of the sodium iodide symporter. J Endocrinol 200:357–365.
Matsuda A, Kosugi S. (1997). A homozygous missense mutation of the sodium/iodide symporter gene causing iodide transport defect. J Clin Endocrinol Metab. 82: 3966-3971.
Montanelli L, Agretti P, Marco G, Bagattini B, Ceccarelli C, Brozzi F, Lettiero T, Cerbone M, Vitti P, Salerno M, Pinchera A, Tonacchera M. (2009). Congenital hypothyroidism and late-onset goiter: identification and characterization of a novel mutation in the sodium/iodide symporter of the proband and family members. Thyroid 19: 1419-1425.
Pearce EN, Lazarus JH, Smythe PP, et al. (2009). Thyroid Function is Not Affected by Environmental Perchlorate Exposure in First Trimester Pregnant Women. Endocrine Society 91st Annual Meeting; USA.
Pearce EN, Lazarus JH, Smyth PP, et al. (2010). Perchlorate and thiocyanate exposure and thyroid function in first-trimester pregnant women. J Clin Endocrinol Metab. 95:3207–3215.
Pohlenz J, Rosenthal IM, Weiss RE, Jhiang SM, Burant C, Refetoff S. (1998). Congenital hypothyroidism due to mutations in the sodium/iodide symporter. Identification of a nonsense mutation producing a downstream cryptic 3′ splice site. J Clin Invest. 101:1028-1035.
Pohlenz J, Medeiros-Neto G, Gross JL, Silveiro SP, Knobel M, Refetoff S. (1997). Hypothyroidism in a Brazilian kindred due to iodide trapping defect caused by a homozygous mutation in the sodium/iodide symporter gene. Biochem Biophys Res Commun. 240: 488-491.
Portulano C, Paroder-Belenitsky M, Carrasco N. (2014). The Na+/I- symporter (NIS): Mechanism and medical impact. Endocr Rev. 35: 106-149.
Rhoden KJ, Cianchetta S, Stivani V, Portulano C, Galietta LJV, Romeo G. (2007). Cell-based imaging of sodium iodide symporter activity with the yellow fluorescent protein variant YFP-H148Q/I152L. Am. J. Physiol., 292, pp. C814–C823.
Schlosser PM. (2016). Revision of the affinity constant for perchlorate binding to the sodium-iodide symporter based on in vitro and human in vivo data. J Appl Toxicol. Dec;36(12):1531-1535.
Spitzweg C, Morris JC. (2010). Genetics and phenomics of hypothyroidism and goiter due to NIS mutations. Mol Cell Endocrinol. 322: 56-63.
Szinnai G, Kosugi S, Derrien C, Lucidarme N, David V, Czernichow P, Polak M. (2006). Extending the clinical heterogeneity of iodide transport defect (ITD): a novel mutation R124H of the sodium/iodide symporter gene and review of genotype-phenotype correlations in ITD. J Clin Endocrinol Metab. 91: 1199–1204.
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.
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, Agretti P, de Marco G, Elisei R, Perri A, Ambrogini E, De Servi M, Ceccarelli C, Viacava P, Refetoff S, Panunzi C, Bitti ML, Vitti P, Chiovato L, Pinchera A. (2003). Congenital hypothyroidism due to a new deletion in the sodium/iodide symporter protein. Clin Endocrinol. 59: 500–506.
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.
Vroye L, Beauwens R, Van Sande J, Daloze D, Braekman JC, Golstein PE. (1998). The Na+/I- co-transporter of th e thyroid: characterization of new inhibitors. Pflugers Archiv. 435:259-266.
Waltz F, Pillette L, Ambroise Y. (2010). A nonradioactive iodide uptake assay for sodium iodide symporter function. Anal Biochem. 396:91-95.
Wen G, Pachner LI, Gessner DK, Eder K, Ringseis R. (2016). Sterol regulatory element-binding proteins are regulators of the sodium/iodide symporter in mammary epithelial cells. J Dairy Sci. Nov;99(11):9211-9226.
Wolff J. (1964). Transport of iodide and other anions in the thyroid gland. Physiol Rev 44: 45-90.
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.