Thyroidal Iodide, Decreased leads to TH synthesis, Decreased

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).

In vitro and in vivo studies have specifically reported data supporting quantitative understanding of this KER.

- Gilbert et al., 2011: This in vivo study examined the relationship between graded levels of iodine (ID) in rats and serum thyroid hormones levels, thyroid iodine content, and urinary iodide excretion. The study provided parametric and dose-response information for development of a quantitative model of the thyroid axis. Female Long Evans rats were fed casein-based diets containing varying iodine (I) concentrations for 8 weeks. Diets were created by adding 975, 200, 125, 25, or 0 μg/kg I to the base diet (~25 μg I/kg chow) to produce 5 nominal I levels, ranging from excess (basal+added I, Treatment 1: 1000 μg I/kg chow) to deficient (Treatment 5: 25 μg I/kg chow). Food intake and body weight were monitored throughout and on 2 consecutive days each week over the 8-week exposure period, animals were placed in metabolism cages to capture urine. Food, water intake, and body weight gain did not differ among treatment groups. Serum T4 was dose-dependently reduced relative to Treatment 1 with significant declines (19 and 48%) at the two lowest I groups, and no significant changes in serum T3 or TSH were detected. Increases in thyroid weight and decreases in thyroidal and urinary iodide content were observed as a function of decreasing ID in the diet. Data were compared with predictions from a published biologically based dose-response (BBDR) model for ID. These results challenged existing models and provide essential information for development of quantitative BBDR models for ID during pregnancy and lactation.

- Spitzweg et al., 1999:  this in vitro study showed that inhibition of TH synthesis (induced by TPO specific inhibitors) decreases the expression of NIS. A 48 hr treatment of FRTL-5 cells with the TPO specific inhibitors MMI (100 µM), PTU (100 µM), and potassium iodide (40 µM), induced a ~ 50% decrease of NIS RNA steady-state levels. Incubation with MMI and PTU resulted in a 20% and 25% decrease of iodide accumulation, respectively, whereas potassium iodide suppressed iodide accumulation by approximately 50%.

- Wu F et al., 2012: An in vivo study found that high dose of NIS inhibitor perchlorate (520 mg/kg b.wt.) in Sprague-Dawley rats (28-day old) caused a decrease of Tg (~ 50% lower than control), and TPO (~ 45% lower than control) gene expression, indicative of reduced TH biosynthesis, together with a decrease of free T3 (~ 50% lower than control) and free T4 levels (~ 50% lower than control), and a remarkable increase of TSH levels (125% higher than control) (Wu F et al. 2012).

Additional studies with quantitative data for this KER are also described in Empirical Support for Linkage. However, further studies are needed in order to drive global conclusions about the magnitude of iodide uptake inhibition required to impact TH synthesis.

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)