Iodide is a trace element and a key component of thyroid hormones (TH). The availability of this halogen is the rate-limiting step for TH synthesis; therefore, thyroidal iodide uptake and recycling during TH synthesis are of major importance in maintaining an adequate supply. In the rat, the thyroid gland co-expresses a distinctive pair of intrathyroidal deiodinating enzymes: the thyroid iodotyrosine dehalogenase (tDh) and the iodothyronine deiodinase type 1 (ID1). In the present work, we studied the activity of these two dehalogenases in conditions of hypo- and hyperthyroidism as well as during acute and chronic iodide administration in both intact and hypophysectomized (HPX) rats. In order to confirm our observations, we also measured the mRNA levels for both dehalogenases and for the sodium/iodide symporter, the protein responsible for thyroidal iodide uptake. Our results show that triiodothyronine differentially regulates tDh and ID1 enzymatic activities, and that both acute and chronic iodide administration significantly decreases rat tDh and ID1 activities and mRNA levels. Conversely, both enzymatic activities increase when intrathyroidal iodide is pharmacologically depleted in TSH-replaced HPX rats. These results show a regulatory effect by iodide on the intrathyroidal dehalogenating enzymes and suggest that they contribute to the iodide-induced autoregulatory processes involved in the Wolff–Chaikoff effect.
Iodide is a micronutrient and a key component of thyroid hormones (TH). Its availability is rate limiting for TH synthesis, and its scarcity in the biosphere can lead to insufficient intake and continues to be a worldwide public health concern (Zimmermann 2009). At the level of the thyroid, the limited availability of iodide is countered by several mechanisms. Uptake of iodide against an electrochemical gradient is exerted by the sodium/iodide symporter (NIS; Dai et al. 1996, Kopp & Solis-S 2009). Moreover, a pair of thyroidal dehalogenases recycles iodide in the rat thyroid gland: iodotyrosine dehalogenase (tDh) and iodothyronine deiodinase type 1 (ID1). tDh (human homolog iodotyrosine deiodinase, IYD or DEHAL1) deiodinates mono- and diiodotyrosines (DIT), thereby recycling iodide for TH synthesis (Gnidehou et al. 2004, Solis-S et al. 2004). ID1 (human homolog DIO1) belongs to the family of selenodeiodinases, which also includes the type 2 (ID2) and type 3 (ID3) isoenzymes. ID1 is able to deiodinate iodothyronines both at the 5′ and 5 positions, while ID2 and ID3 only remove iodide from the 5′ and 5 positions respectively. In addition, a physiological role for ID1 as a scavenger enzyme has been recently proposed due to its capacity to remove iodide from reverse triiodothyronine (rT3) and other inactive and sulfated iodothyronines (St Germain et al. 2009). tDh and the three iodothyronine selenodeiodinases are the only enzymes known to catalyze reductive dehalogenation in mammals, though they are structurally and mechanistically different (Rokita et al. 2010). However, and in spite of the importance of dehalogenation, little is known about the regulation of this intrathyroidal enzymatic system. Early studies in intact rats reported that TSH administration increases rat tDh (rtDh) activity (Roche et al. 1953, Maayan & Rosenberg 1963). Similarly, thyroidal ID1 activity (Erickson et al. 1982) and mRNA (Toyoda et al. 1992) are increased by TSH and TH in vivo and in vitro. Remarkably, iodide itself acts as a regulator of TH synthesis. Evidence supporting this came as early as 1923 in a pioneer study highlighting the inhibitory effect of iodide in patients with Graves' disease (Plummer 1923). Further in vitro (Morton et al. 1944) and in vivo (Wolff & Chaikoff 1948) studies showed that thyroidal iodide organification was blocked by the administration of large quantities of inorganic iodide. This inhibition, or arrest in hormonogenesis, which is secondary to elevated plasmatic iodide levels, is known as the Wolff–Chaikoff effect (Wolff & Chaikoff 1948). However, this blockade is transitory, and iodide organification generally resumes once the serum iodide concentration decreases below a threshold level. Furthermore, even when the circulating levels of iodide remain elevated, the thyroid gland resumes iodide organification after 24–48 h, a situation known as ‘the escape’ or ‘adaptation’ to the Wolff–Chaikoff effect (Wolff & Chaikoff 1948). It is known that this escape phenomenon involves, among other mechanisms, a reduced expression of NIS, thus decreasing iodide uptake and total intrathyroidal iodide content (Uyttersprot et al. 1997, Eng et al. 1999). Although it was described more than 60 years ago, several important questions remain to be answered about this noteworthy thyroidal autoregulatory mechanism.
In the present work, we studied the activity and mRNA expression of the intrathyroidal dehalogenating enzymes rtDh and ID1, during hypo- and hyperthyroidism, as well as during acute and chronic iodide administration, in both intact and hypophysectomized (HPX) rats, in order to determine how they are regulated in various physiological conditions.
Materials and Methods
Bovine TSH (bTSH), T3, methimazole (MMI), KClO4, iodide, DIT, flavin adenine dinucleotide (FAD), reduced NADPH, and rT3 were purchased from Sigma Chemical Co.; NaI125 (specific activity: 17.4 Ci/mg) was purchased from Amersham Pharmacia. 125I-labeled rT3 (specific activity: 1174 μCi/μg) was obtained from Perkin Elmer-NEN, Inc. (Boston, MA, USA). Resins AG 50W-X8 and AG 50W-X2 (both mesh size 100–200) were acquired from Bio-Rad Laboratories. Dithiothreitol (DTT) was obtained from Calbiochem (La Jolla, CA, USA). Radiolabeled substrates were purified prior to use by means of a SEP-PACK C18 cartridge from Millipore Waters Chromatography (Boston, MA, USA).
Animals, HPX, and housing
Adult male rats (∼300 g body weight) of the Sprague–Dawley strain were maintained six per cage in a controlled environment (22 °C, 12 h light:12 h darkness cycle) and fed with standard Purina chow and water made available ad libitum. HPX were performed via ventral neck as described previously (Alvarez-Buylla et al. 1991). The animals were maintained in a separate, controlled environment (30 °C, 12 h light:12 h darkness cycle) and fed with red apples and 2% glucose in drinking water for 7 days post surgery. All treatments were initiated 1 week after surgery. Procedures regarding handling and killing of animals were reviewed and approved by the Animal Welfare Committee of the Institute of Neurobiology.
To dissect the putative in vivo effects of TSH, T3, and iodide upon the activity of the two thyroidal enzymes (rtDh and ID1), groups of 7–15 intact or HPX rats were handled according to the experimental protocols detailed in Table 1. Intact animals were divided into the following five groups: control, hypothyroid (treated with MMI+KClO4 and I-depleted), hyperthyroid (T3-treated), acute iodide load (24 h), and chronic iodide load (7 days). HPX rats were divided into the following five groups: HPX control, HPX+TSH, HPX+TSH+I-depleted, HPX+T3, and HPX+TSH+T3.
Treatments received by the experimental groups and their expected thyroidal state
|Groups||Experimental protocol||n||Treatment||Expected thyroidal state|
|Intact pituitary||Control||15||No treatment||Control|
|Hypothyroid (I-depleted)||15||0.1% MMI+1% KClO4 in DW ad libitum for 7 days||Disruption of TH-negative feedback on HPT axis: increased TSH and low TH. Iodide-depleted thyroid gland|
|Hyperthyroid||15||Single dose (100 μg/100 g BW) of T3 via i.p. 24 h before killing||Inhibition of HPT axis by TH: low TSH and high TH levels|
|Acute KI load||15||0.05% KI in DW for 24 h||HPT axis undisrupted, at 24 h: thyroid with acute WCE; at 7 days: thyroid adapted to WCE|
|Chronic KI load||15||0.05% KI in DW for 7 days|
|Hypophysectomized||Control||7||Vehicle via i.p. every 12 h for 3 days||Endogenous TSH absent: hypothyroidism due to impaired TH production|
|TSH-replaced||7||1 IU bTSH i.p. every 12 h for 3 days||TH synthesis stimulated by TSH replacement; controlled TSH levels|
|TSH+I-depleted||7||0.1% MMI+1% KClO4 in DW for 7 days ad libitum +1 IU bTSH i.p. every 12 h for 3 days||Iodide-depleted thyroid gland, controlled TSH levels without TH production|
|T3-replaced||8||Single dose (100 μg/100 g BW) of T3 via i.p. 24 h before killing||High TH levels with suppressed TSH|
|TSH+T3-replaced||8||Single dose (100 μg/100 g BW) of T3 via i.p. 24 h before killing +1 IU bTSH i.p. every 12 h for 3 days||High TH levels with controlled TSH replacement|
MMI, methimazole; KClO4, potassium perchlorate; DW, drinking water; KI, potassium iodide; BW, body weight; HPT axis, hypothalamic–pituitary–thyroidal axis; WCE, Wolff–Chaikoff effect.
Hormone measurement, sample preparation, and deiodination assay
Animals were killed by decapitation, and blood was collected for TSH and T3 measurements. For T3, a single-species-adapted antibody technique was used as previously described (Anguiano et al. 1991). In the case of TSH, a rat TSH (rTSH-125I) Biotrak Assay System (Amersham Biosciences) was used as indicated by the manufacturer. The enzymatic assays for rtDh and ID1 activities were performed as previously described (Solis-S et al. 2004). In brief, thyroid, liver, and kidney tissue samples were homogenized (1:5 w/v) in phosphate (0.5 M, pH 7.4) and HEPES buffer (0.01 M, pH 7.0) for rtDh and ID1 respectively. Homogenates were centrifuged at 13 000 g for 5 min, 4 °C, divided in aliquots, and protein content was measured by Bradford's method (Bradford 1976). For the rtDh assay, 125I-DIT was radiolabeled by the exchange method (Cahnman 1972) to a mean-specific activity of 765±110 μCi/μmol; the assay mixture contained 2 μM DIT, 8 pmol 125I-DIT (∼10 000 c.p.m.), 200 μg protein, 50 mM 2-mercaptoethanol, 200 mM KCl, 30 μM FAD, 1.5 mM MMI, and 30 μM NADPH in a final volume of 500 μl. The ID1 assay mixture contained 1 μM rT3, 200 fmol 125I-rT3 (∼50 000 c.p.m.), 20 μg protein, and 5 mM DTT in a final volume of 100 μl. Both assay mixtures were incubated in a covered water bath with shaking for 60 min at 37 °C, and the reactions were stopped by adding 50% human plasma, 10 mM propylthiouracil, and 10% trichloroacetic acid. In both cases, the assay mixture was centrifuged (1300 g for 15 min), and the supernatant was decanted onto a 1 ml AG 50W-X2 column equilibrated in 10% acetic acid and eluted with 2 ml of 10% acetic acid. In all cases, <30% of the substrate was consumed during the reaction. The amount of 125I in the eluate, which is an index of enzyme deiodinating activity, was determined in a gamma scintillation counter. Results for both enzymes are expressed as picomoles of 125I-released/mg protein×h. All enzymatic assays were performed in duplicate, with a minimum of three repetitions.
Quantitative real-time PCR
mRNA extraction, reverse transcription, and real-time PCR were performed as previously described (Anguiano et al. 2007). Briefly, 2 μg total RNA extracted from thyroid tissue (TRIZOL reagent; Life Technologies) was reverse-transcribed (Superscript II system; Invitrogen) according to the manufacturer's instructions. PCR was performed on the sequence detector system Roto-Gene 3000 (Corbett Research, Mortlake, NSW, Australia) using SYBR green as a marker for DNA amplification. Gene-specific primers are listed in Table 2. The reaction was performed with 1 μl cDNA template and the quantitative real-time PCR (qPCR) supermix-UDG kit (Invitrogen), using 40 cycles of three-step amplification (94 °C for 30 s, 58 °C for 30 s, and 72 °C for 30 s). The PCR generated only the expected, specific amplicon, which was corroborated in each case by the melting temperature profile (dissociation curve) and by electrophoresis of 5 μl of the PCR product through a 2% agarose gel containing ethidium bromide in TAE (0.04 M Tris-acetate/0.01 M EDTA electrophoresis buffer). No PCR products were observed in the absence of template. Gene expression was calculated using the Dcycle threshold (DCt) method and normalized to actin mRNA content. All measurements were performed in triplicate.
Oligonucleotide sequences employed for real-time PCR
|Genes||Sense sequence||Antisense sequence||Alignment temperature (°C)|
|Actin||ACA GAG TAC TTG CGC TCA GGA||CCA TCA TGA AGT GTG ACG TTG||58|
|rtDh||GAC CAT TCT CCT CAC TC||GGC AGA CTCT CCT ATG AGA AT||58|
|ID1||ATT TGA CCA GTT CAA GAG ACT CGT AG||CCA CGT TGT TCT TAA AAG CCC A||58|
|NIS||CCG GAT CAA CCT GAT GGA CT||CCT GAG GGT GCC ACT GTA AG||58|
rtDh, rat thyroidal dehalogenase; ID1, iodothyronine deiodinase type 1; NIS, sodium/iodide symporter.
Statistical analyses were performed with the Prism software (v. 4.03, GraphPad Software, Inc., San Diego, CA, USA). Comparison between groups was performed by one-way ANOVA followed by Tukey's multiple comparison/post hoc tests wherever applicable; a P value ≤0.05 was considered statistically significant. Results are shown as the mean±s.e.m.
TSH and T3 serum levels
Table 3 summarizes circulating levels of TSH and T3 in all experimental groups. As expected, TSH levels increased significantly in the hypothyroid group and decreased in the hyperthyroid group, while T3 exhibited the opposite pattern. Iodide administration had no significant effect on either hormone. Pituitary ablation resulted in TSH and T3 levels well below control values. Owing to the lack of cross reactivity between the administered bTSH with the endogenous rat hormone with the RIA kit employed, TSH replacement was not reflected on circulating levels (Table 3). However, TSH replacement significantly stimulated T3 secretion by the intact thyroid gland. Conversely, this response to TSH replacement in the thyroid gland of HPX rats, which were I-depleted, was blunted. As expected, T3 levels in HPX rats, either T3- or TSH+T3-replaced, were significantly increased.
TSH and triiodothyronine (T3) serum values
|Group||Experimental protocol||Serum TSH (ng/ml)||Serum T3 (ng/dl)|
|Acute KI load||5.47±0.9||48±2.9|
|Chronic KI load||4.75±1.7||61.64±5.5|
*P<0.05, compared to the control group; †P<0.001, compared to the control group.
Effect of hypo- and hyperthyroidism on rtDh and ID1 enzymatic activities
Intact rats rendered hypothyroid by the MMI+KClO4 treatment (the I-depleted group) showed a 200 and 50% increase in rtDh and ID1 activities respectively (Fig. 1). However, administration of T3 differentially regulated the activity of the two enzymes: rtDh decreased by 50%, whereas ID1 increased by 75% (Fig. 1).
Effect of acute and chronic iodide administration on rtDh and ID1 dehalogenating activities
As depicted in Fig. 2, rtDh and ID1 activities were significantly decreased in intact rats after exposure to either an acute (24 h) or a chronic (7 days) iodide overload. This inhibitory effect of the halogen was sustained up to day 7 of treatment, showing a 60 and 50% decrease for rtDh and ID1 respectively (Fig. 2).
Effect of HPX and iodide depletion on both enzymatic activities
To further dissect the effects of TSH and T3, HPX animals were exposed to several experimental manipulations. Thus, TSH replacement increased rtDh and ID1 activities by 2.8- and 9-fold respectively (Fig. 3). This stimulatory effect of TSH on rtDh and ID1 activities was dramatically enhanced (to 6- and 52-fold increases respectively) when intrathyroidal iodide was depleted by concomitant MMI+KClO4 treatment (Fig. 3). As in the case of hyperthyroid intact animals, in T3-replaced HPX rats, only ID1 activity exhibited a significant increase (17-fold, Fig. 3). Furthermore, when T3 was combined with TSH, the activity of both enzymes significantly increased relative to control animals. However, when comparing this group to the HPX+T3-treated animals, the increase was only significant for rtDh (Fig. 3).
Effect of hypo- and hyperthyroidism on ID1 activity in liver and kidney of HPX rats
ID1 activity in kidney and liver was significantly up-regulated by TSH in HPX rats, increasing 100 and 150% respectively (Fig. 4). However, this TSH stimulatory effect was not observed in I-depleted rats in which endogenous T3 synthesis was blocked by MMI+KClO4 (Fig. 4). Nevertheless, T3 alone was sufficient to increase ID1 activity in both tissues by 320 and 400% in liver and kidney respectively (Fig. 4). When T3 and TSH were co-administered, kidney and liver ID1 activity increased 130 and 320% respectively (Fig. 4).
Effect of iodide on tDh and ID1 mRNA expression
The expression levels of mRNA for tDh and ID1 in the thyroid of the hypothyroid, hyperthyroid, and the acute and chronic iodide-treated groups were determined. mRNA levels for the HPX group were not measured due to the limited volume of tissue available. Both tDh and ID1 mRNA expression diminished during acute iodide administration. However, only tDh mRNA remained significantly decreased during chronic iodide administration (Fig. 5). In addition, NIS mRNA levels were increased in hypothyroidism, and profoundly decreased in the hyperthyroid state, as well as during acute and chronic iodide administration (Fig. 5).
The results obtained for both enzymes with the different experimental protocols are summarized in Table 4.
Summary of results. Statistically significant increments/decrements are shown by comparing each experimental group to their corresponding control (see figures)
|Acute KI load||↓||↓||↓||↓||↓|
|Chronic KI load||↓||↓||↓||↔||↓|
|Hypophysectomized rats (activity)|
↑, increase; ↓, decrease; ↔, no change; ND, not determined; tID1, thyroidal ID1; hID1, hepatic ID1; kID1, kidney ID1.
To the best of our knowledge, this is the first study to examine the regulation of the intrathyroidal dehalogenases rtDh and ID1 simultaneously. Early reports have shown the important regulatory effect of TSH on rtDh, as well as of both TSH and TH on ID1 (Roche et al. 1953, Maayan & Rosenberg 1963, Erickson et al. 1982, Toyoda et al. 1992). By dissecting in vivo the influence of the three major players involved in thyroidal homeostasis (TSH, TH, and iodide) on thyroidal dehalogenating enzymes, our results add further insights into their regulation and, hence, contribute to the understanding of fundamental aspects of thyroid physiology.
Blockade of TH synthesis (by MMI+KClO4) caused a sustained increase in TSH, which led, in turn, to significant increases in the activity of both thyroidal enzymes. These results could be interpreted as a direct stimulation by TSH; however, it should be emphasized that besides being hyper-stimulated by TSH, the thyroid glands of this hypothyroid group are deficient in TH and iodide. Thus, any of these three factors could be responsible for the observed changes in enzyme activity. Nevertheless, and as previously showed in cell cultures for tDh (Gnidehou et al. 2004) and ID1 mRNAs (Toyoda et al. 1992), the finding that both enzyme activities increase in HPX animals receiving TSH supports a direct positive effect of this pituitary hormone on the activity of the two intrathyroidal dehalogenases. Furthermore, this TSH stimulatory effect is enhanced when the thyroid gland of HPX animals is iodide-depleted, data that are consistent with the inhibitory effect exerted on both enzymes by either acute or chronic iodide overload.
The differential response of rtDh (decrease) and ID1 (increase) activities in intact animals treated with supraphysiological doses of T3 (hyperthyroidism model) further supports the positive effect of TSH on rtDh. Furthermore, the stimulatory effect of T3 on ID1 activity is demonstrated by its significant increase in HPX animals. The response of ID1 to T3 was expected, because TH-responsive elements are present in the promoter region of the Dio1 gene (Toyoda et al. 1992, Koenig 2005). Similarly, ID1 activity also increased in the kidney and liver of HPX T3-treated rats. Interestingly, in all tissues assayed, ID1 activity increased significantly in HPX TSH-replaced rats. However, this increase was prevented in kidney and liver when endogenous TH synthesis was pharmacologically blocked (MMI+KClO4). Together, these data support the notion that extrathyroidal ID1 is T3 dependent, and they confirm previous studies showing that only thyroidal ID1 is TSH dependent (Erickson et al. 1982). Consistent with their known stimulatory effect on TSH receptor expression (Denereaz & Lemarchand-Beraud 1995), when co-administered to HPX rats, TSH and T3 exerted additive effects on the activity of both intrathyroidal dehalogenases, but not on hepatic or renal ID1 activities. As expected, the level of NIS mRNA decreased in hyperthyroid animals but increased in hypothyroid animals, thus reflecting its regulation by TSH. In addition, NIS mRNA levels also significantly decreased after acute and chronic iodide administration; again, this was the expected response since acute exposure to iodide triggers the Wolff–Chaikoff effect (Eng et al. 1999).
A major finding of the present study consists of the result that the halogen overload (acute and chronic) significantly inhibits the activity and expression of both intrathyroidal dehalogenases when iodide organification is maintained. In this regard, the well-known inhibitory effect exerted by iodide on TSH responsiveness in the thyroid gland (Cochaux et al. 1987) could be related to the observed decrease in the intrathyroidal dehalogenation by blocking TSH stimulation on both enzymes. However, the fact that TSH and T3 circulating levels did not significantly differ from control group suggests an active thyroidal stimulation by TSH in the presence of the halogen, which argues against an inhibition in TSH responsiveness by iodide. In this regard, although there was no significant decrease in T3 circulating levels with iodide administration, lower serum T3 levels were found with the acute iodide administration while compared to the controls, which is in agreement with the inhibition in thyroid hormonogenesis induced by the Wolff–Chaikoff effect. The activity of both enzymes was highest when both iodide uptake and organification were pharmacologically inhibited (the I-depleted model). This was observed in both intact (with elevated TSH circulating levels) and HPX rats (with controlled TSH serum levels), which suggests a TSH- and T3-independent inhibitory effect by iodide upon intrathyroidal dehalogenation. Consistent with this observation, Wang et al. (2009) recently reported a significant decrease in both ID1 activity and mRNA expression in thyroid glands of rats chronically treated (months) with iodide excess in drinking water. The results presented here and the findings by Wang et al. strongly suggest that the iodide inhibitory effect on intrathyroidal dehalogenation represents a pivotal mechanism to ensure thyroid homeostasis during an iodide overload. Specifically, we suggest that the down-regulation of the two dehalogenases contributes to the mechanisms involved in the escape from the Wolff–Chaikoff effect. In addition to the effect on TSH responsiveness, Wolff–Chaikoff effect involves the inhibition in the expression of NIS and TPO, as well as inhibition in H2O2 generation, all of which result in a negative impact on TH hormonogenesis (Cochaux et al. 1987, Corvilain et al. 1988, Laurent et al. 1989, Panneels et al. 1994, Uyttersprot et al. 1997, Eng et al. 1999). Paradoxically, for this inhibition to occur, it is mandatory that iodide uptake and/or organification remain intact; i.e. when TPO is pharmacologically blocked before iodide administration, the Wolff–Chaikoff effect does not occur (van Sande et al. 1975). To explain this paradox, the participation of an unknown inhibitory iodinated compound has been suggested, possibly a lipid derivative like iodolactone or iodohexadecanal (Dugrillon et al. 1990, Panneels et al. 1996). Our results are consistent with these observations because intrathyroidal dehalogenation is not inhibited, but enhanced when iodide uptake and organification are blocked in HPX animals. It is known that for the escape phenomenon to occur, there must be a decrease in the intrathyroidal, inorganic iodide concentration (Eng et al. 1999). Since the intrathyroidal iodide concentration depends on the balance of its uptake (in) and recycling (out), and given that the halogen inhibits rtDh and ID1, our results support the proposal that both intrathyroidal dehalogenases participate in the escape phenomenon from the Wolff–Chaikoff effect, presumably by contributing to a decrease in the total intrathyroidal iodide concentration.
In conclusion, the present results provide additional insights into the complex mechanisms involved in the Wolff–Chaikoff effect and its escape phenomenon. This is the first study that shows a regulatory effect of iodide upon the activity of the intrathyroidal dehalogenases rtDh and ID1, and it underscores the important role of autoregulatory processes within thyroid follicular cells.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
This study was partially supported by grants CoNaCyT 106214, 080420, SEP-PROMEP UAQ-PTC-156, and PAPIIT UNAM IN203409.
We are especially grateful to Dr Peter A Kopp for his invaluable advice and suggestions in the preparation of this manuscript. We also thank Dr J Martin Garcia for his help in obtaining the biological samples, and Leonor Casanova and Rafael Silva for their invaluable technical support, and Dr Dorothy Pless for critically reading the manuscript.
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