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Endocrinology Vol. 148, No. 6 2747-2752
Copyright © 2007 by The Endocrine Society

Induction of Goitrous Hypothyroidism by Dietary Iodide in SJL Mice

Haiyan S. Li and George Carayanniotis

Divisions of Endocrinology and Basic Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada A1B 3V6

Address all correspondence and requests for reprints to: G. Carayanniotis, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada A1B 3V6. E-mail: gcarayan{at}mun.ca.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Prolonged intake of large amounts of iodide has been reported to increase the incidence of goiter and/or hypothyroidism in humans as well as animals prone to spontaneous autoimmune thyroiditis. In the current study, we investigated the role of dietary iodide on the development of hypothyroidism, as well as thyroiditis, in strains of mice that do not develop spontaneous autoimmune thyroiditis. Intake of 0.05% NaI via drinking water for 10 wk induced hypothyroidism in SJL/J mice as indicated by elevated TSH and depressed total T4 values in serum and formation of colloidal goiter with an inactive flattened thyroid epithelium. Hypothyroidism did not appear to have an autoimmune basis because only focal mononuclear cell infiltrates were found intrathyroidally, and antithyroglobulin antibodies or increased organification of iodide were not detected. These phenomena were not observed in similarly treated CBA/J mice, suggesting polymorphisms in genes controlling events downstream of iodide uptake by thyrocytes. Interestingly, RT-PCR analysis indicated that unlike CBA/J, SJL/J mice could not down-regulate Na/I symporter gene expression during the NaI treatment. No significant temporal or strain differences were observed regarding the expression of thyroglobulin, pendrin, thyroid peroxidase, and DUOX1 and DUOX2 genes after NaI intake. Our results point to the generation of a mouse model for the study of iodine-induced hypothyroidism, which does not seem to have an autoimmune basis.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
OVER THE LAST 4 decades, numerous studies have reported that excessive iodine intake can promote development of goiter and/or hypothyroidism in normal subjects (reviewed in Refs. 1, 2, 3). Endemic goiter has been described in otherwise euthyroid populations consuming iodine-rich seaweed in coastal regions of Japan (4) or drinking iodide-rich water in China (5, 6). Large quantities of iodide ingestion have also been linked to development of hypothyroidism, assessed by elevated serum TSH concentrations, in schoolchildren (7), elderly subjects (8, 9), or healthy adults (10, 11, 12). In many instances, it was inconclusive whether this iodide effect had an autoimmune basis, and the mechanisms behind these observations remain unclear. It has been postulated that they may involve inhibitory effects of iodine excess on iodide organification or the release of the hormones T4 or T3 from the thyroid (3). Also, iodide administration has been clearly shown to increase the incidence and/or severity of disease in animals prone to develop spontaneous autoimmune thyroiditis (SAT), such as Cornell C strain (CS) chickens (13), 30-d-old BB/W rats (14), and NOD.H-2h4 mice (15, 16). In these studies, however, direct iodine effects on thyroid function remained speculative because serum thyroid hormone levels were either not examined (15, 16) or found unchanged regardless of the accelerated SAT (13, 14). The genetic background of the host played a pivotal role because excess iodide administration to mice and rats that do not develop SAT did not lead to similar effects (14, 16, 17).

The basic steps in the process of iodide organification have been well delineated. Serum iodide is actively absorbed from the basolateral membrane of thyrocytes via the Na+/I– symporter (NIS) (18) and translocated into the follicular lumen probably via pendrin, an iodide/chloride transporter present in the apical membrane (19). On the outer site of apical surface, iodide is rapidly oxidized and incorporated into tyrosyl residues in thyroglobulin (Tg) (20). This process is catalyzed by thyroid peroxidase (TPO) in the presence of an H2O2-generating system. H2O2 is formed from the oxidation of nicotinamide adenine dinucleotide phosphate by a thyroidal nicotinamide adenine dinucleotide phosphate oxidase (Thox2 or Duox2), a 1548-amino acid integral membrane flavoprotein. Closely linked to the THOX2 gene, on chromosome 15q15.3, lies another gene, THOX1, encoding the very similar 1551-amino acid protein Thox1 or Duox1 (21, 22) whose role as a thyroid H2O2 generator is under debate. Iodine, in an oxidized form, can inhibit its own organification by TPO, a process known as the Wolff-Chaikoff effect (23), by inhibiting H2O2 production, perhaps via reducing the availability of the mature Duox2 protein (24, 25, 26). The pituitary-derived TSH, interacting with its receptor (TSHR) at the basolateral membrane of thyrocytes is the main regulator of thyroid hormone synthesis (20).

The enhanced immunogenicity of iodine-rich Tg (I-Tg) at both the B and T cell level (27, 28, 29, 30) is believed to contribute to the pathogenesis of autoimmune thyroiditis. We have previously reported that I-Tg is highly immunopathogenic in SJL mice, a strain that does not develop SAT, causing experimental autoimmune thyroiditis (EAT) of higher incidence and severity as well as stronger B and T cell responses than those elicited by normal Tg (31). Processing of I-Tg in macrophages or dendritic cells of SJL mice generated the cryptic pathogenic peptide p2495 (2495–2503) (31). Recently we identified that iodotyrosyl formation within Tg peptides can form neoantigenic determinants causing EAT in CBA/J hosts (32). These findings allowed us to postulate that Tg iodination may promote generation of pathogenic epitopes to which immune tolerance has not been previously established. In the present study, we reasoned that if iodine administration promotes Tg iodination in SJL mice, this might lead to sensitization of autoreactive T cells responding to p2495 or other pathogenic determinants. Unexpectedly, we observed iodide-induced goiter, hypothyroidism, and only focal thyroiditis in these mice.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and antigens
Female, 4- to 6-wk-old CBA/J and SJL/J mice were purchased from the Jackson Laboratories (Bar Harbor, ME) and placed on normal tap drinking water (controls) or water containing 0.05% NaI, for 10–12 wk. All experimental procedures were approved by the Animal Care Ethics Committee at the Memorial University of Newfoundland. Tg was purified by gel filtration of thyroid gland homogenates on Sepharose CL-4B columns, as previously described (33). Frozen thyroid glands of outbred ICR mice were obtained from Bioproducts for Science (Indianapolis, IN). The iodine content in Tg was determined by a modified nonincinerative method based on the catalytic activity of iodine in the ceric-arsenite reaction, as described in an earlier study (31). Ovalbumin (OVA) was purchased from Sigma (St. Louis, MO).

Determination of thyroid hormone levels using RIA
Mouse serum TSH levels were assessed by RIA in Dr. A. F. Parlow’s laboratory (Harbor-UCLA Medical Center, Torrance, CA). Serum total T4 was determined using the DYNOtest T4 kit (BRAHMS Diagnostica GmbH, Berlin, Germany) according to the manufacturer’s instructions. Briefly, T4 standards and sera samples were added to anti-T4-coated tubes and incubated for 2 h in the presence of 125I-labeled free T4. The tubes were then dried, and radioactivity was measured in a Wallac 1277 Gammamaster (PerkinElmer Life Sciences, Boston, MA). The total T4 values in each sample were extrapolated from the standard curve and were expressed in micrograms per deciliter.

Thyroid histology
Thyroid glands were placed in 10% buffered formalin, embedded in methacrylate, step sectioned, mounted on glass slides, and stained with hematoxylin and eosin. The mononuclear cell infiltration index (I.I.) was scored as follows: 0, no infiltration; 1, interstitial accumulation of cells between two or three follicles; 2, one or two foci of cells at least the size of one follicle; 3, diffuse infiltration 10–40% of total area; 4, extensive infiltration 40–80% of total area; and 5, extensive infiltration greater than 80% of total area. The highest infiltration score observed per gland was assigned to each mouse.

T cell activation assay
After a 10-wk period of NaI administration, splenocytes were collected (two mice per group) and cultured for 4 d at 4 x 105 cells per 200 µl medium/well in 96-well plates in the presence of titrated amounts of antigen. 3[H]thymidine (1 µCi/well) was added for the last 18 h; the cells were then harvested, and incorporated radioactivity was measured in a TopCount NXTM counter (Canberra Packard, Concord, Ontario, Canada). Stimulation index (S.I.) is defined as counts per minute in the presence of peptide/counts per minute in the absence of peptide.

Measurement of IgG responses by ELISA
The presence of Tg-specific IgG antibodies (Abs) in mouse sera was determined by ELISA. Briefly, pooled immune sera (six to eight samples per experimental group) were initially diluted at 1:50 in PBS/Tween 20/ 0.1% BSA and added to Tg or OVA-coated wells in serial dilutions for 1 h at room temperature. Ab binding was detected with alkaline phosphatase-conjugated goat antimouse IgG antibodies (Sigma), and light absorption of the p-nitrophenylate product was determined at 405 nm using a Vmax plate reader (Molecular Devices, Sunnyvale, CA).

RT-PCR analysis of intrathyroidal mRNA expression
Total thyroid RNA was extracted using Trizol reagent (Invitrogen, Carlsbad, CA) and reverse transcribed to first-strand cDNA using Amersham Bioscience cDNA synthesis kits (Buckinghamshire, UK). Two microliters of cDNA were amplified in a 50-µl PCR, consisting of denaturation at 94 C for 5 min, 30 cycles of denaturation at 94 C for 1 min, annealing at 55 C for 1 min, and extension at 72 C for 1 min, followed by a final 7-min extension at 72 C (34). PCR products were analyzed on 1.5% agarose gels, and relative expression was calculated as the ratio of the relative OD of the specific gene band to that of the glyceraldehyde-3-phosphate dehydrogenase in the same sample and under similar conditions but with 25 cycles of amplification. Primers for Tg, TSHR, NIS, pendrin, TPO, DUOX1, and DUOX2 are listed in Table 1Go.


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  		TABLE 1. The sequences of PCR primers used in this study

 
Statistical analysis
Statistical comparison of EAT scores between various groups was performed by the Wilcoxon rank sum test using GraphPad Prism 4.0 software (GraphPad Inc., San Diego, CA). Statistical analysis of data involving the iodine content of Tg, serum thyroid hormone levels, stimulation indices, and OD values was performed by the t test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
High iodide intake induces thyroid goiter and focal thyroiditis in SJL mice
Female mice from the non autoimmune-prone strains SJL and CBA/J (eight mice per group) were provided with drinking water supplemented or not with 0.05% NaI. Ten weeks later, all SJL mice placed on NaI developed a goitrous enlargement in both thyroid lobes, whereas the thyroids of mice fed normal water were unaffected (Fig. 1AGo). Unlike the histological appearance of normal thyroids (Fig. 1Go, B and E), the majority of the follicles in the goitrous glands were lined with flattened epithelial cells, suggesting metabolic inactivity and hyposecretion of thyroid hormones (Fig. 1Go, C and F). In addition, small foci of mononuclear cell infiltration were observed among the thyroid follicles (Fig. 1Go, D and G), in all SJL mice with high iodine intake with a mean I.I. of 2 (Table 2Go). However, there was no detection of concomitant development of T cell responses or auto-Abs to Tg, the major thyroid autoantigen, in the splenocytes and sera, respectively, of these mice (Table 2Go). These macroscopic and histological changes were not apparent at the 3- and 6-wk intervals after the initiation of high iodide intake (data not shown). In addition, all the above symptoms were not observed in any of the similarly treated CBA/J mice (Table 2Go), suggesting influence of polymorphic genes on the biological response to high iodide intake.


Figure 1
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  		FIG. 1. Morphological and histological appearance of SJL thyroid glands after 10 wk of high NaI intake. A, Thyroids from SJL mice fed normal water (1 and 2) or water supplemented with 0.05% NaI (3 and 4). B and E, Histological appearance of normal thyroid follicles. C and F, Thyroid follicles of goitrous glands. D and G, Focal mononuclear cell infiltrates (arrows) among the follicles of goitrous glands. Magnifications (B–D), x200; (E–G), x400.

 

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  		TABLE 2. Effects of high iodine intake on induction of thyroiditis and Tg-specific immune responses

 
High iodide intake does not lead to increased iodide organification and inhibits thyroid hormone release in SJL mice
To determine whether dietary NaI intake led to enhanced organification of iodide, we examined the iodine content in Tg purified from glands of 15 SJL or CBA/J mice after 10 wk of NaI administration. It was found that Tg derived from NaI-treated mice did not have a higher iodine content than normal Tg; instead, the iodine levels were slightly lower (13 vs. 20 iodine atoms per monomeric unit) but did not reach statistical significance (Fig. 2Go). To investigate the effect of iodide on thyroid hormone release, serological determination of TSH and total T4 was performed in 35 SJL mice (seven mice per group per time point) at 1, 3, 6, and 10 wk after administration of NaI or 3 wk after its withdrawal. An equal number of mice were used as controls. As shown in Fig. 3AGo, the mean total T4 concentration in the experimental group was significantly lower than that of the control group (2.6 vs. 3.6 µg/dl, P < 0.0001) as early as 1 wk after iodide administration. This difference remained significant until 10 wk (1.9 vs. 3.0 µg/dl, P < 0.0001) when goiter formation became evident (Fig. 3AGo). A compensatory elevation in mean serum TSH concentration (1.36 vs. 0.90, 1.41 vs. 1.03, 2.61 vs. 0.98, 3.82 vs. 1.04 ng/ml at wk 1, 3, 6, 10, respectively) was observed in NaI-treated SJL mice vs. the controls (Fig. 3BGo). Three weeks after NaI withdrawal, the mean total T4 value increased (2.5 µg/dl), approaching that of the control group (2.8 µg/dl), and the mean TSH level decreased but remained significantly higher than that of the controls (2.18 vs. 1.00 ng/ml) (Fig. 3Go, A and B). In contrast, hypothyroidism was not observed in CBA/J mice fed NaI at 1, 3, and 6 wk (data not shown) or 10 wk (Fig. 3Go, A and B).


Figure 2
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  		FIG. 2. Determination of iodine content in Tg preparations. A, Reduction of absorbance at 410 nm in the first 60 sec of the I-catalyzed ceric-arsenite reaction as a function of I added (supplied as T4). B, Iodine content in normal Tg (filled bars), Tg purified from glands 10 wk after the initiation of 0.05% NaI intake (striped bars), or Tg maximally iodinated in vitro by the Iodogen method (open bars), extrapolated from the standard curve. Statistical significance was determined by the t test.

 

Figure 3
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  		FIG. 3. Determination of thyroid hormone levels in the sera of SJL and CBA/J mice. Sera were collected at 1, 3, 6, and 10 wk after placing the animals on normal water ({circ}) or water containing 0.05% NaI (bullet). After 10 wk of NaI supplementation, some mice were placed on normal water for 3 more weeks (+3 w). A, Determination of total T4. B, Determination of TSH. *, P < 0.05; **, P < 0.0001; n.s., not significant; TT4, total T4.

 
Intrathyroidal expression of genes involved in iodide transportation and organification
To identify candidate genes that might account for the development of goitrous hypothyroidism, we examined by RT-PCR the expression levels of thyroidal mRNA encoding Tg, TSHR, NIS, pendrin, TPO, Duox1, and Duox2 at 1 or 10 wk after NaI administration (four mice per group). It was found that the TSHR mRNA was significantly up-regulated at 10 wk in hypothyroid SJL mice but not in similarly treated euthyroid CBA/J mice (Fig. 4Go, A and B). At the same time, the high iodine intake down-regulated significantly the NIS mRNA expression in CBA/J mice. In contrast, the intrathyroidal expression of NIS mRNA in SJL mice remained unchanged throughout the duration of the experiment and was not significantly different between mice placed on NaI vs. the controls (Fig. 4Go, A and B). No significant differences were observed regarding the relative mRNA expression of the other genes in hypothyroid vs. euthyroid mice.


Figure 4
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  		FIG. 4. Intrathyroidal mRNA expression of candidate genes involved in iodide transportation and organification. A, RT-PCR analysis of samples obtained from animals (four mice per group) after 1 and 10 wk of high iodine intake or controls. B, Relative expression of mRNA encoding TSHR and NIS in control (open bars) or NaI-treated (filled bars) SJL and CBA/J mice. The data represent the mean ± SD of two independent experiments. GAPDH, Glyceraldehyde-3-phosphate dehydrogenase.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study was initiated to investigate intrathyroidal formation of I-Tg in mice with a high dietary iodine intake and possible development of EAT, in analogy to earlier similar studies with CS chickens (30). We found that iodide organification was not enhanced in mice fed NaI, and thyroid hormone release was significantly inhibited in SJL, but not CBA/J mice, after 10 wk of NaI administration, leading to development of goitrous hypothyroidism that was reversed upon NaI withdrawal. These serendipitous findings suggest that the inhibitory effect of high NaI intake on thyroid hormone release in SJL mice is under the influence of polymorphic genes. To our knowledge, our data describe, for the first time, a murine model of iodide-induced hypothyroidism in a nonautoimmune-prone strain. High iodine diet-induced hypothyroidism has been previously reported in dogs (35).

The intrathyroidal mononuclear cell infiltrates in hypothyroid SJL/J mice were only focal in nature and in contrast to the rather extensive infiltrates frequently observed in EAT as well as in Hashimoto’s disease in humans. Furthermore, we could not obtain evidence for autoreactive B or T cell responses developing against murine Tg. Whereas it is possible that immune responses might have emerged against other thyroid autoantigens, such as TPO (36), it is quite clear that the observed hypothyroidism cannot be attributed to thyroid destruction by autoimmune processes. In fact, when SJL mice were challenged with Tg in Freund’s complete adjuvant after 10 wk of NaI intake, they developed significantly lower Tg-specific B and T cell responses than SJL mice placed on normal water (data not shown). Low thyroid autoimmune reactivity and development of thyroid-associated ectopic thymic tissue have previously been reported in normal, nonautoimmune-prone, female Wistar rats placed on an enriched iodine diet (37). On the other hand, our results contrast with those from several studies examining the effects of high dietary intake of iodine on animals developing spontaneous thyroiditis, such as CS chickens (13), 30-d-old BB rats (14), and NOD.H-2h4 mice (15, 16). In those cases, iodine increased the incidence and/or severity of thyroiditis as well as formation of anti-Tg antibodies. The reasons for this discrepancy remain unclear. Iodine has direct stimulatory effects on lymphoid cells (38, 39), and as previously hypothesized (37, 40), it may promote dysregulation in an already malfunctioning immune system or it may be particularly toxic for thyrocytes that demonstrate a high metabolic activity. This would lead to release of thyroid autoantigens and stimulation of autoimmunity (41).

The histological appearance of the SJL thyrocytes after iodide exposure and the iodine organification data argue for iodide-mediated suppressive effects on the metabolic activity of these cells. In accordance with a concept proposed first by Braverman and Ingbar in 1963 (42) and confirmed by recent studies (43, 44, 45, 46, 47), we hypothesize that under the influence of genetic polymorphism(s), SJL, but not CBA/J, thyrocytes fail to escape from the acute Wolff-Chaikoff effect. This hypothesis is supported by the significant reduction of NIS mRNA in CBA/J but not SJL thyrocytes after NaI administration. Decrease in iodide transport reduces the intrathyroidal iodide concentration below a critical inhibitory level and allows iodination to resume (2). In SJL thyrocytes, the NIS mRNA levels seem to be unaffected by NaI, allowing continuous iodide transport into the cells, but the SJL genes that influence this process remain unknown. Excess iodine can significantly decrease NIS activity, even in the presence of high serum concentrations of TSH, as suggested by studies in rats (46). The pendrin mRNA levels were also not influenced by NaI, in agreement with results of in vitro studies with FRLT-5 cells (19). Lastly, we did not detect reduction of Duox2 mRNA in either SJL or CBA/J thyrocytes, in confirmation of the view that inhibition of H2O2 release by an oxidized form of iodide takes place at a posttranscriptional level by reducing the availability of the mature Duox2 protein (25).

The iodide-induced goitrous hypothyroidism of SJL mice models the nonautoimmune hypothyroidism observed among normal subjects in several parts of the world consuming large quantities of iodine (2, 4, 5, 6, 9). When iodine intake is restricted, the increased serum TSH concentrations are normalized in patients lacking antithyroid Abs but remain elevated in those with positive Abs (11). Our findings may also model the amiodarone-induced hypothyroidism observed occasionally among cardiac patients with no underlying thyroid disease (3). Treatment of these subjects with potassium perchlorate, a competitive inhibitor of NIS, allows resumption of normal thyroid function because the excess intrathyroidal iodide is reduced (48). Identification of the genetic polymorphic traits that underlie the dysregulation of NIS expression under conditions of high iodide intake may aid in the design of nutritional or therapeutic modalities.


   Footnotes
 
First Published Online March 8, 2007

Abbreviations: Ab, Antibody; CS, Cornell C strain; EAT, experimental autoimmune thyroiditis; I.I., infiltration index; I-Tg, iodine-rich Tg; NIS, Na+/I– symporter; OVA, ovalbumin; Tg, thyroglobulin; TPO, thyroid peroxidase; SAT, spontaneous autoimmune thyroiditis; S.I., stimulation index; TSHR, TSH receptor.

This work was supported by a grant from the Canadian Institutes of Health Research.

Current address for H.S.L.: Department of Pathology, The Johns Hopkins University, Baltimore, Maryland 21205.

Disclosure Statement: The authors have nothing to disclose.

Received January 19, 2007.

Accepted for publication March 1, 2007.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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