The trace element selenium and the thyroid gland.

Apart from the essential trace element iodine, which is the central constituent of thyroid hormones, a second essential trace element, selenium, is required for appropriate thyroid hormone synthesis, activation and metabolism. The human thyroid gland has the highest selenium content per gram of tissue among all organs. Several selenocysteine-containing proteins respectively enzymes are functionally expressed in the thyroid, mainly in thyrocytes themselves: three forms of glutathione peroxidases (cGPx, pGPx, and PH-GPx), the type I 5-deiodinase, thioredoxin reductase and selenoprotein P. The thyroidal expression of type II 5-deiodinase still is controversial. As thyrocytes produce H2O2 continuously throughout life an effective cell defense system against H2O2 and reactive oxygen intermediates derived thereof is essential for maintenance of normal thyroid function and protection of the gland. In experimental animal models long-term and strong selenium deficiency leads to necrosis and fibrosis after high iodide loads. Combined iodide and selenium deficiency such as in central Zaire is thought to cause the myxedematous form of endemic cretinism. Inadequate selenium supply and prediagnostically low serum selenium levels are significantly correlated with the development of thyroid carcinoma and other tumors. Though selenium supply controls expression and translation of selenocysteine-containing proteins no direct correlation is found between selenium tissue content and expression of various thyroidal selenoproteins, indicating that other regulatory factors contribute to or override selenium-dependent expression control, e.g., in thyroid adenoma, carcinoma or autoimmune disease. As both trace elements, iodine and selenium, were washed out from the upper layers of the soil during and after the ice ages in many regions of the world adequate supply with these essential compounds needs to be provided either by a balanced diet or supplementation.     

Thyroid function and polyamines. III. Changes in ornithine decarboxylase activity and polyamine contents in the rat thyroid during hyperplasia and involution

Changes in ornithine decarboxylase (ODC) activity and in polyamine contents of the rat thyroid were studied under various experimental conditions. Methylthiouracil (MTU) treatment produced several-fold increases in the thyroid ODC activity and in the content of putrescine, spermidine and spermine within a week. While serum thyrotropin (TSH) levels increased gradually up to 3 weeks, the content of both putrescine and spermidine tended to reach a plateau after 2 weeks of the goitrogen treatment; spermine content continued to increase progressively for 3 weeks. Discontinuance of MTU at 7 days resulted in a rapid decline in the elevated thyroid ODC activity, followed by a diminution of putrescine, spermidine and RNA contents. Thyroidal putrescine, spermidine and RNA responded more sensitively to both introduction and withdrawal of TSH stimulation than thyroidal spermine and DNA. Excess iodide, having no effect on the basal level of thyroid ODC, suppressed the MTU-induced increase in this enzyme activity without affecting circulating TSH, thyroxine (T4) and triiodothyronine (T3) levels. There was a significant negative correlation between the ODC activity and intrathyroidal concentration of iodine in MTU-pretreated rats. Theophylline increased the thyroid weight and ODC activity when given to rats fed with a subeffective dose of MTU. Analyses of serum TSH, T4, T3 and of thyroidal iodine revealed that TSH-induced thyroid ODC activity was suppressed by increased circulating thyroid hormones and/or intrathyroidal iodine. Furthermore, it was suggested that thyroid hormones and excess iodide acted directly on the thyroid to alter polyamine biosynthesis, possibly by changing the responsiveness of the gland to TSH.     

The Impact of Iodine Excess on Thyroid Hormone Biosynthesis and Metabolism in Rats

Thyroid function ultimately depends on appropriate iodine supply to the gland. There is a complex series of checks and balances that the thyroid uses to control the orderly utilization of iodine for hormone synthesis. The aim of our study is to evaluate the mechanism underlying the effect of iodine excess on thyroid hormone metabolism. Based on the successful establishment of animal models of normal-iodine (NI) and different degrees of high-iodine (HI) intake in Wistar rats, the content of monoiodotyrosine (MIT), diiodotyrosine (DIT), T₄, and T₃ in thyroid tissues, the activity of thyroidal type 1 deiodinase (D1) and its (Dio1) mRNA expression level were measured. Results showed that, in the case of iodine excess, the biosynthesis of both MIT and DIT, especially DIT, was increased. There was an obvious tendency of decreasing in MIT/DIT ratio with increased doses of iodine intake. In addition, iodine excess greatly inhibited thyroidal D1 activity and mRNA expression. T₃ was greatly lower in the HI group, while there was no significant difference of T₄ compared with NI group. The T₃/T₄ ratio was decreased in HI groups, antiparalleled with increased doses of iodine intakes. In conclusion, the increased biosyntheses of DIT relative to MIT and the inhibition of thyroidal Dio1 mRNA expression and D1 activity may be taken as an effective way to protect an organism from impairment caused by too much T₃. These observations provide new insights into the cellular regulation mechanism of thyroid hormones under physiological and pathological conditions.     

Dietary flavonoids and iodine metabolism

Flavonoids have inhibiting effects on the proliferation of cancer cells, including thyroidal ones. In the treatment of thyroid cancer the uptake of iodide is essential. Flavonoids are known to interfere with iodide organification in vitro, and to cause goiter. The influence of flavonoids on iodine metabolism was studied in a human thyroid cancer cell line (FTC-133) transfected with the human sodium/iodide transporter (NIS). All flavonoids inhibited growth, and iodide uptake was decreased in most cells. NIS mRNA expression was affected during the early hours after treatment, indicating that these flavonoids can act on NIS. Pendrin mRNA expression did not change after treatment. Only myricetin increased iodide uptake. Apeginin, luteolin, kaempferol and F21388 increased the efflux of iodide, leading to a decreased retention of iodide. Instead myricetin increased the retention of iodide; this could be of use in the radioiodide treatment of thyroid cancer.     

The Normal Thyroidal Uptake of Iodine

The range of values for the 24-hour thyroidal accumulation of radioactive iodine in euthyroid persons varies with geographic location. In the San Bernardino Valley region of Southern California the “normal range” is 6 percent to 33 percent in euthyroid subjects. This is lower than in studies from other areas of the United States. The urinary iodide excretion and the absolute iodine uptake of the thyroid are higher than in studies from many other areas of the United States, pointing to iodine abundance as the reason for this difference. The geographic variation and the possibility of changing dietary iodine intake of normal persons point to the necessity of current and local determinations of the “normal range” of the thyroidal uptake of radioiodine if the results of this thyroid function test are to be properly interpreted.     

Quantitative modulation of thyroid iodide peroxidase by thyroid stimulating hormone

The activity of rat thyroid iodide peroxidase fell to 8% of the normal value 48 hours after hypophysectomy. Rats given injections of thyroid stimulating hormone manifested an enzyme activity indistinguishable from that of the sham-operated animals. Cycloheximide prevented the thyroid stimulating hormone-induced restoration of the enzyme activity. The incorporation of ¹⁴C-leucine into the thyroid gland decreased gradually and reached two thirds of the sham-operated group by 48 hours after hypophysectomy. Thyroid stimulating hormone administration prevented this decrease, as observed for iodide peroxidase activity. Thyroidal RNA contents decreased also in hypophysectomized rats, thyroid stimulating hormone treatment prevented the reduction of RNA contents and no significant change was observed in thyroidal DNA contents. These data are consistent with the idea that protein biosynthesis is involved in thyroid stimulating hormone regulation of thyroidal iodide peroxidase and that the life span of the peroxidase is less than 48 hours.     

A Comparative Toxicological Assessment of Perchlorate and Thiocyanate Based on Competitive Inhibition of Iodide Uptake as the Common Mode of Action

Thiocyanate and perchlorate are known to competitively inhibit thyroidal iodide uptake at the sodium-iodide symporter. Estimates of their relative potencies have recently been refined; thiocyanate is 15 times less potent than perchlorate on a serum concentration basis. Numerous studies have been published relating serum thiocyanate concentrations (or surrogate measures) with thyroid function in various populations including pregnant women and neonates in regions with varying degrees of iodine deficiency. Fifteen published studies were located that relate serum thiocyanate concentrations with thyroid function. In the absence of severe iodine deficiency or iodine excess, adverse thyroidal effects occur with chronic serum thiocyanate concentrations ≥ 200 μ mol/L whereas non-adverse effects are observed with concentrations in the range of 65–85 μ mol/L. No adverse or non-adverse effects are observed at serum concentrations below 50 μ mol/L, even among sensitive subpopulations. Recently, studies relating serum perchlorate concentrations with perchlorate dose have become available, thus making it possible to predict the perchlorate dose associated with a serum perchlorate concentration. Serum thiocyanate concentrations found to induce non-adverse or adverse thyroid effects can thereby be used to predict the perchlorate concentration and thus the perchlorate dose that would be expected to induce similar effects. To place a perspective on environmental perchlorate exposure, a serum thiocyanate concentration of 50 μ mol/L is equivalent to a serum perchlorate concentration of 3.3 μ mol/L in terms of iodine uptake inhibition. This serum perchlorate concentration would require a perchlorate dose of 0.27 mg/kg-day, or a drinking water equivalent level of 9 mg/L using standard default assumptions of a 70 kg adult drinking 2 liters of water daily.     

Iodide excess exerts oxidative stress in some target tissues of the thyroid hormones

Environmental iodine deficiency continues to be a significant public health problem worldwide. On the other hand, iodide excess results principally from the use of iodine-containing medicinal preparations or radiographic contrast media. For this reason we intended to explore iodide excess impairment on prooxidant/antioxidant balance of the thyroid gland, hepatic tissue and in blood and the effect of selenium administration on oxidative stress markers under the same circumstances. Experiments were performed for 10 days with white, male, Wistar rats, as follows: group 1: control-normal iodine supply group; 2: high iodine diet, group; 3: high iodine diet and selenium; group 4: high iodine diet and Carbimasole. Oxidative stress markers such as lipid peroxides were determined in thyroid gland, hepatic tissue and in blood. Measuring H+ donor ability of the sera and catalase activity in thyroid gland and in hepatic tissue assessed antioxidant defense. Iodide excess had prooxidant effects, leading to an increased lipid peroxides level and catalase activity in target tissues and in blood and to a decreased H+ donor ability of the sera. Selenium supplementation had opposite effects. Present data allow us to conclude that the alterations due to iodide excess in thyroid gland, hepatic tissue and in blood are mediated through oxidative stress.     

Metabolism of bromide and its interference with the metabolism of iodine

The present knowledge about the metabolism of bromide with respect to its goitrogenic effects, including some conclusions drawn from our recent research on this subject, is reviewed. Firstly, the biological behavior of bromide ion is compared with that of chloride and iodide. Secondly, the details about distribution and kinetics of bromide ions in the body and in 15 different organs and tissues of the rat are given. Significant correlation between the values of the steady-state concentration of bromide in the respective tissue and of the corresponding biological half-life was found in most tissues examined. A remarkably high concentration of radiobromide was found in the skin, which represents, due to its large mass, the most abundant depot of bromide in the body of the rat. Thirdly, the effects of excessive bromide on the rat thyroid are summarized, along with the interference of exogenous bromide with the whole-body metabolism of iodine. It is suggested that high levels of bromide in the organism of experimental animals can influence their iodine metabolism in two parallel ways: by a decrease in iodide accumulation in the thyroid and skin (and in the mammary glands in lactating dams), and by a rise in iodide excretion by kidneys. By accelerating the renal excretion of iodide, excessive bromide can also influence the pool of exchangeable iodide in the thyroid. Finally, our recent results concerning the influence of high bromide intake in the lactating rat dam on iodine and bromide transfer to the suckling, and the impact of seriously decreased iodine content and increased bromide concentration in mother's milk on the young are discussed. We must state, however, that the virtue of the toxic effects of excessive bromide on the thyroid gland and its interference with the biosynthesis of thyroid hormones, as well as the exact mechanism of bromide interference with postnatal developmental processes remains to be elucidated.     

Molecular and cellular mechanisms of transepithelial iodide transport in the thyroid

Thyroid hormone is an essential regulator of developmental growth and metabolism in vertebrates. Iodine is a necessary constituent of thyroid hormone. Due to the scarcity and uneven distribution of iodine on the Earth's crust, the structure of the thyroid gland is adjusted to collect and store this element in order to secure a continuous supply of thyroid hormone throughout life. Still, disease resulting from hypothyroidism due to iodine deficiency is a global health problem, illustrating the great biological significance that iodine saving mechanisms have evolved. Iodide is accumulated together with prohormone (thyroglobulin) in the lumen of the thyroid follicles. The rate-limiting step of this transport is the sodium/iodide symporter located in the basolateral plasma membrane of the thyroid follicular cells. Iodide is also transferred across the apical plasma membrane into the lumen where hormonogenesis takes place. In this review, recent progress in the understanding of transepithelial iodide transport in the thyroid is summarized.     

Thyroidal autoregulation: Iodide-induced suppression of thyrotropin-stimulated cyclic AMP production and iodinating activity in thyroid cells

In continuing our study of the thyroidal autoregulation phenomenon, we have investigated the effects of iodide on several thyroidal responses to thyrotropin. Thus, we have found that the 2–4-fold thyrotropin stimulation of protein iodination in beef thyroid cells was reduced about 30% by 4 h of preincubation with 10 μM iodide, and virtually abolished with 50 μM iodide. Similarly the 8-fold thyrotropin stimulation of cyclic AMP accumulation in the cells was reduced about 30% by 3 h of preincubation with 50 μM iodide. It appears therefore that the so-called autoregulation of the thyroid gland does include influences of iodide on the thyrotropin stimulation of cyclic AMP production, iodide transport, and protein iodination which can be demonstrated in vitro in the dispersed thyroid cell system. Two other effects of thyrotropin, namely, the stimulation of [¹⁴C]leucine incorporation into protein and of iodide efflux were not at all affected by treatment with excess iodide, and hence may not be subject to the autoregulatory influence of iodide.     

Iodine-Induced Thyroid Blockade: Role of Selenium and Iodine in the Thyroid and Pituitary Glands

The purpose of this study was to determine the content of iodine and selenium in the thyroid and pituitary glands of rats under iodine-induced blockade of the thyroid gland. Electron probe microanalysis, wavelength-dispersive spectrometry, and point analysis were used in this investigation. We also determined the expression of sodium iodide symporter and caspase 32 in the thyroid and pituitary glands and the expression of thyroid-stimulating hormone in the pituitary. The samples for iodine analysis must be thoroughly dehydrated, and for this purpose, we developed a method that produced samples of constant mass with minimal loss of substrate (human thyroid gland was used for the investigation). Normal levels of iodine and selenium were found in the thyroid, pituitary, ovaries, testes hypothalamus, and pancreas of healthy rats. The levels of iodine and selenium in I- or Se-positive points and the percentage of positive points in most of these organs were similar to those of controls (basal level), except for the level of iodine in the thyroid gland and testes. Blockade of the thyroid gland changed the iodine level in iodine-positive points of the thyroid and the pituitary glands. On the sixth day of blockage, the iodine level in iodine-positive points of the thyroid gradually decreased to the basal level followed by an abrupt increase on the seventh day, implying a rebound effect. The opposite was found in the pituitary, in which the level of iodine in iodine-positive points increased during the first 6 days and then abruptly decreased on the seventh day. Expression of the thyroid-stimulating hormone in the pituitary decreased during the first 5 days but sharply increased on the sixth day, with a minimum level of iodine in the thyroid and maximum in the pituitary, before normalization of the iodine level in both glands preceding the rebound effect. The expression of sodium iodide symporter increased during the first 4 days of blockage and then decreased in both glands. The fluctuations of the thyroid-stimulating hormone in the pituitary gland reflected the changes of iodine in the thyroid gland more precisely than the changes of sodium iodide symporter. The selenium level in the selenium-positive points changed only in the pituitary, dropping to zero on the second and fifth day of the blockade. Simultaneously, the maximum induction of caspase 32 was observed in the pituitary gland. We believe that these results may help to clarify a role of the pituitary gland in the thyroid blockade.     

From the molecular characterization of iodide transporters to the prevention of radioactive iodide exposure

In the event of a nuclear reactor accident, the major public health risk will likely result from the release and dispersion of volatile radio-iodines. Upon body exposure and food ingestion, these radio-iodines are concentrated in the thyroid, resulting in substantial thyroidal irradiation and accordingly causing thyroid cancers. Stable potassium iodide (KI) effectively blocks thyroid iodine uptake and is thus used in iodide prophylaxis for reactor accidents. The efficiency of KI is directly related to the physiological inhibition of the thyroid function in the presence of high plasma iodide concentrations. This regulation is called the Wolff-Chaikoff effect. However, to be fully effective, KI should be administered shortly before or immediately after radioiodine exposure. If KI is provided only several hours after exposure, it will elicit the opposite effect e.g. lead to an increase in the thyroid irradiation dose. To date, clear evaluation of the benefit and the potential toxicity of KI administration remain difficult, and additional data are needed. We outline in this review the molecular characterization of KI-induced regulation of the thyroid function. Significant advances in the knowledge of the iodide transport mechanisms and thyroid physiology have been made. Recently developed molecular tools should help clarify iodide metabolism and the Wolff-Chaikoff effect. The major goals are clarifying the factors which increase thyroid cancer risk after a reactor accident and improving the KI administration protocol. These will ultimately lead to the development of novel strategies to decrease thyroid irradiation after radio-iodine exposure.     

The experimental optimization of iodine prophylaxis for decreasing the radiation load from the accidental uptake of radioiodine]

As is proved by nuclear disaster in Chernobyl Nuclear Power Plant (NPP), iodine prophylaxis may be respected as one of the most urgent and effective methods of prevention of radiation injury of the thyroid gland in the population affected. Author has studied factors and methods of its efficacy and reliability. On the basis of experiments in rats, analytical ways of determination of the dietary iodine intake (iodine supply) of people living around NPP Paks (Hungary) as well as compartment modelling, experiments it is shown, that for optimisation of iodine prophylaxis in masses it is very important to increase the iodine supply up to the recommended values. Combined use of decreased doses of potassium iodide and perchlorate was found to be the optimal way for removal of radioiodine from pregnant organisms and their offsprings following accidental intake of radioiodine.     

Iodine deficiency activates antioxidant genes and causes DNA damage in the thyroid gland of rats and mice

Because thyroid nodules are frequent in areas with iodine deficiency the aim of this study was to characterise molecular events during iodine deficiency that could explain mutagenesis and nodule formation. We therefore studied gene expression of catalytic enzymes prominent for H(2)O(2) detoxification and antioxidative defence, quantified DNA oxidation and damage as well as spontaneous mutation rates (SMR) in mice and rats fed an iodine controlled diet. Antioxidative enzymes such as superoxide dismutase 3, glutathione peroxidase 4 and the peroxiredoxins 3 and 5 showed increased mRNA expression, which indicates increased radical burden that could be the cause of additional oxidized base adducts found in thyroidal genomic DNA in our experiments of iodine deficiency. Furthermore, the uracil content of thyroid DNA was significantly higher in the iodine-deficient compared to the control group. While SMR is very high in the normal thyroid gland it is not changed in experimental iodine deficiency. Our data suggest that iodine restriction causes oxidative stress and DNA modifications. A higher uracil content of the thyroid DNA could be a precondition for C-->T transitions often detected as somatic mutations in nodular thyroid tissue. However, the absence of increased SMR would argue for more efficient DNA repair in response to iodine restriction.     

Effect of potassium iodide and perchlorate on the process of thyroid hormone secretion]

The influence of potassium iodide and perchlorate on the parameters characterizing the thypoid hormones secretion, such as the cAMP level in the gland tissue and the number of intracellular colloid droplets under condition of stimulation by thyrotropic hormone was studied. It was shown that the abovementioned parameters were depressed by an excess of iodide, but perchlorate administration prevented the inhibitory effect of iodide. The results obtained favour the conception on the sensitivity of the thyroid adenylate cyclase system to the organic iodine concentration. Apparently and excess of iodide depressed the capacity of perchlorate to influence its concentration in the gland, and thereby the process of iodine organification and of the thyroid hormone secretion maintained at the optimal leve.     

Iodinated phospholipids and the iodination of proteins of dog thyroid gland in vitro

Slices of dog thyroid gland were incubated with liposomes consisting of (125)I-labelled phosphatidylcholine (the iodine was covalently linked to unsaturated fatty acyl chains). The (125)I label of (125)I-labelled liposomes was incorporated into thyroid protein and/or thyroglobulin at a higher rate than was the (131)I label of either Na(131)I or (131)I(2). The iodine was shown to be protein-bound by the co-migration of the labelled iodine with protein under conditions where free iodine, iodide and lipid-bound iodine were removed from protein. The uptake of iodine from the iodinated phospholipid was probably due to phospholipid exchange between the iodinated liposomes and the thyroid cell membrane, since (a) (14)C-labelled phospholipid was metabolized to (14)CO(2) and (b) many lipids in the tissue slice became (14)C-labelled. A very strong inhibition of iodide ;uptake' from Na(131)I, caused by thiosulphate, produced only a minor inhibition of the incorporation of (125)I from (125)I-labelled liposomes into thyroid protein and/or thyroglobulin. This implies that free iodide may not necessarily be formed from the iodinated phospholipids before their entrance or utilization in the cell. Synthetic polytyrosine polypeptide suspensions showed some iodination by (131)I-labelled liposomes. In tissues with low tyrosine contents, such as liver and kidney, only a trace uptake was observed. Salivary gland showed some uptake. Endoplasmic reticulum of thyroid gland showed a higher iodine uptake than that of the corresponding plasma membranes. These experiments, together with the demonstration of the diet-dependent presence of iodinated phospholipids in dog thyroid, leads us to suggest that iodination of the membrane phospholipids of thyroid cells may be directly or indirectly involved at some stage in the synthesis of thyroglobulin, or exists as a scavenger mechanism, to re-utilize and/or recover released iodine from unstable compounds inside the thyroid cell.     

<Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of Transdermal Iodide Microemulsion for Treating Iodine Deficiency Using Sprague Dawley Rats

The objective of this study was to evaluate the transdermal efficiency of iodide microemulsion in treating iodine deficiency using rats as an animal model. Animals were fed either iodine-deficient diet (20 μg/kg iodide) or control diet (200 μg/kg iodide) over a 17-month period. At month 14, iodide microemulsion was applied topically in iodine-deficient group and physiological evaluations of thyroid gland functions were characterized by monitoring the thyroid hormones (T₃, T₄), thyroid-stimulating hormone (TSH), iodide ion excretion in urine, and the overall rat body weights in both groups. Moreover, morphological evaluations of thyroid gland before and after treatment were performed by ultrasound imaging and through histological assessment. Prior to microemulsion treatment, the levels of T₃, T₄, and TSH in iodine-deficient group were statistically significant as compared to that in the control group. The levels of T₃ and T₄ increased while TSH level decreased significantly in iodine-deficient group within the first 4 weeks of treatment. After treatment, iodide concentration in urine increased significantly. There was no statistical difference in weight between the two groups. Ultrasound imaging and histological evaluations showed evidence of hyperplasia in iodine-deficient group. Topical iodide microemulsion has shown a promising potential as a novel delivery system to treat iodine deficiency.     

Iodine and breast cancer A 1982 update

Research has been directed towards investigating the role of the trace element, iodine, in breast cancer etiology, diagnosis, and therapy. In many controled studies, iodine has been established as a requirement for breast tissue normalcy, since deficiency of the element results in histopathology consistent with dysplasia and atypia in rodents. Clinically severe hyperplasia and fibrocystic disease is seen in the breasts of women who have low iodine levels. These precancerous lesions result in a high-risk state as well as persistent symptomatology in women. Iodine replacement therapy has been shown to be efficacious in reducing these conditions in clinical trials. Basic research is directed towards intracellular pathways and metabolism for breast iodide, emulating those seen in the thyroid gland. Thus, using a rat model, iodine intracellular organification is being correlated with risk factors for breast cancer including early and late pregnancies, onset of puberty, menopause, and aging. From our research there is significant evidence that iodine maintains homeostasis in reproductive, effected tissues and is responsible for breast tissue growth and development.     

Effect of increased bromide intake on iodine excretion in rats

The time course of iodine excretion in adult male rats substantially differs from bromine excretion. Bromine is excreted at a single rate, whereas iodine evinces two excretion rates. Even a strong increase in bromide intake in experimental animals failed to affect the rate of iodine excretion but it lowered the fraction of iodine accumulated increase in bromide intake in experimental animals failed to affect the rate of iodine excretion but it lowered the fraction of iodine accumulated in the thyroid gland by 20% probably by affecting the transport of iodide into the thyroid gland.