Developmental Iodine Deficiency and Hypothyroidism Impair Neural Development, Upregulate Caveolin-1, and Downregulate Synaptotagmin-1 in the Rat Cerebellum

Adequate thyroid hormone is critical for cerebellar development. Developmental hypothyroidism induced by iodine deficiency during gestation and postnatal period results in permanent impairments of cerebellar development with an unclear mechanism. In the present study, we implicate cerebellar caveolin-1 and synaptotagmin-1, the two important molecules involved in neuronal development, in developmental iodine deficiency, and in developmental hypothyroidism. Two developmental rat models were created by administrating dam rats with either iodine-deficient diet or propylthiouracil (PTU, 5 or 15?ppm)-added drinking water from gestational day?6 till postnatal day (PN) 28. Nissl staining and the levels of caveolin-1 and synaptotagmin-1 in cerebella were assessed on PN28 and PN42. The results show that the numbers of Purkinje cells were reduced in the iodine-deficient and PTU-treated rats. The upregulation of caveolin-1 and the downregulation of synaptotagmin-1 were observed in both iodine-deficient and PTU-treated rats. These findings may implicate decreases in the number of Purkinje cells and the alterations in the levels of caveolin-1 and synaptotagmin-1 in the impairments of cerebellar development induced by developmental iodine deficiency and hypothyroidism.     

Effect of long-term administration of arsenic (III) and bromine with and without selenium and iodine supplementation on the element level in the thyroid of rat

The aim of this study was to evaluate the influence of arsenic and bromine exposure with or without iodine and selenium supplementation on the element level in the thyroid of rats. Four major groups of Wistar female rats were fed with respective diets: group A - standard diet, group B - iodine rich diet (10 mg I/kg food), group C - selenium rich diet (1 mg Se/kg) and group D - iodine and selenium rich diet (as in group B and C). Each group was divided into four subgroups per 7 animals each receiving either NaAsO(2) ip (6.5 mg.kg(-1) twice a week for two weeks and 3.25 mg.kg(-1) for six weeks) or KBr in drinking water (58.8 mg.l(-1)) for 8 weeks or combined administration of both substances. Remaining subgroup served as controls. After 8 weeks thyroid glands were analyzed by ICP-MS for As, Br, Se, and I content. The exposition of rat to arsenic or bromine causes the accumulation of these elements in the thyroid gland ( approximately 18 ppm of As, approximately 90 ppm of Br) and significantly affects iodine and selenium concentration in the thyroid. In iodine and/or selenium supplemented rats the bromine intake into the thyroid was lowered to approximately 50% of the level in unsupplemented animals. Also selenium thyroid level elevated due to KBr administration was lowered by iodine supplementation in the diet. The accumulation of arsenic in the thyroid was not influenced by selenium or iodine supplementation; however, As(III) administration increased iodine thyroid level and suppressed selenium thyroid level in selenium or iodine supplemented group of animals.     

Maternal iodine supplementation improves motor coordination in offspring by modulating the mGluR1 signaling pathway in mild iodine deficiency-induced hypothyroxinemia rats

Iodine is an essential component for thyroid hormone synthesis. Epidemiological investigations have demonstrated that maternal mild iodine deficiency (ID)-induced hypothyroxinemia can affect intellectual and behavioral function in offspring. There is no definitive evidence demonstrating the effects of maternal iodine supplementation on neurobehavioral function in regional areas with mild ID. Thus, we aimed to clarify the effects of maternal mild ID and iodine supplementation on motor coordination in offspring and illuminate the underlying molecular mechanisms. Animal models of maternal mild ID and iodine supplementation were generated by providing Wistar rats an iodine-deficient diet and deionized water supplemented with potassium iodide during pregnancy and lactation. We found that mild ID-induced hypothyroxinemia led to a shorter latent time before falling down from the rotarod, a longer time to traverse the balance beam and poorer wire grip of the forelimbs, which imply motor coordination dysfunction. However, these impairments in the offspring were improved by iodine supplementation during pregnancy and lactation. We further observed that the ultrastructure and dendritic tree morphology of cerebellar Purkinje cells were altered in mild ID-induced hypothyroxinemia but that these changes could be reversed by iodine supplementation. Maternal mild ID and iodine supplementation also affected expression of the mGluR1 signaling pathway in offspring. Together, iodine supplementation during pregnancy and lactation can improve motor coordination in offspring by modulating the mGluR1 signaling pathway in mild ID-induced hypothyroxinemia rats.     

Fenvalerate Exposure Alters Thyroid Hormone Status in Selenium- and/or Iodine-Deficient Rats

Considering the potential adverse effects of selenium and iodine deficiencies, and taking into account the widespread but often careless use of pyrethroid insecticides and their possible endocrine-disrupting effects, this study was undertaken to investigate the effects of fenvalerate on thyroid hormone parameters in both healthy and selenium- and/or iodine-deficient rats. Fenvalerate exposure had no effect on the TT4 levels of healthy controls but caused significant increases both in iodine deficiency (ID) and selenium plus iodine deficiency (ISeD), and a significant decrease in selenium deficiency (SeD). Dramatic increases in TT3 of all groups were observed by fenvalerate. Moreover, it caused insignificant decrease of thyroid stimulating hormone in healthy controls, no effect in SeD, and significant elevation in ID and ISeD. These results, thus, showed that the widely used pyrethroid insecticide fenvalerate has the potential to change significantly thyroid hormone parameters both in normal and deficiency states, and consequences of its thyroid status modifying effect might be of critical importance particularly in sensitive individuals and patients with thyroid dysfunction.     

Selenium and/or iodine deficiency alters hepatic xenobiotic metabolizing enzyme activities in rats

The objective of this study was to investigate the effects of iodine (I(2)) and/or selenium (Se) deficiency on thyroid hormones and hepatic xenobiotic metabolizing enzyme systems using a triple animal model. Three-week-old male Wistar rats were fed for seven weeks. Se deficiency was introduced by a diet containing <0.005 mg/kg Se, and I(2) deficiency was produced by sodium perchlorate containing drinking water. The levels of plasma thyroid hormones [total T(4) (TT(4)), total T(3) (TT(3))], thyroid stimulating hormone (TSH); total microsomal cytochrome P450 (CYP450) and cytochrome b5 (CYP b5) levels; activities of microsomal NADPH-cytochrome P450 reductase (P450R), microsomal aniline hydroxylase (CYP2E1), microsomal 7-ethoxyresorufin O-deethylase (EROD), microsomal 7-pentoxyresorufin O-depentylase (PROD) and cytosolic glutathione S-transferase (GST) were determined. In I(2) deficiency total CYP450 levels, activities of CYP2E1, EROD and GST decreased, and CYP b5 content increased significantly. In Se-deficient rats, total CYP450 level and CYP2E1 activity increased, and EROD and GST activities and CYP b5 level decreased significantly. In combined I(2) and Se deficiency, except for CYP450 content and CYP2E1 activity, all enzyme activities and CYP b5 content decreased significantly compared to control group. Overall results of this study have suggested that metabolism of xenobiotics as well as endogenous compounds is affected by Se and I(2) status.     

Role of iodine in antioxidant defence in thyroid and breast disease

The role played in thyroid hormonogenesis by iodide oxidation to iodine (organification) is well established. Iodine deficiency may produce conditions of oxidative stress with high TSH producing a level of H_2O_2, which because of lack of iodide is not being used to form thyroid hormones. The cytotoxic actions of excess iodide in thyroid cells may depend on the formation of free radicals and can be attributed to both necrotic and apoptotic mechanisms with necrosis predominating in goiter development and apoptosis during iodide induced involution. These cytotoxic effects appear to depend on the status of antioxidative enzymes and may only be evident in conditions of selenium deficiency where the activity of selenium containing antioxidative enzymes is impaired. Less compelling evidence exists of a role for iodide as an antioxidant in the breast. However the Japanese experience may indicate a protective effect against breast cancer for an iodine rich seaweed containing diet. Similarly thyroid autoimmunity may also be associated with improved prognosis. Whether this phenomenon is breast specific and its possible relationship to iodine or selenium status awaits resolution.     

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.     

Thyroid function and deiodinase activities in rats with marginal iodine deficiency

The hypothesis tested was whether marginal iodine deficiency for a period of 6 wk affects iodothyronine deiodinase activities in liver and brain of rats. Male rats were fed purified diets either deficient or sufficient in iodine; the diets were fed on a restricted basis (60% ofad libitum intake). Body weight gain of the two groups was comparable. Iodine deficiency was evidenced by increased thyroid weight (26%), reduced urinary iodine excretion (80%), and reduced plasma T₄ concentrations (22%). Activities of liver type I and brain type III deiodinase were unchanged, but the activity of type II deiodinase in brain was increased (28%) in the iodine-deficient rats. Food restrictionper se significantly lowered T₃ (30%) and T₄ (22%) concentrations in plasma and decreased type III deiodinase activity in brain (30%). These results indicate that in marginal iodine deficiency the activities of hepatic type I deiodinase and brain type III deiodinase are unchanged, whereas that of brain type II deiodinase is increased.     

Thyroid homeostasis in animals with iodine deficiency

The content of total iodine, its hormonal and nonhormonal fractions as well the level of protein-bound iodine in blood and basic tissue targets in representatives of 4 classes of animals: Esox lucius L., Rana esculenta, Streptopelia decaocto Priv., Lepus europaeus Pall. inhabiting the mountain regions with iodine deficiency in environment and in the lowlands of Transcarpathia with higher iodine provision have been investigated. A considerable decrease of general and hormone iodine level in the animal tissues of the mountain area accompanied by the suppression of the thyroid function has been stated. The utilization of thyroid hormones under the iodine deficiency condition is increased in the majority of cases and the level of protein-bound iodine is lowered that testifies to the transition of animal organism in the iodine-deficient areas to the lower level of thyroid homeostasis.     

Iodine requirements and the risks and benefits of correcting iodine deficiency in populations.

Iodine deficiency has multiple adverse effects on growth and development due to inadequate thyroid hormone production that are termed the iodine deficiency disorders (IDD). IDD remains the most common cause of preventable mental impairment worldwide. IDD assessment methods include urinary iodine concentration, goiter, thyroglobulin and newborn thyrotropin. In nearly all iodine-deficient countries, the best strategy to control IDD is salt iodization, one of the most cost-effective ways to contribute to economic and social development. When salt iodization is not possible, iodine supplements can be targeted to vulnerable groups. Introduction of iodized salt to regions of chronic IDD may transiently increase the incidence of thyroid disorders, and programs should include monitoring for both iodine deficiency and excess. Although more data on the epidemiology of thyroid disorders caused by differences in iodine intake are needed, overall, the relatively small risks of iodine excess are far outweighed by the substantial risks of iodine deficiency.     

The role of selenium in thyroid hormone metabolism and effects of selenium deficiency on thyroid hormone and iodine metabolism

Selenium deficiency impairs thyroid hormone metabolism by inhibiting the synthesis and activity of the iodothyronine deiodinases, which convert thyroxine (T₄) to the more metabolically active 3,3′-5 triiodothyronine (T₃). Hepatic type I iodothyronine deiodinase, identified in partially purified cell fractions using affinity labeling with [¹²⁵I]N-bromoacetyl reverse triiodothyronine, is also labeled with⁷⁵Se by in vivo treatment of rats with⁷⁵Se-Na₂SeO₃. Thus, the type I iodothyronine 5′-deiodinase is a selenoenzyme. In rats, concurrent selenium and iodine deficiency produces greater increases in thyroid weight and plasma thyrotrophin than iodine deficiency alone. These results indicate that a concurrent selenium deficiency could be a major determinant of the severity of iodine deficiency.     

Status of selenium and antioxidant enzymes of goitrous children is lower than healthy controls and nongoitrous children with high iodine deficiency

In order to investigate the relations of iodine deficiency and/or goiter with selenium (Se) and antioxidant enzyme (AOE) status, we determined the relevant parameters of goitrous high school children living in an endemic goiter area of Turkey. Subjects were selected by a simple random sampling technique after screening the whole population of the high schools of two towns by neck palpation. The results of the goitrous group (n = 48, aged 15-18 yr) were compared with those of nongoitrous control children (n = 49) from the same populations, and with an outside control group (n = 24) from a lower-goiter-prevalence area. The overall prevalence of goiter was 39.6% in the high school population of the area. Activities of erythrocyte AOE (glutathion peroxidase, catalase, and superoxide dismutase) and concentrations of plasma and erythrocyte Se and urinary iodine were found to be significantly lower in goitrous children than both in-region and out-region of the control groups. When the whole study group was reclassified according to the severity of iodine deficiency, it was found that the AOE and Se status of those control children without goiter but with high iodine deficiency was significantly higher than goitrous children, although they did not differ from nondeficient control group. This might be the result of the possibility that goitrous children are exposed of oxidative stress, which may introduce alterations to the antioxidant defense system and/or the antioxidant status is relatively lower in goitrous children than those children who are highly iodine-deficient but did not develop goiter. The results of this study seem to support the view that the risk of goiter development may be higher in highly iodine-deficient children with lower enzymatic antioxidant and Se status.     

The role of selenium in thyroid hormone metabolism and effects of selenium deficiency on thyroid hormone and iodine metabolism

Selenium deficiency impairs thyroid hormone metabolism by inhibiting the synthesis and activity of the iodothyronine deiodinases, which convert thyroxine (T₄) to the more metabolically active 3,3′–5 triiodothyronine (T₃). Hepatic type I iodothyronine deiodinase, identified in partially purified cell fractions using affinity labeling with [¹²⁵I]N-bromoacetyl reverse triiodothyronine, is also labeled with⁷⁵Se by in vivo treatment of rats with⁷⁵Se−Na₂SeO₃. Thus, the type I iodothyronine 5′-deiodinase is a selenoenzyme. In rats, concurrent selenium and iodine deficiency produces greater increases in thyroid weight and plasma thyrotrophin than iodine deficiency alone. These results indicate that a concurrent selenium deficiency could be a major determinant of the severity of iodine deficiency.     

Effect of iodine supplement on iodine status and 5′-deiodinase activity in the brain of neonatal rats with iodine deficiency

The weanling Wistar rats of iodine deficiency were divided into three groups for supplementation of different levels of iodine (iodine-excessive [IE], iodine-adequate [IA], and iodine-deficient [ID]), with a control group (C). The iodine content in the thyroid was determined by epithermal neutron activation analysis. The activities of 5′-deiodinase and 5-deiodinase in the brains were assayed by determining the conversion ratios of T4 to T3 and rT3, respectively. The thyroid hormones levels in serum were also tested. The results indicated that the ID group had a goiter containing a small amount of iodine, but the IE group had a slightly swollen thyroid with rich iodine; the concentration of iodine per unit mass of thyroid was lower in group IE than in groups IA and C. The highest 5′-deiodinase and lowest 5-deiodinase activities in group ID and the lowest 5′-deiodinase activity in group IE were found. The iodine deficiency or excess resulted in a compensated hypothyroid state. The results suggest that the iodine status and the deiodinases activities would become normal for the rats of iodine deficiency if adequate iodine is supplemented soon after birth. Meanwhile, it is also critical to avoid excessive intake of iodine to reduce the risk for overcorrecting.     

<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.     

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.     

Effects of iodine deficiency in pregnancy

Dietary iodine requirements are increased in pregnancy due to increased thyroid hormone production, increased renal iodine losses, and fetal iodine requirements. Adverse effects of iodine deficiency in pregnancy include maternal and fetal goiter, cretinism, intellectual impairments, neonatal hypothyroidism, and increased pregnancy loss and infant. Dietary iodine requirements remain increased in lactation due to the concentration of iodine in breast milk. Iodine deficiency remains a significant global public health problem. Excess iodine ingestion in pregnancy, while a relatively uncommon problem, may also have adverse fetal effects. However, the safe upper limit for chronic iodine ingestion in pregnancy and lactation is not currently well defined.     

Selenium status in an iodine deficient population of the West Ivory Coast

Selenium is an essential trace element which is part of the active site of seleno-dependent glutathione peroxidase and type 1 deiodinase. Therefore, it plays a key role in thyroid hormone metabolism. The present work was undertaken in order to evaluate selenium status in two Ivory Coast populations: the first with high (Glanlé) and the second with low (Abidjan) prevalence of iodine deficiency. Selenium, glutathione peroxidase, glutathione reductase, glutathione and diglutathione were determined in blood and/or urine. In plasma and erythrocytes, selenium and glutathione peroxidase were dramatically low in Glanlé. Compared to Abidjan, selenium, glutathione peroxidase, vitamin E and riboflavin status were decreased whereas diglutathione was increased in Glanlé. The results clearly demonstrate a selenium deficiency and suggest an oxidant stress in Glanlé. Causes and consequences of this selenium deficiency and oxidant stress remain to be determined.     

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.