Microscopic distribution of iodine radioisotopes in the thyroid of the iodine deficient new-born rat: insight concerning the Chernobyl accident.

Thyroid cancer markedly increased in children exposed to iodine radioisotopes following the Chernobyl accident. This increase exceeded predictions based on dose estimates to the whole organ. We sought to investigate whether iodine deficiency may have influenced the pattern of microscopic distribution of radioiodines, which may be important to interpretation of the observed effects. Iodine-deficient new-born rats were injected with iodine-129 (129I) and the microscopic distribution in the thyroid tissue was studied at 24 hr and at one week after administration, using secondary ion mass spectrometry (SIMS). Twenty-four hr after administration, SIMS images showed large differences in 129I uptake among thyroid follicles, with more than a factor ten variation in the local concentration. In addition, the distribution of 129I inside follicles varied with time. At 24 hr, the highest concentration was found at the periphery of the colloid, close to the thyroid cells. There also was enhanced concentration of 129I at one pole of follicles. Distribution inside follicles was homogeneous at 7 days. Conclusions: 1/Dosimetric models, which assume uniform iodine uptake by thyroid follicles, give an oversimplified picture of radiation dosimetry in cases involving iodine deficiency, which induces patchy tissue irradiation. 2/The dynamic pattern of iodine distribution within thyroid follicles suggests that decay events from short-lived iodines will occur closer to thyroid cells than events resulting from iodine-131.     

Effects of iodine repletion on thyroid morphology in iodine and/or selenium deficient rat term fetuses, pups and mothers.

It has been suggested that selenium deficiency aggravates the iodine-induced thyroid inflammation and necrosis in iodine-deficient Wistar rats and possibly in man. Studies were carried out to determine whether large amounts of iodine given to iodine-deficient pregnant Sprague-Dawley rats with or without selenium deficiency would induce inflammation and necrosis in their term fetal thyroids. Iodine deficiency was induced in the dams by a low iodine diet or perchlorate in the drinking water and iodine excess was achieved by iodinated drinking water during pregnancy or daily subcutaneous injections of iodine from days 20 to 22 of pregnancy, 1 day after perchlorate was discontinued. Studies were also carried out in 30-day-old pups whose nursing mothers were iodine-deficient (perchlorate) with or without selenium deficiency from conception onward. The administration of iodine restored the morphologic changes in the thyroid induced by iodine deficiency, irrespective of selenium status, toward normal without inflammatory changes or necrosis. Possible explanations for these unexpected findings are discussed.     

Changes in iodine mapping in rat thyroid during the course of iodine deficiency: imaging and relative quantitation by analytical ion microscope

The analytical ion microscope (AIM) makes possible imaging and relative quantitation of multiple stable or labeled elements on an even tissue section, according to their mass. The purpose of this work was to follow at the rat thyroid follicle level the changes in 127I mapping during low iodine diet (LID) in relation to the ability of thyroid to pick up radioiodine (129I) and to synthesize Tg from its precursor, 2H-labeled leucine. The overall picture of images and countings of 127I shows a progressive decrease of the luminal iodine concentration which on day 80 was 10-fold lower than that of control value. In control rat thyroid cell, concentration was 10-fold lower than that of follicular lumina and was unchanged until 35 days, but the size of the cytoplasmic compartment increased, suggesting a redistribution of iodine stores between thyroid cells and follicular lumina. 129I was always found in colloid as well as in cells at all stages. After 35 days of LID, cytoplasmic and luminal radioiodine concentrations decreased. In control rats, [2H]leucine was found mainly in the cells. During LID its localization was evidenced progressively in most of the lumina. The most striking fact was the presence up to 35 days of some large residual follicles with high 127I concentration and low 129I and 2H incorporation. These data demonstrate the follicular heterogeneity of thyroid response to progressive chronic TSH stimulation induced by LID.     

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.     

Free and total thyroid hormone levels after parenteral administration of iodine contrast media

An effect of the iodine contrast media used in bronchography and urography on both free and total thyroidal hormones was investigated. Hormones concentrations were assayed prior to and 7 and 30 days following an administration of the contrast. Iodine contrast media have no effect on T3, T4, free T3, and free T4 levels. Therefore, one may conclude that the administration of i.v. contrast media containing iodine does not significantly change the results of thyroid hormones assays does not affect an interpretation of the results.     

The role of iodine in human growth and development

Iodine is an essential component of the hormones produced by the thyroid gland. Thyroid hormones, and therefore iodine, are essential for mammalian life. Iodine deficiency is a major public health problem; globally, it is estimated that two billion individuals have an insufficient iodine intake. Although goiter is the most visible sequelae of iodine deficiency, the major impact of hypothyroidism due to iodine deficiency is impaired neurodevelopment, particularly early in life. In the fetal brain, inadequate thyroid hormone impairs myelination, cell migration, differentiation and maturation. Moderate-to-severe iodine deficiency during pregnancy increases rates of spontaneous abortion, reduces birth weight, and increases infant mortality. Offspring of deficient mothers are at high risk for cognitive disability, with cretinism being the most severe manifestation. It remains unclear if development of the offspring is affected by mild maternal iodine deficiency. Moderate-to-severe iodine deficiency during childhood reduces somatic growth. Correction of mild-to-moderate iodine deficiency in primary school aged children improves cognitive and motor function. Iodine prophylaxis of deficient populations with periodic monitoring is an extremely cost effective approach to reduce the substantial adverse effects of iodine deficiency throughout the life cycle.     

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.     

Kinetics of intracolloidal iodine within the thyroid of newborn rats. Direct imagery using secondary ion mass spectrometry

The spatiotemporal distribution of cellular uptake site of radiotoxics is essential data for microdosimetric studies. As early as 1950, the heterogeneity of iodine incorporation within the thyroid has been shown using autoradiography. The objective of this study is to describe the kinetic cellular distribution of newly organified iodine in the thyroid of newborn rats using secondary ion mass microscopy (NanoSIMS50). Ionic images obtained at high mass resolution and with a lateral resolution of about 50 nm show that the early distribution of iodine is heterogeneous from one follicle to another, from one thyrocyte to another inside the same follicle, and that this distribution varies as a function of time. The obtained kinetic profile will allow us to refine the studies concerning the aetiopathology of thyroid cancers of the Chernobyl children.     

Transfer of iodine through the milk in protein-restricted lactating rats

Iodine supply is important to avoid neonatal hypothyroidism. This study evaluated whether protein restriction during lactation affects iodine transfer to the pups through the milk. We studied lactating rats fed an 8% protein-restricted diet (PR), a control 23% protein diet (C), and an energy-restricted diet group (ER). On days 4, 12 and 21, mothers were separated from their pups for 4 h, injected with (131)I IP, and put together with their pups. The animals were killed 2 h later. PR pups had a significant decrease in iodine uptake in the gastric content and duodenal mucosa on the 4th day. On the contrary, at 12 and 21 days radioiodine was increased in the gastric content and in the duodenal mucosa. ER pups had an increase in iodine uptake in the gastric content and in the duodenal mucosa only at the end of lactation. The thyroid iodine uptake in PR pups was significantly decreased on the 4th day and significantly increased on the 21st day compared to control. When injected IP with an equivalent amount of (131)I, the PR pups had a decrease in thyroid iodine uptake on the 4th and 12th day, while ER pups had no significant changes. So, these data suggest that protein restriction during lactation was associated with lower iodine secretion into the milk in the beginning of lactation. However, at the end of lactation, an adaptation process seems to occur leading to a higher transfer of iodine through the milk that compensates the impairment of thyroid iodine uptake in these pups.     

Leptin treatment during lactation increases transfer of iodine through the milk

We have previously shown that protein restriction during lactation is associated with changes in iodine secretion into the milk and that a pup's serum leptin concentration was increased at the end of lactation. So, here we evaluate whether leptin treatment during lactation affects iodine transfer through the milk to the pups. Lactating rats were divided into two groups: the leptin (Lep) group, single injected with recombinant rat leptin (8 microg/100g of body weight, daily for 3 consecutive days), and the control (C) group that received the same volume of saline. We studied iodine transfer to the pups through the milk on Days 4, 12 and 21 of lactation. In those days, the dams were separated from their pups for 4 h. Then, the mothers received an injection of 131I (2.22x10(4) Bq ip) and the pups were allowed to nurse for 2 h. The animals were sacrificed 2 h later. Leptin, total serum T3 and total serum T4 concentrations were higher (P<.05) in pups of Lep mothers only on Day 4, suggesting a higher transfer of leptin through the milk at this period, probably with a direct stimulatory effect on thyroid hormone secretion. In other periods, however, even without a detectable increase in a pup's serum leptin concentration, maternal leptin administration increased the pup's thyroid iodine uptake (Day 12, 39%; Day 21, 34%), probably caused by a higher transfer of iodine through the milk, since they had a higher gastric content of 131I on Days 12 (31%) and 21 (128%).     

A model of radioiodine transfer to goat milk incorporating the influence of stable iodine

Previously reported models for radioiodine in ruminants cannot account for the effect of variations in stable iodine intake including large countermeasure doses of stable iodine on the transfer of radioiodine to goat milk. A metabolically based model of radioiodine transfer in goats has been parameterised using new experimental data on the effect of countermeasure doses of stable iodine on radioiodine transfer to milk. To account for the effect of dietary stable iodine levels, the model represents the transfer of iodine from the extracellular fluid to milk with Michaelis-Menten kinetics. The model shows good agreement with the experimental data, and the estimated parameters compare favourably with values which can be estimated from the literature. The parameterised model accounts for 95% of the variation in the observed data for milk, faeces, urine and thyroid (n=199). The model has been used to predict the effects of variation in stable iodine intake and the extent of consequent chemical contamination of milk by stable iodine. The time taken for radio-iodine to reach peak concentrations in milk following a deposition event is predicted to vary significantly (ca. 2 days) over a range of expected stable iodine intakes. Doses of stable iodine sufficient to reduce the radioiodine transfer to milk will result in stable iodine concentrations in milk greatly in excess of internationally advised limits. Therefore, we recommend that stable iodine supplementation not be used as a countermeasure to reduce radioiodine transfer to milk. Indeed, model predictions suggest that reductions in stable iodine intake would be a more effective countermeasure. However, this is unlikely to be feasible since the short physical half-life of ¹³¹I may not allow adequate time to implement changes in feed manufacture. The model described in this paper is freely available in ModelMaker 3.0 format (http://www.notingham.ac.uk/environmental-modelling/). Received: 16 August 1999 / Accepted in revised form: 15 November 1999     

Maximal lactate steady state in rats submitted to swimming exercise.

The higher concentration during exercise at which lactate entry in blood equals its removal is known as 'maximal lactate steady state' (MLSS) and is considered an important indicator of endurance exercise capacity. The aim of the present study was to determine MLSS in rats during swimming exercise. Adult male Wistar rats, which were adapted to water for 3 weeks, were used. After this, the animals were separated at random into groups and submitted once a week to swimming sessions of 20 min, supporting loads of 5, 6, 7, 8, 9 or 10% of body wt. for 6 consecutive weeks. Blood lactate was determined every 5 min to find the MLSS. Sedentary animals presented MLSS with overloads of 5 and 6% at 5.5 mmol/l blood lactate. There was a significant (P<0.05) increase in blood lactate with the other loads. In another set of experiments, rats of the same strain, sex and age were submitted daily to 60 min of swimming with an 8% body wt. overload, 5 days/week, for 9 weeks. The rats were then submitted to a swimming session of 20 min with an 8% body wt. overload and blood lactate was determined before the beginning of the session and after 10 and 20 min of exercise. Sedentary rats submitted to the same acute exercise protocol were used as a control. Physical training did not alter the MLSS value (P<0.05) but shifted it to a higher exercise intensity (8% body wt. overload). Taken together these results indicate that MLSS measured in rats in the conditions of the present study was reproducible and seemed to be independent of the physical condition of the animals.     

Disturbance of thyroidal iodine metabolism in BB/W rat.

To investigate the thyroid function in Bio-Breeding Worcester (BB/W) rats, we have examined the iodine metabolism, serum TSH and thyroid hormone levels in 8- and 16-week-old BB/W and normal Wistar (W) rats. At 8 weeks of age, serum TSH levels were significantly higher in BB/W rats than in W rats, although there was no difference in the serum levels of free T3 and free T4. Furthermore, the thyroidal radioactive iodine incorporation at 48 h was significantly lower in BB/W rats, suggesting that they might have some defects in iodine organification. At 16 weeks of age, serum TSH levels were also significantly higher in BB/W rats than in W rats. Furthermore, serum TSH levels in 16-week-old BB/W rats were significantly higher than in 8-week-old BB/W rats. The thyroid weight was significantly greater in BB/W rats, probably due to the increased serum TSH. The thyroidal radioactive iodine uptake at 48 h and the iodine content in the thyroid homogenates were significantly lower in BB/W rats. These results suggest that BB/W rats have some defect in iodine metabolism resulting in impaired thyroid hormone synthesis.     

Biologically available iodine in goitrogenic diets

Eight different sources of low-iodine diet (LID) were tested in mice over 14 years. The available iodine in each diet was measured by isotopic equilibration. Commercially prepared Remington diets contained 6.8 to 69.3 ng available iodine/g, and the results were usually different from shipment to shipment. Some samples produced greatly enlarged thyroids. The Remington diets from two sources were occasionally low in iodine but produced little thyroid enlargement. Between 1977 and 1980 only one shipment of Remington diet was found to contain less than 10 ng available I/g, and it resulted in large goiters. Since 1980 other compositions of LID have been used, but they caused additional abnormalities during breeding or chronic feeding. A low-iodine wheat diet produced goiter in mice more readily than in rats. In the course of testing for unavailable forms of dietary iodine, it was found that only 34.2% of thyroxine iodine was available to the thyroid iodine pool of mice. It is concluded that unidentified nutritional deficiency or dietary contaminants can alter the goitrogenic response to restricted iodine intake. Furthermore, at least one natural form of potential dietary iodine is incompletely available to mice.     

Iodine metabolism in the thyroid gland in chronic uranium poisoning]

The exchange of radioactive and stable iodine was studied for 21 days after the I131 injection in the thyroid gland and the blood of rats against the background of chronic uranium intoxication. The latter was accompanied by a decrease in the number of iodine-transport loci of the gland, as well as of the value of the intrathyroid iodine pool and of the stable iodine concentration in the thyroid tissue. The compensatory reaction of the thyroid gland was expressed in the increase of its mass and the rate of the thyroid metabolism as well.     

Thyroid hormone induces a nerve-independent precocious expression of fast myosin heavy chain mRNA in rat hindlimb skeletal muscle

The appearance of the mRNA for the adult fast IIB myosin heavy chain (MHC) was examined during postnatal development of rats using an S1 nuclease assay. In normal rats, a large increase in the adult MHC mRNA began at 6-7 days after birth, whereas daily injections of newborn rats with 3 micrograms of triiodothyronine (T3) resulted in a precocious increase of the mRNA as early as 3 days after birth. Injection of a range of doses of T3 demonstrated that a large effect was obtained between 30 and 300 ng of T3/day/rat. Fast myosin protein was also precociously induced over the same range of T3 doses. This effect was also seen in denervated muscles, and muscles responded similarly to the different doses of T3 whether they were denervated or not. These results suggest that either thyroid hormone or some circulating factors induced by thyroid hormone are limiting factors in controlling the neonatal-to-adult fast MHC transition and that these factors may act directly on muscle tissue.     

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.     

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.     

Influence of chronic treatment with iopanoic acid on thyroxine metabolism in the newborn rat

Parameters of the peripheral metabolism of thyroxine (T4) were studied in the early postnatal period. Iopanoic acid (IOP) was administered to newborn rats that were either euthyroid or rendered hypothyroid in utero by propylthiouracil (PTU) or methimazole (MMI) administration to the mothers during gestation and injected with thyroxine on postnatal days 6 and 7. In euthyroid newborn rats given IOP from postnatal day 6, the plasma T4 level increased (+50%) while the plasma 3,3',5'-triiodothyronine (T3) level slightly decreased (-18%). Peripheral deiodination of T4 was also reduced (about -50%) as estimated by thyroid 125I uptake after injection of 125I (3'-5')L-T4. In the newborn rats rendered hypothyroid in utero and given T4 on postnatal days 6 and 7, IOP treatment started on day 4 decreased the constant rate of elimination (-50%), the distribution volume (-43%) and the metabolic clearance (-74%) of plasma T4. The results were the same in PTU- and MMI-treated newborn rats. The differences between newborn and adult animals under IOP treatment are discussed.