Thyroid Iodide Uptake Research Articles

Tissue-specific deiodinase regulation during food restriction and low replacement dose of leptin in rats

The relationship between thyroid function and leptin has been extensively studied; however, the mechanisms underlying the changes in thyroid hormone economy that occur during caloric deprivation remain elusive. Our goal was to evaluate the thyroid function of rats submitted to 40% food restriction after chronic leptin replacement. Caloric restriction for 25 days led to significantly reduced serum leptin, thyroid-stimulating hormone (TSH), thyroxine (T(4)), and triiodothyronine (T(3)) and increased serum corticosterone, while liver, kidney, and thyroid type I deiodinase (D1) and brown adipose tissue (BAT) type II deiodinase (D2) activities were decreased and hypothalamic D2 was significantly increased. Interestingly, thyroid iodide uptake was unchanged by caloric restriction, but thyroperoxidase (TPO) activity was significantly reduced. Leptin replacement for the last 10 days of caloric restriction normalized serum leptin and TSH levels, but serum T(4) and T(3) levels and thyroid D1 and TPO activities were not reestablished. Also, a negative effect of leptin administration on Na(+)-I(-) symporter function was detected. Liver and kidney D1 and hypothalamic and BAT D2 were normalized by leptin, while pituitary D2 was significantly decreased. In conclusion, a tissue-specific modulation of deiodinases might be implicated in the normalization of thyroid function during leptin replacement in food-restricted rats. Although leptin restores the hypothalamus-pituitary axis during food restriction, it exerts a direct negative effect on the thyroid gland; thus normalization of serum thyroid hormones might depend on changes in deiodinase activities and the long-term thyroid stimulation by TSH to counterbalance the direct negative effects of leptin on the thyroid gland.

The Sodium-Iodide Symporter NIS and Pendrin in Iodide Homeostasis of the Thyroid

Thyroid hormones are essential for normal development and metabolism. Thyroid hormone biosynthesis requires iodide uptake into the thyrocytes and efflux into the follicular lumen, where it is organified on selected tyrosyls of thyroglobulin. Uptake of iodide into the thyrocytes is mediated by an intrinsic membrane glycoprotein, the sodium-iodide symporter (NIS), which actively cotransports two sodium cations per each iodide anion. NIS-mediated transport of iodide is driven by the electrochemical sodium gradient generated by the Na(+)/K(+)-ATPase. NIS is expressed in the thyroid, the salivary glands, gastric mucosa, and the lactating mammary gland. TSH and iodide regulate iodide accumulation by modulating NIS activity via transcriptional and posttranscriptional mechanisms. Biallelic mutations in the NIS gene lead to a congenital iodide transport defect, an autosomal recessive condition characterized by hypothyroidism, goiter, low thyroid iodide uptake, and a low saliva/plasma iodide ratio. Pendrin is an anion transporter that is predominantly expressed in the inner ear, the thyroid, and the kidney. Biallelic mutations in the SLC26A4 gene lead to Pendred syndrome, an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification. In thyroid follicular cells, pendrin is expressed at the apical membrane. Functional in vitro data and the impaired iodide organification observed in patients with Pendred syndrome support a role of pendrin as an apical iodide transporter.

Competitive Inhibition of Thyroidal Uptake of Dietary Iodide by Perchlorate Does Not Describe Perturbations in Rat Serum Total T 4 and TSH

BackgroundPerchlorate (ClO4−) is an environmental contaminant known to disrupt the thyroid axis of many terrestrial and aquatic species. ClO4− competitively inhibits iodide uptake into the thyroid at the sodium/iodide symporter and disrupts hypothalamic–pituitary–thyroid (HPT) axis homeostasis in rodents.ObjectiveWe evaluated the proposed mode of action for ClO4−-induced rat HPT axis perturbations using a biologically based dose–response (BBDR) model of the HPT axis coupled with a physiologically based pharmacokinetic model of ClO4−.MethodsWe configured a BBDR-HPT/ClO4− model to describe competitive inhibition of thyroidal uptake of dietary iodide by ClO4− and used it to simulate published adult rat drinking water studies. We compared model-predicted serum thyroid-stimulating hormone (TSH) and total thyroxine (TT4) concentrations with experimental observations reported in these ClO4− drinking water studies.ResultsThe BBDR-HPT/ClO4− model failed to predict the ClO4−-induced onset of disturbances in the HPT axis. Using ClO4− inhibition of dietary iodide uptake into the thyroid, the model underpredicted both the rapid decrease in serum TT4 concentrations and the rise in serum TSH concentrations.ConclusionsAssuming only competitive inhibition of thyroidal uptake of dietary iodide, BBDR-HPT/ClO4− model calculations were inconsistent with the rapid decrease in serum TT4 and the corresponding increase in serum TSH. Availability of bound iodide in the thyroid gland governed the rate of hormone secretion from the thyroid. ClO4− is translocated into the thyroid gland, where it may act directly or indirectly on thyroid hormone synthesis/secretion in the rat. The rate of decline in serum TT4 in these studies after 1 day of treatment with ClO4− appeared consistent with a reduction in thyroid hormone production/secretion. This research demonstrates the utility of a biologically based model to evaluate a proposed mode of action for ClO4− in a complex biological process.

Thyroidal angiogenesis in zebrafish ( Danio rerio ) exposed to high perchlorate concentration

As a well known environmental contaminant, perchlorate inhibits thyroidal iodide uptake and reduces thyroid hormone levels. In zebrafish (Danio rerio) exposed to high concentrations of sodium perchlorate (200, 350 and 500 mg/L) for 10 days, remarkable angiogenesis was identified, not only histopathologically but also statistically by counting of the small, medium and large sized (grades 1 to 3) vessels per unit area. Angiogenic response is concluded as the most sensitive parameter for rating of high concentrations of perchlorate exposure.

Prolactin inhibition at the end of lactation programs for a central hypothyroidism in adult rat

Malnutrition during lactation is associated with hypoprolactinemia and failure in milk production. Adult rats whose mothers were malnourished presented higher body weight and serum tri-iodothyronine (T(3)). Maternal hypoprolactinemia at the end of lactation caused higher body weight in adult life, suggesting an association between maternal prolactin (PRL) level and programming of the offspring's adult body weight. Here, we studied the consequences of the maternal PRL inhibition at the end of lactation by bromocriptine (BRO) injection, a dopaminergic agonist, upon serum TSH and thyroid hormones, thyroid iodide uptake, liver mitochondrial alpha-glycerophosphate dehydrogenase (mGPD), liver and pituitary de-iodinase activities (D1 and/or D2), and in vitro post-TRH TSH release in the adult offspring. Wistar lactating rats were divided into BRO - injected with 1 mg/twice a day, daily for the last 3 days of lactation, and C - control, saline-injected with the same frequency. At 180 days of age, the offspring were injected with (125)I i.p. and after 2 h, they were killed. Adult animals whose mothers were treated with BRO at the end of lactation presented lower serum TSH (-51%), T(3) (-23%), and thyroxine (-21%), lower thyroid (125)I uptake (-41%), liver mGPD (-55%), and pituitary D2 (-51%) activities, without changes in the in vitro post-TRH TSH release. We show that maternal PRL suppression at the end of lactation programs a hypometabolic state in adulthood, in part due to a thyroid hypofunction, caused by a central hypothyroidism, probably due to decreased TRH secretion. We suggest that PRL during lactation can regulate the hypothalamus-pituitary-thyroid axis and programs its function.

Acute and chronic leptin effect upon in vivo and in vitro rat thyroid iodide uptake

Leptin has stimulatory effects on the hypothalamic-pituitary-thyroid axis and on deiodinases activities. Here, we evaluated the effect of leptin injection upon in vivo and in vitro thyroid 125I uptake (RAIU). We designed two experiments: acute leptin (LepA) with a single dose of leptin (8 μg/100 g BW/sc), and chronic leptin (LepC), injected with the same dose of LepA, once a day, for 6 days. In parallel, control groups were saline-injected. For in vivo study, part of the animals were injected with 125I (3700 Bq) and killed after 15 or 120 min. In vivo thyroid RAIU was not changed in LepA animals. However, LepC animals showed higher in vivo thyroid RAIU (15 min:+ 130% and 120 min:+ 72%; p < 0.05). For in vitro study, the other animals were killed and their thyroids were incubated with 125I. Thyroids explants from LepA and LepC groups presented lower thyroid 125I content (− 32% and − 29% p < 0.05, respectively). The amount of our data suggest that, in vitro, leptin causes a direct inhibition of the rat thyroid RAIU, but in vivo, the effect of leptin was different according to the treatment period, which indicates that other indirect mechanisms are involved in the in vivo leptin chronic stimulation of the thyroid gland.

Perchlorate Inhibition of Iodide Uptake in Normal and Iodine-deficient Rats

Perchlorate-induced inhibition of thyroidal iodide uptake was measured in normal and iodine-deficient female Sprague-Dawley rats. Rats that were made iodine-deficient by long-term restriction of iodine in the diet absorbed a gavage dose of 131I to the thyroid in proportionally greater amounts than rats fed a normal diet. Furthermore, the iodine-deficient rats maintained their high rates of absorption even when challenged by levels of perchlorate in their drinking water sufficient to produce pronounced inhibition of 131I uptake in rats fed a normal diet. Every dose of perchlorate used in this study (1.1, 5.6, and 28 mg/L) produced significant inhibition of iodide uptake in normally fed rats, but only the highest level of perchlorate (28 mg/L) significantly inhibited thyroidal uptake of 131I in the iodine-deficient rats. Taken together, these results demonstrate that iodide-deficient animals exhibit increased resistance to the inhibition of iodine absorption resulting from perchlorate exposure.

Perchlorate and Radioiodide Kinetics Across Life Stages in the Human: Using PBPK Models to Predict Dosimetry and Thyroid Inhibition and Sensitive Subpopulations Based on Developmental Stage

Perchlorate (ClO4 − ) is a drinking-water contaminant, known to disrupt thyroid hormone homeostasis in rats. This effect has only been seen in humans at high doses, yet the potential for long term effects from developmental endocrine disruption emphasizes the need for improved understanding of perchlorate’s effect during the perinatal period. Physiologically based pharmacokinetic/dynamic (PBPK/PD) models for ClO4 − and its effect on thyroid iodide uptake were constructed for human gestation and lactation data. Chemical specific parameters were estimated from life-stage and species-specific relationships established in previously published models for various life-stages in the rat and nonpregnant adult human. With the appropriate physiological descriptions, these kinetic models successfully simulate radioiodide data culled from the literature for gestation and lactation, as well as ClO4 − data from populations exposed to contaminated drinking water. These models provide a framework for extrapolating from chemical exposure in laboratory animals to human response, and support a more quantitative understanding of life-stage-specific susceptibility to ClO4 −. The pregnant and lactating woman, fetus, and nursing infant were predicted to have higher blood ClO4 − concentrations and greater thyroid iodide uptake inhibition at a given drinking-water concentration than either the nonpregnant adult or the older child. The fetus is predicted to receive the greatest dose (per kilogram body weight) due to several factors, including placental sodium-iodide symporter (NIS) activity and reduced maternal urinary clearance of ClO4 −. The predicted extent of iodide inhibition in the most sensitive population (fetus) is not significant (∼1%) at the U.S. Environmental Protection Agency reference dose (0.0007 mg/kg-d).

Research Paper Effects of 13-HPODE on Expression of Genes Involved in Thyroid Hormone Synthesis, Iodide Uptake and Formation of Hydrogen Peroxide in Porcine Thyrocytes

It has been shown that dietary oxidized fats influence thyroid function in rats and pigs. Mechanism underlying this phenomenon are unknown. This study was performed to investigate whether 13-hydroperoxy-9,11 -octadecadienic acid (13-HPODE), a primary oxidation product of linoleic acid, affects expression of gene involved in thyroid hormone synthesis and formation of hydrogen peroxide in primary porcine thyrocytes. Thyrocytes were treated with 13-HPODE in concentrations between 20 and 100 microM. Cells treated with vehicle alone ("control cells") or with equivalent concentrations of linoleic acid were considered as controls. Treatment of cells with 13-HPODE did not affect cell viability but increased the activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase (p < 0.05) compared to control cells or cells treated with linoleic acid. Relative mRNA concentrations of genes involved in thyroid hormone synthesis like sodium iodide symporter, thyrotropin receptor, and thyroid peroxidase, as well as iodide uptake, did not differ between cells treated with 13-HPODE and control cells or cells treated with linoleic acid. Treatment of cells with 13-HPODE, however, reduced the relative mRNA concentrations of dual oxidase-2 and the formation of hydrogen peroxide compared to control cells or cells treated with linoleic acid (p < 0.05). Because the production of hydrogen peroxide is rate-limiting for the synthesis of thyroid hormones, it is suggested that 13-HPODE could have an impact on the formation of thyroid hormones in the thyroid gland.

Estrogen effects on thyroid iodide uptake and thyroperoxidase activity in normal and ovariectomized rats

Sex steroids interfere with the pituitary–thyroid axis function, although the reports have been controversial and no conclusive data is available. Some previous reports indicate that estradiol might also regulate thyroid function through a direct action on the thyrocytes. In this report, we examined the effects of low and high doses of estradiol administered to control and ovariectomized adult female rats and to pre-pubertal females. We demonstrate that estradiol administration to both intact adult and pre-pubertal females causes a significant increase in the relative thyroid weight. Serum T3 is significantly decreased in ovariectomized rats, and is normalized by estrogen replacement. Neither doses of estrogen produced a significant change in serum TSH and total T4 in ovariectomized, adult intact and pre-pubertal rats. The highest, supraphysiological, estradiol dose produced a significant increase in thyroid iodide uptake in ovariectomized and in pre-pubertal rats, but not in control adult females. Thyroperoxidase activity was significantly higher in intact adult rats treated with both estradiol doses and in ovariectomized rats treated with the highest estradiol dose. Since serum TSH levels were not significantly changed, we suggest a direct action of estradiol on the thyroid gland, which depends on the age and on the previous gonad status of the animal.

Effects of Six Months of Daily Low-Dose Perchlorate Exposure on Thyroid Function in Healthy Volunteers

Perchlorate has been detected in U.S. drinking water supplies at levels ranging from 4 to 200 microg/liter as well as in agricultural products. Perchlorate is known to be a competitive inhibitor of iodine uptake by the thyroid through the sodium-iodide symporter. The objective of the study was to determine whether prolonged exposure (6 months) to low levels of perchlorate would perturb thyroid function. This was a prospective, double-blinded, randomized trial. The study population consisted of 13 healthy volunteers. INTERVENTIONs included placebo vs. 0.5 mg or 3.0 mg potassium perchlorate daily. Serum thyroid function tests, 24-h radioactive iodine uptake, serum thyroglobulin (Tg), urinary iodine and perchlorate, and serum perchlorate were measured. Mean urinary perchlorate value during ingestion of 0.5 mg perchlorate daily was 332.7 +/- 66.1 microg per 24 h or 248.5 +/- 64.5 microg/g creatinine and mean values for the four subjects who received 3 mg perchlorate daily were 2079.5 +/- 430.0 microg per 24 h or 1941.7 +/- 138.5 microg/g creatinine. There was no significant change in the thyroid (123)I uptakes during perchlorate administration. There were no significant changes in serum T(3), free T(4) index, TSH, or Tg concentrations during the exposure period, compared to baseline or postexposure values. Urine iodine values for the 3-mg perchlorate group were higher, but not significantly so, at baseline than during perchlorate exposure. We observed that a 6-month exposure to perchlorate at doses up to 3 mg/d had no effect on thyroid function, including inhibition of thyroid iodide uptake as well as serum levels of thyroid hormones, TSH, and Tg.

Amiodarone Inhibits Thyroidal Iodide Transportin Vitroby a Cyclic Adenosine 5′-Monophosphate- and Iodine-Independent Mechanism

Thyroid side effects are common in patients treated for cardiac arrhythmias with amiodarone (AM). A major disturbance is inhibited thyroidal radioiodine uptake in AM-induced thyrotoxicosis, which makes 131I therapy ineffective. On the other hand, failure to escape from the Wolff-Chaikoff effect by down-regulation of the sodium/iodide symporter (NIS) is proposed to explain AM-induced hypothyroidism. However, previously no experimental studies on the possible mechanisms have been conducted. We therefore investigated the early effects of AM on thyroidal iodide transport using bicameral chamber cultures of primary pig thyrocytes that reproduce the three tissue compartments (epithelium, lumen, and extrafollicular space) of the gland. AM dose-dependently (1-50 microm) inhibited the TSH-stimulated transepithelial (basal to apical) transport of 125I- by up to 90%. The inhibitory effect was noticed already after 8 h and was further pronounced after 1-4 d, depending on the AM concentration. The intracellularly accumulated 125I- was reduced by perchlorate but not AM, and quantitative real-time RT-PCR revealed no change in the NIS expression in AM-treated cells. Blocking of cAMP degradation with 3-isobutyl-1-methylxanthine or withdrawal of AM reversed AM-induced changes in electrolyte transport but were unable to recover the suppressed 125I- transport. The iodine-free AM analog dronedarone also inhibited 125I- transport to the same extent as AM. The findings indicate that AM blocks thyroidal iodide uptake by reducing the iodide permeability of the apical plasma membrane of the thyroid epithelial cells. The effect is iodine independent and long-lasting and does not involve impaired function of NIS or the TSH receptor/cAMP signaling pathway.

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

ABSTRACT 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.

Development of a Health-Protective Drinking Water Level for Perchlorate

We evaluated animal and human toxicity data for perchlorate and identified reduction of thyroidal iodide uptake as the critical end point in the development of a health-protective drinking water level [also known as the public health goal (PHG)] for the chemical. This work was performed under the drinking water program of the Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency. For dose–response characterization, we applied benchmark-dose modeling to human data and determined a point of departure (the 95% lower confidence limit for 5% inhibition of iodide uptake) of 0.0037 mg/kg/day. A PHG of 6 ppb was calculated by using an uncertainty factor of 10, a relative source contribution of 60%, and exposure assumptions specific to pregnant women. The California Department of Health Services will use the PHG, together with other considerations such as economic impact and engineering feasibility, to develop a California maximum contaminant level for perchlorate. We consider the PHG to be adequately protective of sensitive subpopulations, including pregnant women, their fetuses, infants, and people with hypothyroidism.

The NAS Perchlorate Review: Adverse Effects?

Ginsberg and Rice (2005) argued that the reference dose for perchlorate of 0.0007 mg/kg per day recommended by the National Academy of Sciences (NAS) Committee to Assess the Health Implications of Perchlorate Ingestion is not adequately protective. As members of the committee, we disagree. Ginsberg and Rice (2005) based their conclusion on three points. The first involves the designation of the point of departure as a NOEL (no observed effect level) versus a LOAEL (lowest observed adverse effect level). The committee chose as its point of departure a dose of perchlorate (0.007 mg/kg per day) that, when given for 14 days to seven normal subjects, did not cause a statistically significant decrease in the group mean thyroid iodide uptake (Greer et al. 2002). Accordingly, the committee considered it a NOEL. Ginsberg and Rice (2005) focused on the fact that only seven subjects were given that dose; they seem to say that attention should be paid only to the results in those subjects in whom there was a decrease in thyroid iodide uptake and that the results in those in whom there was no decrease or an increase should be ignored. They considered the dose to be a LOAEL because of the decrease in uptake in those few subjects. It is important to note that a statistically significant decrease of, for example, 5% or even 10% would not be biologically important and, more important, would not be sustained. For example, in another study (Braverman et al. 2004), administration of 0.04 mg/kg per day to normal subjects for 6 months had no effect on thyroid iodide uptake when measured at 3 and 6 months, and no effect on serum thyroid hormone or thyrotropin concentrations measured monthly. [Inspection of Figure 5A in Greer et al. (2002) suggests that this dose would inhibit thyroid iodide uptake by about 25% if measured at 2 weeks.] The second issue involves database uncertainty. In clinical studies, perchlorate has been administered prospectively to 68 normal subjects for 2 weeks to 6 months. In one study (Brabant et al. 1992), a dose of 9.2 mg/kg per day for 4 weeks had no effect on thyroid function. In occupational studies, doses as high as 0.5 mg/kg per day had no effect on thyroid hormone or thyrotropin production in workers. In epidemiologic studies, there were no abnormalities in growth or thyroid function in children exposed life-long to 100–120 μg perchlorate per liter of drinking water, or in pregnant women and newborn infants similarly exposed. Given the choice of a nonadverse effect (inhibition of iodide uptake by the thyroid) as the point of departure and the multiple studies in which doses of perchlorate much higher than 0.007 mg/kg per day had no effect on any aspect of thyroid function, the committee did not apply a database uncertainty factor. Finally, Ginsberg and Rice (2005) argued that inhibition of thyroid iodide uptake is adverse. That conclusion assumes that any acute inhibition would be sustained, so thyroid hormone production would decrease. That is not the case. There is remarkable compensation for even substantial reductions in thyroid iodide uptake—and thyroid hormone production. As noted above, subjects given 0.04 mg/kg per day for 6 months and 9.2 mg/kg per day for 4 weeks—doses that certainly would inhibit thyroid iodide uptake for a few weeks—had no decrease in serum thyroid hormone or increase in serum thyrotropin concentrations (the hallmark of even mild hypothyroidism). Short-term inhibition of thyroid iodide uptake is not an adverse effect; it has no adverse consequences because there is rapid compensation mediated by several independent processes. One of these processes is up-regulation of the thyroid sodium-iodide transport system, as a result of intrathyroidal iodide deficiency. The second, should there be even a very small decrease in thyroid hormone production, is an increase in thyrotropin secretion, resulting in overall stimulation of the thyroid gland. Analyses of the effects of any substance on thyroid function must take these compensatory processes into account, particularly the fact that the effect of any substance that inhibits thyroid function will diminish with time. Only if all of these mechanisms fail will there be hypothyroidism, the first adverse effect in the continuum of effects resulting from perchlorate ingestion. If there is no inhibition of iodide uptake to begin with, there will be no other changes in thyroid function at any time. We believe that the committee’s recommended reference dose of 0.0007 mg/kg per day provides a wide margin of safety for all subjects of all ages.

Effects of ammonium perchlorate on thyroid function in developing fathead minnows, Pimephales promelas.

Perchlorate is a known environmental contaminant, largely due to widespread military use as a propellant. Perchlorate acts pharmacologically as a competitive inhibitor of thyroidal iodide uptake in mammals, but the impacts of perchlorate contamination in aquatic ecosystems and, in particular, the effects on fish are unclear. Our studies aimed to investigate the effects of concentrations of ammonium perchlorate that can occur in the environment (1, 10, and 100 mg/L) on the development of fathead minnows, Pimephales promelas. For these studies, exposures started with embryos of < 24-hr postfertilization and were terminated after 28 days. Serial sectioning of thyroid follicles showed thyroid hyperplasia with increased follicular epithelial cell height and reduced colloid in all groups of fish that had been exposed to perchlorate for 28 days, compared with control fish. Whole-body thyroxine (T4) content (a measure of total circulating T4) in fish exposed to 100 mg/L perchlorate was elevated compared with the T4 content of control fish, but 3,5,3′-triiodothyronine (T3) content was not significantly affected in any exposure group. Despite the apparent regulation of T3, after 28 days of exposure to ammonium perchlorate, fish exposed to the two higher levels (10 and 100 mg/L) were developmentally retarded, with a lack of scales and poor pigmentation, and significantly lower wet weight and standard length than were control fish. Our study indicates that environmental levels of ammonium perchlorate affect thyroid function in fish and that in the early life stages these effects may be associated with developmental retardation.

Rapid regulation of thyroid sodium–iodide symporter activity by thyrotrophin and iodine

Transport of iodide into thyrocytes, a fundamental step in thyroid hormone biosynthesis, depends on the presence of the sodium-iodide symporter (NIS). The importance of the NIS for diagnosis and treatment of diseases has raised several questions about its physiological control. The goal of this study was to evaluate the influence of thyroid iodine content on NIS regulation by thyrotrophin (TSH) in vivo. We showed that 15-min thyroid radioiodine uptake can be a reliable measurement of NIS activity in vivo. The effect of TSH on the NIS was evaluated in rats treated with 1-methyl-2-mercaptoimidazole (MMI; hypothyroid with high serum TSH concentrations) for 21 days, and after 1 (R1d), 2 (R2d), or 5 (R5d) days of withdrawal of MMI. NIS activity was significantly greater in both MMI and R1d rats. In R2d and R5d groups, thyroid iodide uptake returned to normal values, despite continuing high serum TSH, possibly as a result of the re-establishment of iodine organification after withdrawal of MMI. Excess iodine (0.05% NaI for 6 days) promoted a significant reduction in thyroid radioiodide uptake, an effect that was blocked by concomitant administration of MMI, confirming previous findings that iodine organification is essential for the iodide transport blockade seen during iodine overload. Therefore, our data show that modulation of the thyroid NIS by TSH depends primarily on thyroid iodine content and, further, that the regulation of NIS activity is rapid.

PBPK Model for Radioactive Iodide and Perchlorate Kinetics and Perchlorate-Induced Inhibition of Iodide Uptake in Humans

Detection of perchlorate (ClO4-) in several drinking water sources across the U.S. has lead to public concern over health effects from chronic low-level exposures. Perchlorate inhibits thyroid iodide (I-) uptake at the sodium (Na+)-iodide (I-) symporter (NIS), thereby disrupting the initial stage of thyroid hormone synthesis. A physiologically based pharmacokinetic (PBPK) model was developed to describe the kinetics and distribution of both radioactive I- and cold ClO4- in healthy adult humans and simulates the subsequent inhibition of thyroid uptake of radioactive I- by ClO4-. The model successfully predicts the measured levels of serum and urinary ClO4- from drinking water exposures, ranging from 0.007 to 12 mg ClO4-/kg/day, as well as the subsequent inhibition of thyroid 131I- uptake. Thyroid iodine, as well as total, free, and protein-bound radioactive I- in serum from various tracer studies, are also successfully simulated. This model's parameters, in conjunction with corresponding model parameters established for the male, gestational, and lactating rat, can be used to estimate parameters in a pregnant or lactating human, that have not been or cannot be easily measured to extrapolate dose metrics and correlate observed effects in perchlorate toxicity studies to other human life stages. For example, by applying the adult male rat:adult human ratios of model parameters to those parameters established for the gestational and lactating rat, we can derive a reasonable estimate of corresponding parameters for a gestating or lactating human female. Although thyroid hormones and their regulatory feedback are not incorporated in the model structure, the model's successful prediction of free and bound radioactive I- and perchlorate's interaction with free radioactive I- provide a basis for extending the structure to address the complex hypothalamic-pituitary-thyroid feedback system. In this paper, bound radioactive I- refers to I- incorporated into thyroid hormones or iodinated proteins, which may or may not be bound to plasma proteins.

Interspecies differences in susceptibility to perturbation of thyroid homeostasis: a case study with perchlorate

Despite many physiological similarities, humans and rats exhibit notably different susceptibilities to thyroid perturbation. Considerable research has recently been conducted on the thyroid-active chemical perchlorate, a chemical of emerging environmental and regulatory interest. While the data indicate humans and rats exhibit similar dose–response relationships in terms of acute inhibition of thyroidal iodide uptake, the two species appear to exhibit notable differences in terms of thyroid hormone response, the toxicologically significant consequence of iodide uptake inhibition. We analyzed dose–response data for changes in serum T 3, T 4, and TSH levels from studies in humans, rats, mice, and rabbits. We found that thyroid homeostasis in the rat appears to be strikingly more sensitive to perchlorate than any of the other species. Rats exhibited an increase in serum TSH at 0.1 mg/kg-day whereas other species remained unresponsive even at doses of 10 mg/kg-day. Less pronounced but consistent effects were seen with serum T 3 and T 4. These cross-species comparisons provide strong evidence that data obtained from rat studies should be critically evaluated for their relevance to humans. If rat data are used to develop toxicity criteria for perchlorate, we propose that this is an instance where an inter-species uncertainty factor less than one is supportable. Disclosure statement: One of the authors (BDB) has been hired by Lockheed Martin Corporation as an expert in litigation involving perchlorate. A portion of the initial research presented in this paper was conducted in conjunction with her role in that matter.

Enzimas envolvidas na organificação tireoideana do iodo

Thyroid hormone biosynthesis depends on iodide uptake and its incorporation into the acceptor protein thyroglobulin (Tg), a high molecular weight protein secreted into the follicular lumen. The sodium-iodide symporter (NIS) is responsible for thyroid iodide uptake, the first step in thyroid hormonogenesis. Iodide is subsequently transported through the cellular membrane by pendrin (PDS) and then incorporated into Tg. Iodide oxidation and organification occur mainly in the thyrocyte apical surface and these reactions are catalyzed by thyroperoxidase (TPO) in the presence of hydrogen peroxide. Thus, thyroid iodide organification depends on TPO activity, which is modulated by the concentration of substrates (thyroglobulin and iodide) and cofactor (hydrogen peroxide). Hydrogen peroxide generation is catalyzed by the thyroid NADPH oxidase (ThOx), which is present in the apical pole of thyrocytes, is stimulated by thyrotropin and is inhibited by iodide. Hydrogen peroxide generation is the limiting step in thyroid hormone biosynthesis under iodine sufficiency conditions.