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.     

Pairs of cyclic AMP analogs, that are specifically synergistic for type I and type II cAMP-dependent protein kinases, mimic thyrotropin effects on the function, differentiation expression and mitogenesis of dog thyroid cells

The role of the two different isozymes of the cAMP-dependent protein kinase is still unclear. We have investigated the potential roles for each isozyme in dog thyroid cells, a model in which the function, expression of differentiation and proliferation are positively regulated by thyrotropin acting through cyclic AMP. The dog thyroid contains both type I and type II cAMP-dependent protein kinases. These isozymes were selectively activated in vitro by type-I-directed and type-II-directed analog pairs. In thyroid slices, both type-I directed and type II-directed analog pairs synergistically activated thyroid hormone synthesis, as measured by incorporation of 131I into proteins and thyroid hormone secretion as determined by the release of butanol-extractable 131I. In primary cultures of dog thyroid cells both isozyme-directed analog pairs synergistically enhanced iodide trapping, a marker of differentiation, and DNA synthesis, as measured by the percentage of cells incorporating [3H]thymidine into their nuclei. However, DNA synthesis was more sensitive to type-I-directed pairs. The results demonstrate that both cAMP-dependent protein kinase isozymes can mediate the action of cAMP on function, differentiation expression and cell proliferation in dog thyroid cells.     

Effect of thyroxine administration to the mother on postnatal radioiodine uptake by the thyroid of partially thyroidectomized rats.

The experiment was carried out on 35 litters of infant rats aged 4-17 days. The animals in each litter were always divided into two groups: control (sham operation) and experimental (hemithyroidectomy). Starting with the day on which the young were operated on, the mothers received daily subcutaneous injections of either saline or of thyroxine in doses of 50, 100 or 200 mug. At the end of the experiment, the young were injected intraperitoneally with 1 muCi 131I. One hour later they were decapitated and the radioactivity in their thyroid was expressed as the percentage of the administered dose per mg thyroid. The following age groups were used, according to the interval between thyroidectomy and decapitation: 4 to 8, 9 to 13, 13 to 15 and 15 to 17 days. 131I uptake by the residue of the thyroid in partially thyroidectomized animals was always compared with the values in the animals from the same litter subjected to sham operation. The results showed that partial thyroidectomy significantly stimulated 131I uptake in all age groups in which the mother was only given saline. In the 4- to 8-day-old group, the administration of 50 or 100 mug thyroxine to the mother inhibited this compensatory increase. In the 9- to 13-day-old group, inhibition occurred only after a dose of 100 mug thyroxine. In animals with an interval from the 13th to the 15th days old the dose of thyroxine administered to the mother had to be raised to 200 mug/day to achieve an inhibitory effect. In the last group (interval 15th to 17th day), not even administration of the maximum thyroxine dose to the mother from the 13th postnatal day succeeded in inhibiting the significant increase in 131I uptake. These results show that thyroxine administered to lactating female rats can be transmitted via the milk to the organism of the young in amounts which can be demonstrated in a physiological tests.     

The changes of in vitro 131I-iodine uptake in the thyroid gland of rats exposed to septal lesions and immobilization stress.

The in vitro uptake of 131I by the thyroid gland was investigated in rats after immobilization stress with special respect to animals lesioned in the septal area. Lesions in a septal area performed 10 days before decreased the iodide accumulation in the thyroid, while stress by immobilization increased it to the control basal value. Repeated immobilization in control rats did not produce any changes in the iodide uptake in vitro. ACTH injected in vivo stimulated the iodide 131I uptake in vitro by thyroid glands of hypophysectomized rats. It is concluded that immobilization stress in rats with septal lesions increases 131I-iodide uptake in vitro and that the increase was probably influenced by both catecholamines and glucocorticoids.     

High bromide intake affects the accumulation of iodide in the rat thyroid and skin

The effect of a high bromide intake on the kinetics of iodide uptake and elimination in the thyroid and skin of adult male rats was studied. In rats fed a diet with sufficient iodine supply (>25 μg I/d), the iodide accumulation in the skin predominated during the first hours after ¹³¹I -iodide application. From this organ, radioiodide was gradually transferred into the thyroid. A high bromide intake (>150 mg Br⁻/d) in these animals led to a marked decrease in iodide accumulation, especially by the thyroid, because of an increase in iodide elimination both from the thyroid and from the skin. In rats kept under the conditions of iodine deficiency (<1 μ I/d), the iodide accumulation in the thyroid, but not in the skin, was markedly increased as a result of a thyrotropic stimulation. The effect of a high bromide intake (>100 mg Br⁻/d) in these animals was particularly pronounced because the rates of iodide elimination were most accelerated both from their thyroid and from their skin. Presented in part at the 20th Workshop on Macro and Trace Elements held in Jena (Germany) on December 1–2, 2000.     

Radioiodination of proteins using prosthetic group: a convenient way to produce labelled proteins with in vivo stability.

Radiolabelled peptides can provide new approaches for radiopharmaceutical development. Several prosthetic groups have been developed for radioiodination of proteins in order to minimize in vivo dehalogenation. In this work, the prosthetic group N-succinimidyl 4-[131I]iodobenzoate ([131I]SIB) was obtained by an alternative procedure that employs Cu(I) assisted radioiododebromination to produce p-[131I]iodobenzoic acid with a radiochemical yield of 92.73 +/- 1.51% (N = 6), followed by the reaction with TSTU (O-(N-succinimidyl)-N,N,N'N'-tetramethyluronium) in alkaline medium. The HPLC profile of the final product, revealed that [131I]SIB was obtained with a radiochemical purity of 98.19 +/- 1.14% (N = 6 Swiss mices (normal group) and animals with inflammation focus developed on the right thigh by tupertine injection) were injected with human immunoglobulin (IgG) radioiodinated with [131I]SIB and by direct method (Iodogen). The comparison of results showed a fast blood clearance, better target organ/background relation and low uptake in thyroid and stomach (p < 0.01) for the protein labelled with [131I]SIB, what suggests a greater in vivo stability.     

Thyroid dose reconstruction for the population of Belarus after the Chernobyl accident

An ¹³¹I environmental transfer model – adapted for Belorussian conditions – was applied to estimate thyroid doses for different population groups. For this purpose the available data were analysed and the important radioecological parameters assessed, i.e. (a) the elimination rate of ¹³¹I from grass due to weathering and growth dilution, (b) the initial interception of ¹³¹I by vegetation, (c) the transfer coefficient for ¹³¹I from grass to cow's milk, (d) the yield of pasture grass and (e) the milk consumption rate. Additionally, the influence of applied countermeasures has been taken into account, such as the interruption of locally produced milk consumption, and the appropriate correction factors have been estimated. As a result, the average age-dependent thyroid doses were assessed for the Belorussian population. The highest average doses in children (> 1 Gy) have been estimated for the Bragin, Khoiniki, Narovlia and Vetka raions of the Gomel oblast. The thyroid exposure tends to decrease from the southeastern (closest to the Chernobyl nuclear power plant areas) to the northwestern part of the republic. When comparing the assessed thyroid doses with dose estimates derived from direct ¹³¹I activity measurements in thyroids (for the locations with more than 15 direct measurements), the results agree fairly well. The model calculation may perhaps overestimate thyroid doses of the population residing in the settlements of the central and northern parts of Belarus, distant from the areas with direct measurements of ¹³¹I activities in soil, grass and milk. These thyroid dose estimates may serve as a basis for further epidemiological studies and risk analyses.     

Inhibition of thyroid function and thyrotrophic activity following the administration of methallibure (ICI-33 828).

1. Goitrogenic action of methallibure (ICI-33828) has been studied in mice gerbil and hedgehog using thyroid weight and histological structure as an index. Liquefaction and vacuolation of thyroid follicles were most prevelant after methallibure administration. 2. The I131 content of the thyroid gland was significantly higher in the methallibure treated groups than in the controls. This denotes a decrease in the rate of discharge of thyroid hormone. 3. Protein bound radioiodine (Pb I131) was low after methallibure administration. 4. Methallibure administration brings about hypertrophy of pituitary thyrotrophs which is also reflected in the increased basophilic cell percentage in gerbil (control: 15.5 percent; methallibure: 22.8 percent). 5. It is concluded that methallibure acts on thyroid function both by a direct effect on the gland as well as by influencing pituitary thyrotrophic activity in enhancing I131 uptake.     

Evaluation of equivalent body burden in the thyroid for the people of Poland on results of 131I absorption after the disaster in Czernobyl. Determination of thyroid blockade with potassium iodide]

An assessment of effectiveness of the administering of single dose of stable iodine in Poland on the reduction of 131I doses in thyroid has been performed. 5-compartment model of metabolism of iodine developed by Johnson has been used to evaluate predicted levels of stable iodine and 131I content in thyroid and commitment dose equivalent H50 for different doses of stable iodine and various age and sex group population. The measured values of 131I concentration in air and in milk and standard values for milk and food consumption and inhalation rate as well as metabolic parameters were used. Theoretical calculations showed that administering of stable iodine on 1986-04-28, 1986-04-29, 1986-04-30 and 1986-05-01 could have reduced committed dose equivalent H50 form ingestion with inhalation pathway by about 44%, 40%, 26%, 12% respectively. On the basis of measured 131I activity in the thyroid for inhabitants from different districts in Poland (1400 measurement) committed dose equivalents were determined and analysis of radiation hazard from 131I were performed. In the most contaminated regions of Poland average H50 doses for children 1-5 and 5-10 years old are close to 50 mSv (permissible level for population) and maximal doses exceed this limit four times. These maximal doses occurred for about from 5% inhabitants from these area. In the moderate and low contaminated regions of Poland the average doses are fivefold and tenfold less respectively.     

Mutagenicity of diagnostic and therapeutical doses of radiopharmaceutical iodine-131 in Wistar rats

Iodine-131 (¹³¹I) is a radioisotope used for the diagnosis and treatment of thyroidal disorders such as hyperthyroidism and cancer. During its decay, ¹³¹I emits beta particles and gamma rays; its physical half-life is 8 days, and it is accumulated preferentially in the thyroid tissue. This study aimed to evaluate the cytotoxicity and mutagenicity of diagnostic and therapeutic doses of ¹³¹I using bone marrow cells of rats treated in vivo in a test system with a single dose by gavage. Concentrations of 5, 25, 50 and 250 μCi in 1 ml of water were used, and after 24 h, the animals were killed. Also, a concentration of 25 μCi/ml of water was used, and the animals were killed after 5 days. The results showed that no concentration of ¹³¹I was cytotoxic and that all concentrations were mutagenic. As a result, there was no statistically significant difference detected by the χ² test in the induction of chromosomal aberrations between the different doses. Thus, the present study demonstrated a significant increase in chromosomal aberration in bone marrow cells exposed to ¹³¹I regardless of the dose or the treatment time.     

Effects of Iodine-131 in sheep depending on the content of stable iodine in the diet]

The biological effect of 131I was studied in sheep kept on a diet deficient in stable iodine. An increased capture and accretion of iodine in the thyroid gland and in the whole body were observed. The disturbances in the structure and function of the thyroid gland, liver and haemopoietic organs were more pronounced in the animals kept on the iodine deficient diet.     

Thyroid doses in Ukraine due to 131I intake after the Chornobyl accident. Report II: dose estimates for the Ukrainian population

This paper describes the revision of the thyroid dosimetry system in Ukraine using new, recently available data on (i) revised ¹³¹I thyroid activities derived from direct thyroid measurements done in May and June 1986 in 146,425 individuals; (ii) revised estimates of ¹³¹I ground deposition density in each Ukrainian settlement; and (iii) estimates of age- and gender-specific thyroid masses for the Ukrainian population. The revised dosimetry system estimates the thyroid doses for the residents of the settlements divided into three levels depending on the availability of measurements of ¹³¹I thyroid activity among their residents. Thyroid doses due to ¹³¹I intake were estimated in this study for different age and gender groups of residents of 30,353 settlements in 24 oblasts of Ukraine, Autonomous Republic Krym, and cities of Kyiv and Sevastopol. Among them, dose estimates for 835 settlements were based on ¹³¹I thyroid activities measured in more than ten residents (the first level), for 690 settlements based on such measurements done in neighboring settlements (the second level), and for 28,828 settlements based on a purely empirical relationship between the thyroid doses due to ¹³¹I intake and the cumulative ¹³¹I ground deposition densities in settlements (the third level). The arithmetic mean of the thyroid doses due to ¹³¹I intake among 146,425 measured individuals was 0.23 Gy (median of 0.094 Gy); about 99.8% of them received doses less than 5 Gy. The highest oblast-average population-weighted thyroid doses were estimated for residents of Chernihiv (0.15 Gy for arithmetic mean and 0.060 Gy for geometric mean), Kyiv (0.13 and 0.051 Gy) and Zhytomyr (0.12 and 0.049 Gy) Oblasts followed by Rivne (0.10 and 0.039 Gy) and Cherkasy (0.088 and 0.032 Gy) Oblasts, and Kyiv City (0.076 and 0.031 Gy). The geometric mean of thyroid doses estimated in this study for the entire Ukraine essentially did not change in comparison with a previous estimate, 0.020 vs. 0.021 Gy, respectively. The ratio of geometric mean of oblast-specific thyroid doses estimated in the present study to previously calculated doses varied from 0.51 to 3.9. The highest increase in thyroid doses was found in areas remote from the Chornobyl nuclear power plant with a low level of radioactive contamination: by 3.9 times for Zakarpatska Oblast, 3.5 times for Luhansk Oblasts and 2.9 times for Ivano-Frankivsk Oblast. The developed thyroid dosimetry system is being used to revise the thyroid doses due to ¹³¹I intake for the individuals of post-Chornobyl radiation epidemiological studies: the Ukrainian-American cohort of individuals exposed during childhood and adolescence, the Ukrainian in utero cohort, and the Chornobyl Tissue Bank.

     

Intrathyroidal iodine metabolism in the rat. The influence of diet and the administration of thyroid-stimulating hormone

1. Ratios of mono[¹³¹I]iodotyrosine and di[¹³¹I]iodotyrosine (R values) and the incorporation of ¹³¹I into iodothyronines have been estimated in rat thyroid glands from 30min. to 38hr. after the administration of [¹³¹I]iodide. 2. In rats receiving a powdered low-iodine diet the R values were close to unity and did not change with time after the administration of [¹³¹I]iodide. In rats receiving a commercial pellet diet the R values fell from a mean of 0·8 at 30min. after [¹³¹I]iodide administration to 0·49 at 38hr. 3. Administration of 0·5–2·0i.u. of thyroid-stimulating hormone before giving the injection of [¹³¹I]iodide caused a small diminution in the R value when the time between injecting [¹³¹I]iodide and killing the animal was 16hr. or more. 4. Iodothyronines represented a greater percentage of the total thyroid-gland radioactivity in the iodine-deficient animals than in animals fed on the pellet diet. Thyroid-stimulating hormone had little effect, if any, on the iodothyronine contents.     

Effect of prolactin administration on ovarian and thyroidal activity in relation to gonadotropic and thyrotropic potency in a freshwater catfish, Heteropneustes fossilis (Bloch).

Radiophosphorus incorporation by ovary was the criterion used for the assessment of ovarian activity in H. fossilis. Prolactin administration at different dose levels failed to elicit any obvious change in ovarian 32P uptake. From the findings of this experiment it appears that prolactin has no influence on ovarian activity. However, it exerted an inhibitory effect on the thyroid activity in intact H. fossilis. It was evident by retarded thyroidal 131I uptake. But the declension in serum PB131I was less pronounced. TSH content of the pituitary gland in response to prolactin administration was also reduced. It seems that prolactin interferes in thyroidal iodine accumulation perhaps by retarding the synthesis of TSH, but apparently does not prevent thyroxine output to a perceptible level.     

Diphasic effect of thyrotropin on the uptake and absorption of iodine-131 by thyroid cell culture]

The studies were performed on the primary culture of thyroid cells of newborn pigs. It was shown that thyroid-stimulating hormone (TSH) within the first 12th of its action inhibited uptake and organification of iodine-131. A negative influence of TSH on 131I uptake was retained both with its simultaneous introduction into the culture medium and with 30 min interval as well as when conducting experiments on the 1st, 3d, 5th and 7th days of cultivation. Previous 72h incubation with TSH sufficient for activation of all the links of iodine transport caused an increase in 131I uptake and organification.     

Physical and radiobiological bases of the use of125I in the management of thyrotoxicosis

Increasing interest is recently shown in the use of¹²⁵I as an alternative isotope to¹³¹I for the management of thyrotoxicosis based on the postulate that there is a relative sparing of the reproductive integrity of the thyroid follicular cell and a consequent possibility of smaller incidence of hypothyroidism after therapy. A review of the dosimetric, radiobiological and clinical aspects of the use of¹²⁵I are presented here.For the same activity though¹²⁵I gives smaller mean glanddose than¹³¹I, the dose computations at microscopic level have revealed that there is a preferential irradiation of the apical membrane compared to the nucleus of the follicular cell. The ratio of the dose to the apical membrane and that to the nucleus increases with the decrease of the percentage colloid mass of the gland. Radiobiological significance of this non-uniform dose distribution across a follicular cell, with¹²⁵I, is brought out using rat thyroid as the biological system. For the same mean gland dose the follicular cell survival is larger with¹²⁵I than with¹³¹I. 24 h radioiodine uptake is reduced in case of¹²⁵I treatment whereas it is not affected with¹²⁵I. Pilot clinical trials using¹²⁵I for the management of thyrotoxicosis are underway in some centres. Preliminary results from centres using doses 3–4 times that of the conventional¹³¹I dose are not very different from those with conventional¹³¹I therapy. Centres that used doses same as or less than the conventional¹³¹I doses, reported smaller incidence of hypothyroidism.Alexander von Humboldt Fellow in Klinikum Steglitz, Berlin     

A radioecological model for thyroid dose reconstruction of the Belarus population following the Chernobyl accident

A radioecological model was developed to estimate thyroid exposures of the Belarus population following the Chernobyl accident. The input of the model includes an extensive data set of the ¹³⁷Cs activity per unit area deposited during the Chernobyl accident, the rainfall data for different regions of Belarus, the ¹³¹I/¹³⁷Cs ratio in the deposit and the start of the grazing period in Belarus in April/May 1986. The output of the model is the age-dependent thyroid exposure due to the intake of ¹³¹I with fresh milk. Age-dependent average thyroid doses were assessed for selected regions of Belarus. The maximum thyroid doses were estimated for the inhabitants of Gomel oblast where the highest deposition was observed among the regions considered here. The lowest doses were estimated for Vitebsk oblast with the lowest level of depositions. The mean exposures for the oblasts of Grodno, Minsk, Mogilev and Brest were very similar. The results were compared with estimations of thyroid exposure that were based on ¹³¹I measurements in human thyroids, and they are in good agreement. The model may be used for the assessment of thyroid doses in Belarus for areas where no ¹³¹I measurements are available.     

Diurnal rhythms of thyroid hormones in rooster chicks (Gallus domesticus). 2. Studies on the protein-bound radioiodine and the "free" hormone portion]

In four week old cockerels the plasma was investigated for cyclic changes in total radioactivity, PB131I, PI131I, and "free" thyroid hormones 24 hours after injection of Na131I. Maxima in total radioactivity were observed at 3.00 am and 9.00 pm. They were significant different from the minima at noon (2P less than 0.005). At the same points of the day maxima, resp. minima were found in the PB131I and the "free" hormones. The "free" hormones expressed in per cent of total hormones showed low values at 6.00 am, 3.00 pm, and 9.00 pm. The diurnal changes in haematocrit and albumin concentration were not responsible for the variation of PB131I. In order to eleminate effects of isotope dilution by ingested iodine the PB131I was expressed in per cent of total radioactivity of plasma (= conversion rate) or resp. in per cent of thyroidal radioiodine uptake. The obtained values showed maxima at 6.00 am and 9.00 pm. From that we conclude again on a stimulation of the thyroid at these times.     

Canaries in the coal mine: a cross-species analysis of the plurality of obesity epidemics

A dramatic rise in obesity has occurred among humans within the last several decades. Little is known about whether similar increases in obesity have occurred in animals inhabiting human-influenced environments. We examined samples collectively consisting of over 20 000 animals from 24 populations (12 divided separately into males and females) of animals representing eight species living with or around humans in industrialized societies. In all populations, the estimated coefficient for the trend of body weight over time was positive (i.e. increasing). The probability of all trends being in the same direction by chance is 1.2 × 10(-7). Surprisingly, we find that over the past several decades, average mid-life body weights have risen among primates and rodents living in research colonies, as well as among feral rodents and domestic dogs and cats. The consistency of these findings among animals living in varying environments, suggests the intriguing possibility that the aetiology of increasing body weight may involve several as-of-yet unidentified and/or poorly understood factors (e.g. viral pathogens, epigenetic factors). This finding may eventually enhance the discovery and fuller elucidation of other factors that have contributed to the recent rise in obesity rates.