Biogeochemistry of the Human Environment.- The Biosphere.- Soils.- Waters.- Air.- Plants.- Humans.- Biogeochemistry of Trace Elements.- Trace Elements of Group 1 (Previously Group Ia).- Trace Elements of Group 2 (Previously Group IIa).- Trace Elements of Group 3 (Previously Group IIIb).- Trace Elements of Group 4 (Previously Group IVb).- Trace Elements of Group 5 (Previously Group Vb).- Trace Elements of Group 6 (Previously Group VIb).- Trace Elements of Group 7 (Previously Group VIIb).- Trace Elements of Group 8 (Previously Part of Group VIII).- Trace Elements of Group 9 (Previously Part of Group VIII).- Trace Elements of Group 10 (Previously Part of Group VIII).- Trace Elements of Group 11 (Previously Group Ib).- Trace Elements of Group 12 (Previously Group IIb).- Trace Elements of Group 13 (Previously Group IIIa).- Trace Elements of Group 14 (Previously Group IVa).- Trace Elements of Group 15 (Previously Group Va).- Trace Elements of Group 16 (Previously Group VIa).- Trace Elements of Group 17 (Previously Group VIIa).

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Trace Elements From Soil to Human

Extrathyroidal cancers could potentially be targeted with 131 I, if the Na/I symporter (NIS) were functional. Using immunohistochemical methods we probed 1278 human samples with anti-NIS antibody, including 253 thyroid and 169 breast conventional whole tissue sections (CWTS). Four high density tissue microarrays containing a wide variety of breast lesions, normal tissues, and carcinoma cores were tested. The results of the normal microarray were corroborated in 50 CWTS. Nineteen of 34 normal tissues, including bladder, colon, endometrium, kidney, prostate, and pancreas, expressed NIS. Nineteen of 25 carcinomas demonstrated NIS immunopositivity; 55.7% of 479 carcinoma microarray cores expressed NIS, including prostate (74%), ovary (73%), lung (65%), colon (62.6%), and endometrium (56%). NIS protein was present in 75% benign thyroid lesions, 73% thyroid cancers, 30% normalappearing, peritumoral breasts, 88% ductal carcinomas in situ, and 76% invasive breast carcinoma CWTS. Comparatively, breast microarray cores had lower immunoreactivity. Plasma membrane immunopositivity was confirmed in thyrocytes, salivary ductal, gastric mucosa, and lactating mammary cells. In other tissues, immunoreactivity was predominantly intracellular, particularly in malignant lesions. Thus, NIS is present in many normal epithelial tissues and is predominantly expressed intracellularly in many carcinomas. Elucidating the regulatory mechanisms that render NIS functional in extrathyroidal carcinomas may make 131 I therapy feasible. (J Clin Endocrinol Metab 88: 1880 –1888, 2003)

Immunohistochemical profile of the sodium/iodide symporter in thyroid, breast, and other carcinomas using high density tissue microarrays and conventional sections.

We have studied whether, or not, tissue-specific regulatory mechanisms provide normal 3,5,3'-triiodothyronine (T3) concentrations simultaneously in all tissues of a hypothyroid animal receiving thyroxine (T4), an assumption implicit in the replacement therapy of hypothyroid patients with T4 alone. Thyroidectomized rats were infused with placebo or 1 of 10 T4 doses (0.2-8.0 micrograms per 100 grams of body weight per day). Placebo-infused intact rats served as controls. Plasma and 10 tissues were obtained after 12-13 d of infusion. Plasma thyrotropin and plasma and tissue T4 and T3 were determined by RIA. Iodothyronine-deiodinase activities were assayed using cerebral cortex, liver, and lung. No single dose of T4 was able to restore normal plasma thyrotropin, T4 and T3, as well as T4 and T3 in all tissues, or at least to restore T3 simultaneously in plasma and all tissues. Moreover, in most tissues, the dose of T4 needed to ensure normal T3 levels resulted in supraphysiological T4 concentrations. Notable exceptions were the cortex, brown adipose tissue, and cerebellum, which maintained T3 homeostasis over a wide range of plasma T4 and T3 levels. Deiodinase activities explained some, but not all, of the tissue-specific and dose related changes in tissue T3 concentrations. In conclusion, euthyroidism is not restored in plasma and all tissues of thyroidectomized rats on T4 alone. These results may well be pertinent to patients on T4 replacement therapy.

https://digital.csic.es/bitstream/10261/24056/1/Replacement%20therapy.pdf

Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats.

We have recently shown that it is not possible to restore euthyroidism completely in all tissues of thyroidectomized rats infused with T4 alone. The present study was undertaken to determine whether this is achieved when T3 is added to the continuous sc infusion of T4. Thyroidectomized rats were infused with placebo or T4 (0.80 and 0.90 microgram/100 g BW.day), alone or in combination with T3 (0.10, 0.15, or 0.20 microgram/100 g BW.day). Placebo-infused intact rats served as euthyroid controls. Plasma and 12 tissues were obtained after 12 days of infusion. Plasma TSH and plasma and tissue T4 and T3 were determined by RIA. Iodothyronine deiodinase activities were assayed using cerebral cortex, pituitary, brown adipose tissue, liver, and lung. Circulating and tissue T4 levels were normal in all the groups infused with thyroid hormones. On the contrary, T3 in plasma and most tissues and plasma TSH only reached normal levels when T3 was added to the T4 infusion. The combination of 0.9 microgram T4 and 0.15 microgram T3/100 g BW.day resulted in normal T4 and T3 concentrations in plasma and all tissues as well as normal circulating TSH and normal or near-normal 5'-deiodinase activities. Combined replacement therapy with T4 and T3 (in proportions similar to those secreted by the normal rat thyroid) completely restored euthyroidism in thyroidectomized rats at much lower doses of T4 than those needed to normalize T3 in most tissues when T4 alone was used. If pertinent to man, these results might well justify a change in the current therapy for hypothyroidism.

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Only the Combined Treatment with Thyroxine and Triiodothyronine Ensures Euthyroidism in All Tissues of the Thyroidectomized Rat

Thyroid dysfunction and diabetes mellitus are closely linked. Several studies have documented the increased prevalence of thyroid disorders in patients with diabetes mellitus and vice versa. This review critically discusses the different underlying mechanisms linking type 1 and 2 diabetes and thyroid dysfunction to demonstrate that the association of these two common disorders is unlikely a simple coincidence. We assess the current state of knowledge on the central and peripheral control of thyroid hormone on food intake and glucose and lipid metabolism in target tissues (such as liver, white and brown adipose tissue, pancreatic β cells, and skeletal muscle) to explain the mechanism linking overt and subclinical hypothyroidism to type 2 diabetes and metabolic syndrome. We also elucidate the common susceptibility genes and the pathogenetic mechanisms contributing to the autoimmune mechanism involved in the onset of type 1 diabetes mellitus and autoimmune thyroid disorders. An untreated thyroid dysfunction can impair the metabolic control of diabetic patients, and this association can have important repercussions on the outcome of both of these disorders. Therefore, we offer recommendations for the diagnosis, management, and screening of thyroid disorders in patients with diabetes mellitus, including the treatment of diabetic patients planning a pregnancy. We also discuss the major causes of failure to achieve an optimal management of thyroid dysfunction in diabetic patients and provide recommendations for assessing and treating these disorders during therapy with antidiabetic drugs. An algorithm for a correct approach of these disorders when linked is also provided.

Thyroid Dysfunction and Diabetes Mellitus: Two Closely Associated Disorders.

Is the fetal thyroid already capable to increase its iodide uptake in response to iodine deficiency? To answer this question, we analyzed the expression of the Na(+)/I(-) symporter and several other genes in the thyroid of rat fetuses at 21 d of gestation from control mothers presenting a mild or more severe iodine deficiency. Female rats were placed on a low iodine diet, not supplemented, or supplemented with iodide or perchlorate for 3 months. The maternal and fetal thyroidal iodide uptake was measured 24 h after injection of 10 microCi Na (125)I into the dams. The absolute iodide uptake of the maternal thyroid was unchanged in a low iodine diet, not supplemented, compared with one supplemented with iodide. In contrast, the fetal thyroid absolute iodide uptake of a low iodine diet, not supplemented, and one supplemented with perchlorate was decreased by 70% and 95% compared with that supplemented with iodide. Na(+)/I(-) symporter mRNA was detected in the fetal thyroid of supplemented with iodide and increased about 2- and 4- fold in the thyroid of fetuses from a low iodine diet, not supplemented, and one supplemented with perchlorate, respectively. Na(+)/I(-) symporter expression was induced in the fetal side of the placenta in both a low iodine diet, not supplemented, and one supplemented with perchlorate; in contrast, Na(+)/I(-) symporter mRNA was never detected in the maternal side of the placenta. Fetal thyroid thyroglobulin and type I deiodinase mRNA contents were only significantly increased with a diet supplemented with perchlorate. Glucose transporter 4 mRNA was decreased in the fetal thyroid of both a low iodine diet, not supplemented, and one supplemented with perchlorate compared with one supplemented with iodide. In conclusion, although the up-regulation of Na(+)/I(-) symporter expression in fetal thyroid and placenta in the low iodine diet, not supplemented group did not lead to restoration of a normal absolute iodide uptake, our data show that all adaptive and/or defending mechanisms against iodine deficiency are already present in the fetus.

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The expression of the sodium/iodide symporter is up-regulated in the thyroid of fetuses of iodine-deficient rats.

Diabetes mellitus and fasting are both associated with low plasma thyroid hormone concentrations and loss of body weight. To discriminate between the separate effects of energy shortage and insulin, we studied control rats, diabetic rats (DM), DM rats treated with insulin (DMI), and rats after modified fasting (MF1 and MF2; 70 and 30% of normal daily food intake, respectively). In double-isotopic equilibrium experiments, we determined the tissue thyroxine (T4) and triiodothyronine (T3) concentrations and the contribution of local T4-to-T3 conversion to total T3 in rat tissues; thyroidal T4 and T3 secretion and extrathyroidal T3 production were calculated. In DM and DMI rats, plasma T4 and T3 decreased; in MF1 and MF2 rats, only plasma T4 decreased. Thyroidal T4 secretion decreased, whereas that of T3 remained normal. The decrease in tissue T4 in MF and DM rats paralleled the decrease in plasma T4. Although plasma T3 did not differ in DM and DMI rats, total T3 concentrations in all tissues were not the same due to changed uptake of T3 from plasma and local T4-to-T3 conversion; these changes were not found in several tissues of MF1 and MF2 rats. Our results suggest that the decrease in tissue T4 during diabetes mellitus is due to the decrease in plasma T4 caused by the decreased thyroidal secretion, possibly due to intracellular energy shortage. The changes in tissue T3 during diabetes mellitus are only partly attributable to the same phenomenon; in several tissues, the decrease in T3 seems more related to the lack of insulin.

Effects of streptozocin-induced diabetes and food restriction on quantities and source of T4 and T3 in rat tissues.

The uptake of iodide in thyroid epithelial cells is mediated by the sodium/iodide symporter (NIS). The uptake of iodide is of vital importance for thyroid physiology and is a prerequisite for radioiodine therapy in thyroid cancer. Loss of iodide uptake due to diminished expression of the human NIS (hNIS) is frequently observed in metastasized thyroid cancer. So far, no animal model for the study of radioiodine therapy in thyroid cancer has been available. Strategies to restore iodide uptake in thyroid cancer include the exploration of hNIS gene transfer into hNIS defective thyroid cancer. We have performed a stable transfection of hNIS into the hNIS defective follicular thyroid carcinoma cell line FTC133. Stably transfected colonies exhibited high uptake of Na125I, which could be blocked completely with sodium perchlorate. hNIS transfected FTC133 and non-transfected cell lines injected subcutaneously in nude mice formed tumors after 6 weeks. Iodide uptake in the hNIS transfected tumor was much higher than in non-transfected tumor, but a rapid release of radioactivity from the hNIS transfected tumor was observed. Further studies are necessary to investigate the role of hNIS in relation to other thyroid specific proteins in iodide metabolism in thyroid cancer.

Expression of the human sodium/iodide symporter (hNIS) in xenotransplanted human thyroid carcinoma.

In man, GHRH has been shown to potentiate the TSH-releasing activity of TRH. To study the way by which GHRH affects TRH-stimulated TSH release, we examined the effect of GHRH (1-29)NH2 on basal and stimulated TSH secretion in intact male rats and superfused dispersed rat pituitary cells. In the intact rats, GHRH(1-29)NH2 potentiated TRH-stimulated TSH release in the evening, but potentiation was not observed in the morning and in dispersed pituitary cells. Basal TSH levels were not changed by GHRH(1-29)NH2. It is concluded that GHRH(1-29)NH2 potentiates the TSH-releasing activity of TRH in the evening in rats possibly through suprahypophyseal disinhibition.

J.P. Schröder van der Elst

Papers

The expression of the sodium/iodide symporter is up-regulated in the thyroid of fetuses of iodine-deficient rats.

Effects of streptozocin-induced diabetes and food restriction on quantities and source of T4 and T3 in rat tissues.

Expression of the human sodium/iodide symporter (hNIS) in xenotransplanted human thyroid carcinoma.

The effect of GHRH on TSH release in rats in vivo and in vitro

Selenium and iodine status of animal and man: is there a relation to persistent enlargement of thyroids in adolescence?