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At least 397 records · Page 22Linked to original sources
PubMed1998

Amphibian metamorphosis as a model for studying the developmental actions of thyroid hormone.

The thyroid hormones L-thyroxine and triiodo-L-thyronine have profound effects on postembryonic development of most vertebrates. Analysis of their action in mammals is vitiated by the exposure of the developing foetus to a number of maternal factors which do not allow one to specifically define the role of thyroid hormone (TH) or that of other hormones and factors that modulate its action. Amphibian metamorphosis is obligatorily dependent on TH which can initiate all the diverse physiological manifestations of this postembryonic developmental process (morphogenesis, cell death, re-structuring, etc.) in free-living embryos and larvae of most anurans. This article will first describe the salient features of metamorphosis and its control by TH and other hormones. Emphasis will be laid on the key role played by TH receptor (TR), in particular the phenomenon of TR gene autoinduction, in initiating the developmental action of TH. Finally, it will be argued that the findings on the control of amphibian metamorphosis enhance our understanding of the regulation of postembryonic development by TH in other vertebrate species.

Amphibians↗
PubMed1999

Amphibian metamorphosis as a model for studying the developmental actions of thyroid hormone.

The thyroid hormones L-thyroxine and triiodo-L-thyronine have profound effects on postembryonic development of most vertebrates. Analysis of their action in mammals is vitiated by the exposure of the developing foetus to a number of maternal factors which do not allow one to specifically define the role of thyroid hormone (TH) or that of other hormones and factors that modulate its action. Amphibian metamorphosis is obligatorily dependent on TH which can initiate all the diverse physiological manifestations of this postembryonic developmental process (morphogenesis, cell death, re-structuring, etc.) in free-living embryos and larvae of most anurans. This article will first describe the salient features of metamorphosis and its control by TH and other hormones. Emphasis will be laid on the key role played by TH receptor (TR), in particular the phenomenon of TR gene autoinduction, in initiating the developmental action of TH. Finally, it will be argued that the findings on the control of amphibian metamorphosis enhance our understanding of the regulation of postembryonic development by TH in other vertebrate species.

Amphibians↗
PubMed2002

The effects of endocrine-disrupting chemicals on thyroid hormone binding to Xenopus laevis transthyretin and thyroid hormone receptor.

We investigated the effects of medical, industrial and agricultural chemicals on 3,3',5-L-[125I]triiodothyronine ([125I]T3) binding to purified recombinant Xenopus laevis (X. laevis) transthyretin (xTTR), a plasma thyroid hormone-binding protein, and to the ligand-binding domain of thyroid hormone receptor-beta (xTR LBD). xTTR derived from X. laevis serum had about 80 times higher affinity for T3 than for L-thyroxine. The xTTR's relative affinities for diethylstilbestrol, pentachlorophenol and ioxynil were 10(-1)- to 10(-2)-fold less than that for T3. However, all chemicals investigated had either a weak or no influence on [125I]T3 binding to xTR LBD. The concentration of diethylstilbestrol, the most potent chemical, required for 50% inhibition of [125I]T3 binding to xTR LBD was 10(4) times greater than that of unlabeled T3. These results indicate the existence of several chemicals that interact with xTTR but not with xTR LBD.

Animals↗
PubMed2004

Thyroid-hormone-dependent negative regulation of thyrotropin beta gene by thyroid hormone receptors: study with a new experimental system using CV1 cells.

The molecular mechanism involved in the liganded thyroid hormone receptor suppression of the TSHbeta (thyroid-stimulating hormone beta, or thyrotropin beta) gene transcription is undetermined. One of the main reasons is the limitation of useful cell lines for the experiments. We have developed an assay system using non-pituitary CV1 cells and studied the negative regulation of the TSHbeta gene. In CV1 cells, the TSHbeta-CAT (chloramphenicol acetyltransferase) reporter was stimulated by Pit1 and GATA2 and suppressed by T3 (3,3',5-tri-iodothyronine)-bound thyroid hormone receptor. The suppression was dependent on the amounts of T3 and the receptor. Unliganded receptor did not stimulate TSHbeta activity, suggesting that the receptor itself is not an activator. Analyses using various receptor mutants revealed that the intact DNA-binding domain is crucial to the TSHbeta gene suppression. Co-activators and co-repressors are not necessarily essential, but are required for the full suppression of the TSHbeta gene. Among the three receptor isoforms, beta2 exhibited the strongest inhibition and its protein level was the most predominant in a thyrotroph cell line, TalphaT1, in Western blotting. The dominant-negative effects of various receptor mutants measured on the TSHbeta-CAT reporter were not simple mirror images of those in the positive regulation under physiological T3 concentration.

Animals↗
PubMed2005

Behavioral deficits associated with fetal alcohol exposure are reversed by prenatal thyroid hormone treatment: a role for maternal thyroid hormone deficiency in FAE.

Children prenatally exposed to alcohol typically exhibit behavioral abnormalities, including hyperactivity, learning deficits, and an increased prevalence of depression. Similar impairments are found in children of hypothyroid mothers, and we have shown that alcohol-consuming rat dams have suppressed hypothalamic-pituitary-thyroid (HPT) function. Therefore, we hypothesized that suppressed maternal thyroid hormonal milieu may contribute to the deleterious consequences of prenatal alcohol exposure. We aimed first to confirm and then to reverse the behavioral deficits in the fetal alcohol exposed (FAE) rat offspring by administration of thyroxine (T4) to the alcohol-consuming dams. Adult offspring prenatally exposed to ethanol (FAE; 35% ethanol-derived calories), pair-fed (PF) or control (C) diets were tested in the Morris water maze (MWM), the forced swim test (FST), and the open field test (OFT) to assess spatial learning, depressive behavior, and exploratory behavior/anxiety, respectively. Adult FAE offspring took longer to locate a hidden platform in the MWM and showed increased depressive behavior in the FST both of which were reversed by administration of T4 to the alcohol-consuming mother. We found sex and brain region-specific alterations in expression of genes involved in these behaviors in FAE adult offspring. Specifically, decreased hippocampal GAP-43 mRNA levels in adult FAE females and decreased glucocorticoid receptor (GR) expression in the amygdala of male and female FAE offspring were observed. The decreased mRNA levels of GAP-43 and GR were normalized by T4 treatment to the alcohol-consuming mother. Our results suggest that the suppressed HPT function of the alcohol-consuming mother contributes to the behavioral and cognitive dysfunctions observed in the offspring.

Animals↗
PubMed1976

Effects of excess iodide and other anions on thyroid hormone secretion in normal or hypophysectomized rats treated with graded doses of thyroid hormone.

In order to obtain further information about the stimulatory action of excess iodide on thyroid hormone secretion in thyroxine (T4)-treated rats, experiments were performed in hypophysectomized rats, or rats treated with graded doses of T4 or triiodothyronine (T3).T3 as well as T4 played a permissive role in the production of the iodide effect in normal animals, but T3 was more effective than T4. Excess iodide stimulated thyroid hormone secretion in hypophysectomized animals, this finding being compatible with the hypothesis that, by inhibiting TSH secretion, T3 and T4 produced a condition in which excess iodide stimulated thyroid hormone secretion in intact rats. However, T4 played an additional role in thyroid hormone secretion by acting directly on the thyroid. In hypophysectomized animals, small doses of T4 stimulated thyroid hormone secretion, and this action was additive to that of excess iodide, whereas large doses of T4 were inhibitory and reduced the effectiveness of excess iodide. The stimulatory action on thyroid hormone secretion was specific for iodide and was not shared by other anions. The action of excess iodide was blocked by methimazole. We suggest that excess iodide stimulates thyroid hormone secretion by increasing intrathyroidal concentrations of cyclic AMP in the absence of TSH, and that this increase in cyclic AMP concentration is blocked by methimazole.

Animals↗
PubMed1997

Octreotide and bromocriptine suppress thyroid hormone levels and thyroid nodule in an acromegalic patient with nontoxic autonomous goiter.

An acromegalic patient with nontoxic autonomous goiter was sequentially treated with octreotide and bromocriptine. Before therapy, serum GH, PRL and insulin-like growth factor-I (IGF-I) levels were increased. Free T3 and free T4 were within the normal range with suppressed TSH levels, whereas 123Iodine-uptake of thyroid was 5.6% after 24 h. During treatment with octreotide and bromocriptine, serum GH, PRL, and IGF-I became normal and free T3 and free T4 were slightly but significantly decreased, but TSH levels remained very low. After thyroidectomy, thyroglobulin, free T3 and free T4 were further decreased, and the TSH levels were recovered to normal. These findings suggested that octreotide and bromocriptine inhibit the release of thyroid hormones from the autonomous thyroid gland directly or indirectly through the decline in IGF-I.

Acromegaly↗
PubMed1982

Thyroid hormone formation catalyzed by human thyroid peroxidase: a new and physiological measurement of thyroid peroxidase.

This report describes a method for measurement of TPO activity by the amount of thyroid hormone production. Thyroid hormone formation was accomplished by incubating purified iodine-poor Tg with human TPO for 60 min at 37 C in the presence of free DIT, KI, and an H2O2 source. Newly formed T3 and T4 were measured by radioimmunoassay of the Tg hydrolysates. With this method, TPO-catalyzed iodination of Tg and thyroid hormone formation were measured simultaneously from eight normal thyroid glands and 15 thyroid glands from MMI-treated patients with Graves' disease. Graves' disease TPO showed iodinating activity and T4 formation which was higher than that of TPO from normal thyroids, and there was a positive linear correlation between the iodinating activity and the amount of T4 formation. T3 production by highly active TPO, however, dissociates from the amount of T4 formation and the degree of Tg iodination. Thus, if the activity of TPO is to be measured by the amount of thyroid hormone production, T4 should be used rather than T3. The method of thyroid hormone formation described here provides a new and physiological measurement of TPO activity and should be useful for investigation of the role of human TPO in thyroid hormone formation.

Diiodotyrosine↗
PubMed1999

Different functions for the thyroid hormone receptors TRalpha and TRbeta in the control of thyroid hormone production and post-natal development.

The biological activities of thyroid hormones are thought to be mediated by receptors generated by the TRalpha and TRbeta loci. The existence of several receptor isoforms suggests that different functions are mediated by specific isoforms and raises the possibility of functional redundancies. We have inactivated both TRalpha and TRbeta genes by homologous recombination in the mouse and compared the phenotypes of wild-type, and single and double mutant mice. We show by this method that the TRbeta receptors are the most potent regulators of the production of thyroid stimulating hormone (TSH). However, in the absence of TRbeta, the products of the TRalpha gene can fulfill this function as, in the absence of any receptors, TSH and thyroid hormone concentrations reach very high levels. We also show that TRbeta, in contrast to TRalpha, is dispensable for the normal development of bone and intestine. In bone, the disruption of both TRalpha and TRbeta genes does not modify the maturation delay observed in TRalpha -/- mice. In the ileum, the absence of any receptor results in a much more severe impairment than that observed in TRalpha -/- animals. We conclude that each of the two families of proteins mediate specific functions of triiodothyronin (T3), and that redundancy is only partial and concerns a limited number of functions.

Animals↗
PubMed1999

Altered thyroid hormone binding to plasma lipoproteins in the syndrome of resistance to thyroid hormones.

Lipoproteins, especially HDL, are carriers of a small fraction of the thyroid hormones in plasma and participate in the intracellular transport of T4. In previous work we showed that a brief period of hypothyroidism alters the hormone distribution among the lipoproteins, causing a decrease in VLDL and LDL binding despite a relative increase in VLDL and LDL cholesterol, an increase in HDL binding, and a reversal of T4 and T3 binding to the smallest HDL size subgroup. The present study of three patients with thyroid hormone resistance and largely compensated hypothyroidism showed thyroid hormone distribution that differed markedly from both normal and hypothyroid subjects. The most striking difference was a much lower binding of both T4 and T3 to HDL and a much higher binding to LDL. If confirmed in a larger group of patients, this might serve as a marker for thyroid hormone resistance.

Cholesterol↗
PubMed1992

Transcriptional activity of a mutant thyroid hormone receptor beta in a family with generalized resistance to thyroid hormone.

We previously reported a family with generalized resistance to thyroid hormone (GRTH) which had a point mutation with codon 448 CCT (proline) being converted to ACT (threonine) in the thyroid hormone receptor (TR) beta. To characterize functional properties of the mutant TR beta, transient expression studies were performed in COS cells. A double stranded oligonucleotide encompassing thyroid hormone response element (TRE) derived from the rat GH gene was synthesized. We constructed chloramphenicol acetyl transferase (CAT) plasmid containing the thymidine kinase promoter under the control of the rat GH TRE. T3 induction of CAT activity by the mutant TR beta was significantly reduced as compared with that of the normal TR beta. This was observed in the presence of 0.5-50 nM T3, but not at 500 nM T3. When the normal and mutant TR beta were cotransfected, the mutant TR beta inhibited gene activation regulated by the normal TR beta. However, a high molar excess was necessary to significantly inhibit the function of the normal receptor. Additionally, the binding of in vitro synthesized mutant TR beta to TRE was preserved.

Animals↗
PubMed1994

Influence of clinical characteristics and parameters associated with thyroid hormone therapy on the bone mineral density of women treated with thyroid hormone.

Reports of reduced bone mineral density (BMD) in patients receiving long-term replacement and suppression therapy with L-thyroxine have generated considerable interest and controversy. A substantial literature has evolved, with interpretation of conflicting results obscured by a variety of confounding factors. We examined the BMD measurements of 202 white women who were taking thyroid hormone to determine the contribution to BMD of a number of clinical characteristics and parameters associated with thyroid hormone therapy. Measurements of BMD (N = 335 over 2.6 +/- 1.6 years) of the spine (L2-L4) were performed in 195 subjects. The BMD of three sites of the hip was measured (N = 247 over 1.8 +/- 1.1 years) in 157 subjects. The BMD of the proximal radius was also measured (N = 172 over 1.8 +/- 1.2 years) in 124 subjects. Increasing age and a history of previous thyrotoxicosis had a deleterious effect on spine BMD. Body mass index (BMI) was positively correlated with spine BMD. Dose of thyroid hormone, duration of therapy, type of underlying thyroid disease, history of thyroidectomy, or serum-free thyroxine index did not influence either the initial BMD or the change in spine BMD over time. In the hip, age correlated with a decrease, and BMI with an increase in BMD. A history of previous thyrotoxicosis was associated with a decrease in hip BMD at all three sites (0.05 < p < 0.10). No other clinical parameters significantly influenced either the initial BMD or the change in hip BMD over time. Increasing age and dose of thyroid hormone, and a prior history of thyrotoxicosis had a deleterious effect on the BMD at the proximal radius. In summary, thyroid hormone therapy was not associated with a significant effect on BMD of the spine or hip, but a decreased BMD of the proximal radius was related to both previous thyrotoxicosis and to dose of thyroid hormone.

Adult↗
PubMed1985

[Changes in thyroid hormone status after injections of iodinated contrast media].

Administration of four different contrast media exerted slight but significant and prolonged effects on the hormonal thyroid status, in 53 euthyroid subjects (four subgroups), without any clinical expression of dysthyroidism. Changes in serum T3, rT3 and T4 demonstrated different trends for each iodinated compound, probably depending on the regulatory thyroid mechanisms, and CM pharmacokinetics. Plasma profiles of free fractions (FT3, FT4) slightly reflected consensual changes with circulating iodothyronines, at various time periods of study, demonstrating high correlation indexes with total fractions. The five hormones profiles correlation study suggest that different mechanisms could be responsible for some features encountered of "low T3 syndrome". These effects may be not only equivalent to giving various sources of iodide, but suggest more complex mechanisms. It is apparent that man has a remarkable and possibly unique system of homeostatic thyroid hormone regulation.

Angiography↗
PubMed2004

Regulation of fibronectin by thyroid hormone receptors.

Thyroid hormones regulate growth, development, differentiation, and metabolic processes by interacting with and activating thyroid hormone receptors and associated pathways. We investigated the triiodothyronine (T3) modulation of gene expression, in human hepatocellular carcinoma cell lines, via a PCR-based cDNA subtraction method. Here we present further data on one of the T3-upregulated genes, fibronectin (FN). We demonstrate that the induction of FN protein expression by T3 in TRalpha1 and TRbeta1 over-expressing cells was time and dose-dependent at the mRNA and protein levels. Blockade of protein synthesis by cycloheximide almost completely inhibited the concomitant induction of FN mRNA by T3, indicating that T3 indirectly regulates FN. Furthermore, nuclear-run on and FN promoter assay clearly can specifically increase the number of FN transcriptional demonstrated that the presence of T3 initiations. In addition, we further confirmed that the up-regulation of FN by T3 was mediated, at least in part, by transforming growth factor-beta (TGF-beta), because the induction of FN was blocked in a dose-dependent manner by the addition of TGF-beta neutralizing antibody. In an effort to elucidate the we demonstrated the involvement of the signaling pathways involved in the activation of FN by T3, mitogen activated protein kinase/c-Jun N-terminal kinase/p38 MAPK (MAPK/JNK/p38) pathway. Although T3 induces the expression of TGF-beta, neither wild-type nor dominant-negative Smad3 or Smad4 over-expression affected the activation of FN by T3. Thus, we demonstrate that T3 regulates FN gene expression indirectly at the transcriptional level, with the participation of the MAPK/JNK/p38 pathway and the TGF-beta signaling pathway but independent of Smad3/4.

Carcinoma, Hepatocellular↗
PubMed1998

Thyroid hormone action on liver, heart, and energy expenditure in thyroid hormone receptor beta-deficient mice.

Thyroid hormone (TH) responsive genes can be both positively and negatively regulated by TH through receptors (TR) alpha and beta expressed in most body tissues. However, their relative roles in the regulation of specific gene expression remain unknown. The TR beta knockout mouse, which lacks both TR beta1 and TR beta2 isoforms, provides a model to examine the role of these receptors in mediating TH action. TR beta deficient (TR beta-/-) mice that show no compensatory increase in TR alpha, and wild-type (TR beta+/+) mice of the same strain were deprived of TH by feeding them a low iodine diet containing propylthiouracil, and were then treated with supraphysiological doses of L-T3 (0.5, 5.5, and 25 microg/day/mouse). TH deprivation alone increased the serum cholesterol concentration by 25% in TR beta+/+ mice and reduced it paradoxically by 23% in TR beta-/- mice. TH deprivation reduced the serum alkaline phosphatase (AP) concentration by 31% in TR beta+/+ mice but showed no change in the TR beta-/- mice. Treatment with L-T3 (0.5 to 25 microg/mouse/day) caused a 57% decrease in serum cholesterol and a 231% increase in serum AP in the TR beta+/+ mice. The TR beta-/- mice were resistant to the L-T3 induced changes in serum cholesterol and showed increase in AP only with the highest L-T3 dose. Basal heart rate (HR) in TR beta-/- mice was higher than that of TR beta+/+ mice by 11%. HR and energy expenditure (EE) in both TR beta+/+ and TR beta-/- mice showed similar decreases (49 and 46%) and increases (49 and 41%) in response to TH deprivation and L-T3 treatment, respectively. The effect of TH on the accumulation of messenger RNA (mRNA) of TH regulated liver genes was also examined. TH deprivation down regulated spot 14 (S14) mRNA and showed no change in malic enzyme (ME) mRNA in both TR beta+/+ and TR beta-/- mice. In contrast treatment with L-T3 produced an increase in S14 and ME but no change in TR beta-/- mice. From these results, it can be concluded that regulation of HR and EE are independent of TR beta. With the exception of serum cholesterol concentration and liver ME mRNA accumulation, all other markers of TH action examined during TH deprivation exhibited the expected responses in the absence of TR beta. Thus, as previously shown for serum TSH, TR beta is not absolutely necessary for some changes typical of hypothyroidism to occur. In contrast, except for HR and EE, the full manifestation of TH-mediated action required the presence of TR beta.

Alkaline Phosphatase↗
PubMed1995

Mitochondrial permeability transition is induced by in vivo thyroid hormone treatment.

Thyroid hormone treatment in vivo results in activation of mitochondrial Ca2+ efflux and temperature-dependent enhanced swelling of Ca(2+)-loaded rat liver mitochondria. Thyroid hormone-induced swelling was effectively prevented in the presence of excess EGTA or cyclosporin A. Thyroid hormone treatment similarly resulted in a dramatic decrease in mitochondrial membrane potential (80%), proton gradient (45%), and proton motive force (69%) measured in Ca(2+)-loaded mitochondria. All three parameters were essentially restored to euthyroid values in the presence of excess EGTA or cyclosporin A. Mitochondrial energy-linked transhydrogenase activity measured in the presence of Ca2+ was 33% increased and 38% decreased in hypothyroid and L-T3-treated hypothyroid rats, respectively, compared to that in euthyroid rats. Hence, in vivo thyroid hormone treatment may induce mitochondrial permeability transition mediated by the cyclosporin A-sensitive permeability transition pore.

Animals↗
PubMed1993

Interaction of human thyroid hormone receptor beta with transcription factor TFIIB may mediate target gene derepression and activation by thyroid hormone.

The human thyroid hormone receptor beta (hTR beta) is capable of both transcriptional silencing and hormone-dependent activation. However, the detailed mechanism of this transcriptional regulation remains to be elucidated. One possibility is that hTR beta interacts directly with factors of the basal transcriptional machinery, thereby modulating basal promoter activity in a direct manner, as has been shown for other transcription factors. Here, we show that hTR beta interacts specifically with the human basal transcription factor TFIIB. Deletion analysis revealed two contact sites in the receptor: one is located in the N terminus, while the other is part of the ligand-binding domain (LBD) and is located at the C terminus. Interestingly, each receptor contact site interacts with different sites in TFIIB. Cotransfection experiments revealed that, when fused to the DNA-binding domain of yeast transcription factor GAL4, the C-terminal interaction site of hTR beta was transcriptionally inactive; however, when it was cotransfected with the remaining part of the LBD on a separate molecule, silencing function was restored. In agreement with that, we show that thyroid hormone is able to significantly decrease the interaction of its receptor LBD with TFIIB. Our data suggest that hTR beta acts as a transcriptional silencer by interacting with TFIIB and that thyroid hormone may act in part by preventing transcriptional repression at this level.

Actins↗
PubMed1993

[Thyroid hormones and depressive disorders--clinical overview and perspectives. Part 2: Thyroid hormones and the central nervous system--basic research].

This paper briefly reviews present knowledge on the uptake, distribution, metabolization, and functions of thyroid hormones in the central nervous system. So far, multiple isolated effects of these hormones could be shown; e.g. a modulation of noradrenergic, serotonergic, and dopaminergic receptor function, and an influence on second messenger, calcium homeostasis, axonal transport mechanisms, and morphology. All these effects are, however, highly specific with respect to brain area and both the biochemical mechanisms and the physiological importance are poorly understood. Antidepressants and neuroleptics influence thyroid hormone metabolism in the CNS. The respective effects depend on the area under investigation, the circadian rhythm, and the specific drug. Future research should investigate primarily the biochemical mechanisms of thyroid hormone action on the central nervous system. Furthermore, it seems worthwhile to examine whether or not the different effects of psychopharmacological drugs on CNS thyroid hormone metabolism are involved in their mechanisms of action.

Brain↗