Tissue T3 Research Articles

Characterization of Recombinant Xenopus laevis Type I Iodothyronine Deiodinase: Substitution of a Proline Residue in the Catalytic Center by Serine (Pro132Ser) Restores Sensitivity to 6-Propyl-2-Thiouracil

In frogs such as Rana and Xenopus, metamorphosis does not occur in the absence of a functional thyroid gland. Previous studies indicated that coordinated development in frogs requires tissue and stage-dependent type II and type III iodothyronine deiodinase expression patterns to obtain requisite levels of intracellular T(3) in tissues at the appropriate stages of metamorphosis. No type I iodothyronine deiodinase (D1), defined as T(4) or reverse T(3) (rT3) outer-ring deiodinase (ORD) activity with Michaelis constant (K(m)) values in the micromolar range and sensitivity to 6-propyl-2-thiouracil (6-PTU), could be detected in tadpoles so far. We obtained a X. laevis D1 cDNA clone from brain tissue. The complete sequence of this clone (1.1 kb, including poly A tail) encodes an ORF of 252 amino acid residues with high homology to other vertebrate D1 enzymes. The core catalytic center includes a UGA-encoded selenocysteine residue, and the 3' untranslated region (about 300 nt) contains a selenocysteine insertion sequence element. Transfection of cells with an expression vector containing the full-length cDNA resulted in generation of significant deiodinase activity in the homogenates. The enzyme displayed ORD activity with T(4) (K(m) 0.5 microm) and rT3 (K(m) 0.5 microm) and inner-ring deiodinase activity with T(4) (K(m) 0.4 microm). Recombinant Xenopus D1 was essentially insensitive to inhibition by 6-PTU (IC(50) > 1 mm) but was sensitive to gold thioglucose (IC(50) 0.1 mum) and iodoacetate (IC(50) 10 microm). Because the residue 2 positions downstream from the selenocysteine is Pro in Xenopus D1 but Ser in all cloned PTU-sensitive D1 enzymes, we prepared the Pro132Ser mutant of Xenopus D1. The mutant enzyme showed strongly increased ORD activity with T(4) and rT3 (K(m) about 4 microm) and was highly sensitive to 6-PTU (IC(50) 2 microm). Little native D1 activity could be detected in Xenopus liver, kidney, brain, and gut, but significant D1 mRNA expression was observed in juvenile brain and adult liver and kidney. These results indicate the existence of a 6-PTU-insensitive D1 enzyme in X. laevis tissues, but its role during tadpole metamorphosis remains to be defined.

Characterization of skeletal phenotypes of TRα1PV and TRβPV mutant mice: implications for tissue thyroid status and T3 target gene expression

Bone development is extremely sensitive to alterations in thyroid status. Recently, we analyzed the skeletal phenotypes of mice with the dominant negative resistance to thyroid hormone (RTH) mutation PV targeted to either the thyroid hormone receptor (TR) α1 or β gene. This perspective summarizes our findings to date and explores the wider implications for thyroid status and T3 target gene expression in individual tissues.

Thyroid and parathyroid hormones and calcium homeostasis

The thyroid gland is under the control of thyroid stimulating hormone (TSH) from the pituitary. It secretes thyroxine (T4) and triiodothyronine (T3). Iodine is essential for the synthesis of thyroid hormones. T4 is probably converted to T3 in peripheral tissues. Thyroid hormones have a role in growth and development but their principal effect is the control of basal metabolic rate. Deficiency or excess affects all the tissues of the body, reducing or increasing the metabolic rate, resulting in hypothermia or hyperthermia, respectively. Deficiency during development produces mental retardation. Lack of iodine leads to thyroid swelling (goitre) caused by continuing stimulation by TSH. Calcium is one of the most tightly controlled ions in the body; abnormalities can produce muscle paralysis. Bone is the major store of calcium. Calcium reabsorption by the kidney is controlled by parathyroid hormone (PTH) produced by the parathyroid glands, which lie in the posterior part of the lobes of the thyroid gland. PTH secretion is controlled by blood calcium concentrations. Phosphate metabolism is intimately bound up with the control of calcium levels, as is the metabolism of vitamin D, which stimulates the absorption of calcium from the gastrointestinal tract and, in part, from the kidney.

Tissue Thyroid Hormone Levels in Critical Illness

Pronounced alterations in serum thyroid hormone levels occur during critical illness. T3 decreases and rT3 increases, the magnitudes of which are related to the severity of disease. It is unclear whether these changes are associated with decreased tissue T3 concentrations and, thus, reduced thyroid hormone bioactivity. PATIENTS AND STUDY QUESTIONS: We therefore investigated, in 79 patients who died after intensive care and who did or did not receive thyroid hormone treatment, whether total serum thyroid hormone levels correspond to tissue levels in liver and muscle. Furthermore, we investigated the relationship between tissue thyroid hormone levels, deiodinase activities, and monocarboxylate transporter 8 expression. Tissue iodothyronine levels were positively correlated with serum levels, indicating that the decrease in serum T3 during illness is associated with decreased levels of tissue T3. Higher serum T3 levels in patients who received thyroid hormone treatment were accompanied by higher levels of liver and muscle T3, with evidence for tissue-specific regulation. Tissue rT3 and the T3/rT3 ratio were correlated with tissue deiodinase activities. Monocarboxylate transporter 8 expression was not related to the ratio of the serum over tissue concentration of the different iodothyronines. Our results suggest that, in addition to changes in the hypothalamus-pituitary-thyroid axis, tissue-specific mechanisms are involved in the reduced supply of bioactive thyroid hormone in critical illness.

Cold Adaptation and Thyroid Hormone Metabolism

Resting oxygen consumption and energy expenditure is sensitive to slight alterations in thyroid function. This means that timing and magnitude of cold adaptation would to some extent depend on thyroid function. Local thyroid hormone metabolism is important for energy expenditure and dissipation of heat in special tissues. Recruitment of brown adipocytes and upregulation of uncoupling protein 1 in mitochondria depends on high tissue T3 concentrations. Most of this T3 is derived from local 5' deiodination of T4. Brown fat is vital for cold exposed mice and rats, and may be important for temperature adaptation in human neonates. The role of thyroid hormone metabolism in adult human cold adaptation has not been finally clarified. Hypothetically, cold exposure may enhance T3 production by deiodination of T4 in skeletal muscle, which may enhance heat production in muscle via a change in muscle fiber type. Another hypothetical possibility is recruitment of brown adipocytes embedded in white adipose tissue in human adults. Understanding cold adaptation in human adults may lead to development of new drugs against obesity.

Potential uses of T 3 in the treatment of human disease

Treatments for hypothyroidism have been available since the late 19th century, and have been continually improved by advancing our understanding of thyroid hormone pharmacology. Thyroxine (T4) monotherapy is currently the standard of care, but may leave some hypothyroid symptoms unaddressed. Triiodothyronine (T3), formed by the monodeiodination of T4, is the biologically active form of thyroid hormone based upon its ability to regulate gene expression at the nuclear level. A variety of human and animal studies have raised the question of whether T4 monotherapy is sufficient to restore tissue and organ intracellular T3 levels to normal. Furthermore, some evidence, albeit controversial, suggests that the addition of T3 (Cytomel) to T4 replacement therapy may improve patients' quality of life, psychometric performance and mood. Further developmental work is needed to refine T3 therapy in a way to enhance efficacy and lower the potential for unwanted effects.

Independence of hyperleptinemia-induced fat disappearance from thyroid hormone

Sustained hyperleptinemia induced in normal rats causes the rapid disappearance of body fat. This is attributed to a marked increase in uncoupled fatty acid oxidation in the white adipocytes, which also occurs in hyperthyroidism. Because hyperleptinemic rats have normal plasma T3 or T4 levels, we tested the possibility of “localized hyperthyroidism” due to increased conversion of T4 to T3 in the adipose tissue. We therefore induced sustained hyperleptinemia in normal rats by intravenous injection of recombinant adenovirus containing the leptin cDNA (AdCMV-leptin) and measured the mRNA and the activity of enzymes involved in T4 metabolism in the disappearing fat. The epididymal fat pad remnants exhibited a decrease in mRNA of deiodinase 1 and a doubling of deiodinase 2 mRNA ( p < 0.05), but their enzyme activities did not differ from normoleptinemic controls. To determine if thyroid hormone was required for the fat-wasting action of hyperleptinemia, we infused AdCMV-leptin into rats made athyroid by total thyroidectomy or by methimazole therapy. The fat loss in hyperleptinemic athyroid rats was as great as in euthyroid controls. We conclude that the fat-wasting effect of sustained hyperleptinemia does not involve “local hyperthyroidism” in white adipose tissue and does not require thyroid hormone.

Multiple messenger ribonucleic acid variants regulate cell-specific expression of human thyroid hormone receptor beta1.

Thyroid hormones are essential for development, growth, and metabolism and act via T3 receptors (TR) alpha and beta. The THRA and THRB genes have discrete physiological roles but their mRNAs are expressed widely in overlapping patterns. There is poor correlation between TR mRNA and protein, indicating that expression may be regulated by posttranscriptional mechanisms. Differences in the relative levels of expressed TRalpha and beta proteins have been suggested to modulate tissue T3 responsiveness. We determined the structure of the human THRB gene, cloned seven alternately spliced 5'-untranslated region (5'-UTR) TRbeta1 mRNAs, and identified five polyadenylation position elements in the 3'-UTR. At least six TRbeta1 mRNAs between 1.35 and 7.5 kb in length were expressed in discrete temporospatial patterns in fetal and adult human tissues. The 5'-UTRs contained up to seven upstream short open reading frames, which did not influence the structure of the TRbeta1 protein. In transfection studies, 5'-UTRs exerted cell-specific effects on mRNA expression but consistently reduced protein expression. Furthermore, each 5'-UTR strongly inhibited translation in vitro. Thus, developmental and tissue-specific expression of human thyroid hormone receptor beta1 5'-UTR mRNAs may regulate T3-responsiveness in target tissues by modulating TRbeta protein translation and thereby controlling the ratio of expressed TRalpha and -beta proteins.

Ex vivo stimulation of renal transport of the cytostatic drugs methotrexate, cisplatin, topotecan (Hycamtin) and raltitrexed (Tomudex) by dexamethasone, T3 and EGF in intact human and rat kidney tissue and in human renal cell carcinoma.

Previous experiments have shown that both in vivo and in vitro pre-treatment with various hormones increases the renal transport capacity for weak organic acids, such as PAH, in rats. The aim of the present study was to test whether or not accumulation of the anticancer drugs methotrexate (MTX), cisplatin (CP), raltitrexed (Tomudex) and topotecan (Hycamtin) can be increased in intact, healthy rat and human renal cortical slices and in human renal cell carcinoma (RCC). Intact, healthy human tissue was obtained from tumour bearing kidneys of patients suffering from RCC. Experiments were intended as a new approach to overcome so-called multidrug resistance. Kidney tissue slices were incubated for 24 h in William's medium E containing various concentrations of dexamethasone, T(3), or EGF. Thereafter slices were placed in anticancer drug containing Cross-Taggart medium and the drug uptake into kidney tissue was measured for 2 h. In intact rat and human renal tissue slices, the uptake of p-aminohippurate (PAH = reference substance) increased significantly after incubation in dexamethasone containing medium (134% and 156%, respectively). There were no stimulating effects of either T(3) or EGF on PAH accumulation. On the other hand, only the accumulation of MTX, but not of CP, raltitrexed or topotecan, was significantly enhanced after hormone pre-treatment both in intact renal tissue and in RCC. A stimulation of renal PAH accumulation can be performed ex vivo, as reported previously, both in intact rat and human renal cortical slices and in RCC. Discrepancies between the effects of dexamethasone and T(3) or EGF indicate different modes of action of these substances at the cellular level. Unfortunately, with the exception of MTX, the uptake of anticancer drugs can not be stimulated effectively ex vivo in human RCC tissue by the substances used. Evidently the transport of these anticancer drugs out of the kidney cells is more effective than their uptake.

Transthyretin as a thyroid hormone carrier: function revisited.

Thyroid hormones are essential for normal mammalian development and for normal metabolism. Thyroxine (T4) is the principal product synthesized by the thyroid follicles, and triiodothyronine (T3), the biologically active hormone, derives mainly from tissue T4 deiodination. More than 99% of the circulating hormone is bound to plasma proteins, mainly to thyroxine-binding globulin, transthyretin and albumin in man, and to transthyretin and albumin in rodents. The role of plasma proteins in the transport of hormones to target tissues has, for a long time, been controversial. The liver and the choroid plexus are the major sites of transthyretin synthesis, tissues from which transthyretin is secreted into the blood and the cerebrospinal fluid, respectively. Transthyretin has been proposed to mediate thyroid hormone transfer into the tissues, particularly into the brain across the choroid-plexus-cerebrospinal fluid barrier. Studies in a transthyretin-null mice strain have shown conclusively that transthyretin is not indespensable for thyroid hormones' entry into the brain and other tissues, nor for the maintenance of an euthyroid status. An euthyroid status is also observed in man totally deprived of thyroxine-binding globulin and in rats without albumin. Taken together, these results exclude dependence of thyroid hormone homeostasis on any major plasma carrier per se. This evidence agrees with the free hormone hypothesis which states that the biologically significant fraction, that is taken up by the tissues, is the free circulating hormone.

Thyroid of Lake Sturgeon, Acipenser fulvescens: I. Hormone Levels in Blood and Tissues

The authors measured thyroid hormone (TH) levels in plasma, whole carcass, and tissues of cultured 2-year-old immature lake sturgeon held in fresh water and in serum of adults at spawning time from the Winnipeg River. Circulating thyroxine (T4) and 3,5,3′-triiodothyronine (T3) levels were low (T4 ∼ 0.3 ng/ml, T3 ∼ 0.2 ng/ml) in all cultured fish and most adults, but a few of the latter had exceptionally high T4 and T3 levels. The percentages of blood TH found in erythrocytes were 19.5% (T4), 6.1% (T3) and 6.9% (reverse T3 = rT3). Equilibrium dialysis showed much higher percentages of plasma free (F) FT4 (1.1%), FT3 (0.4%), and FrT3 (3,3′,5′-triiodothyronine = rT3, 3.0%) for sturgeon than for rainbow trout, indicating more limited TH binding to sturgeon plasma sites. However, concentrations of FT4 and FT3 were close to those reported for salmonids. T3 levels exceeded T4 levels in most extrathyroidal tissues of cultured sturgeon but in most cases were less than 0.1 ng/g and 10 to 100 times lower than reported for salmonids; only the whole brain T3 concentration (5.6 ng/g) approached that of salmonids. The digested thyroid contained 21.3 ng T3/g and 2.4 ng T4/g. The authors conclude that lake sturgeon have a low circulating reserve of bound TH but have FT4 and FT3 concentrations close to those of salmonids. The high thyroidal T3:T4 ratio and low tissue T4 levels suggest that, in contrast to teleosts studied to date, the thyroid may be a significant direct source of T3, the primary TH in sturgeon tissues. High serum T4 and T3 levels in some sturgeon at spawning time may suggest a thyroid role in reproduction.

Endocrine disruption: thyroid dysfunction in mummichogs ( Fundulus heteroclitus) from a polluted habitat

Mummichogs ( Fundulus heteroclitus) from Piles Creeks (PC), New Jersey (a polluted site), are sluggish and show poorer prey capture and predator avoidance than reference fish from Tuckerton (TK). The behavioral dysfunction of the PC fish may be associated with thyroid impairment due to endocrine disruption. In this study, we compared thyroid histology and thyroid hormones in the two populations and determined experimentally whether the polluted environment could alter thyroid hormone levels. PC fish had larger thyroid follicles, greater follicle cell heights, and contained higher plasma thyroxine (T4) levels than TK fish. However, there were no significant differences in either plasma or tissue triiodothyronine (T3). TK fish held in simulated PC environments had higher plasma T4 and lower plasma T3 than field-sampled fish. PC fish held in clean water had lower plasma T4 and T3 than field-sampled fish. In either case, there was no significant difference in tissue T3 content. The contaminants in PC alter thyroid structure and function, which may relate to the behavioral differences between fish from the polluted and reference sites.

Thyroidal status of mummichogs (Fundulus heteroclitus) from a polluted versus a reference habitat

AbstractPrevious studies have demonstrated that mummichogs (Fundulus heteroclitus) collected from Piles Creek (PC), New Jersey, USA (a site polluted with heavy metals and organic materials), were sluggish and showed poorer prey capture and predator avoidance than those from a reference site (Tuckerton [TK], NJ, USA). We hypothesized that the behavioral dysfunction of the PC fish might be associated with thyroid impairment due to toxic exposures. In this preliminary study, we compared thyroid histology and thyroid hormones in the two populations and experimentally determined whether a polluted or an unpolluted environment could alter levels of thyroid hormones. In comparison to TK, PC fish had larger thyroid follicles and greater follicle epithelial cell heights and also contained significantly higher plasma thyroxine (T4) levels. However, no significant differences were found in levels of either plasma or tissue triiodothyronine (T3). The TK fish raised in a simulated PC environment contained higher plasma T4 and lower plasma T3 levels than those sampled from the field. The PC fish raised in clean water showed a reduction in both plasma T4 and T3 levels in comparison to field‐sampled fish. In either case, no significant difference was found in tissue T3 content. The contaminants in PC may cause the differences in thyroid structure and function, which may be partly responsible for the behavioral differences between fish from the polluted PC and from the reference TK.

Effect of triiodothyronine administration on reduced expression of type 1 iodothyronine deiodinase messenger ribonucleic acid in streptozotocin-induced diabetic rats.

To examine the mechanism behind a decrease in type 1 iodothyronine deiodinase (D1) gene expression in diabetes mellitus, we evaluated the effect of administering T3 and/or insulin on D1 activity and the mRNA levels in the liver of streptozotocin (STZ)-induced diabetic rats. STZ (100 mg/kg BW) was administered to male Wistar rats, and the rats were divided into four groups as follows: (1) STZ alone, (2) STZ and T3 (5 microg/100 g BW daily for 7 days), (3) STZ and insulin (intermediate-acting insulin, 4 units/100 g BW daily for 7 days), and (4) STZ, T3, and insulin. Blood glucose levels increased in Group 1, but were normalized in Group 3. Serum T3 levels were markedly decreased in Group 1. They were within normal limits 24 hours after the last administration of T3 in Group 2 and after the administration of insulin in Group 3. T3 levels were supranormal in Group 4. TSH levels were normal in Groups 1 and 3, but were suppressed in Groups 2 and 4, suggesting that rats in Groups 2 and 4 were actually in a hyperthyroid state after injecting a large amount of T3. D1 activity in Group 1 was reduced significantly, but it was normal in Groups 2 and 3, and increased in Group 4. D1 mRNA levels in the liver in Group 1 decreased significantly, but they were increased to within normal limits by adding insulin in Group 3. They were also normal in Group 2 where hyperglycemia was evident and rats were hyperthyroid after administering T3. D1 mRNA in Group 4 increased significantly where glucose levels were normal and T3 levels were increased. We suggest that the decrease in hepatic D1 mRNA in STZ-induced diabetic rats is due to metabolic derangement caused by insulin deficiency in addition to a possible decrease in tissue T3 availability.

Direct measurement of the contributions of type I and type II 5'-deiodinases to whole body steady state 3,5,3'-triiodothyronine production from thyroxine in the rat.

Production of T3 from T4 in tissues is catalyzed by two 5'-deiodinases, type I (D1) and type II (D2), but the quantitative contribution of each pathway to whole body T3 production is not well established. In the presence of propylthiouracil (PTU), D1, but not D2, can be effectively blocked, providing an experimental probe for addressing this problem. Decades ago, this approach provided indirect estimates ranging from 23-44% contribution by D2, based on plasma T3 appearance rate comparisons (PAR3 = PCR3 [T3]p) in periodically T4-injected athyreotic rats vs. controls. Two, more recent studies, using constant infusions of T4 for replacement, achieved 22% and 65% estimates, respectively, from PAR3 comparisons. We have revisited this problem more directly and precisely, with two major differences in experiment design. We used direct whole body steady state measurements of T3 production, instead of indirect plasma-only data (PAR3). We also used (euthyroid) physiological doses of both T4 (0.9 microg/day x 100 g BW) and T3 (0.15 microg/day x 100 g BW) for replacement in two thyroidectomized rat groups, instead of T4 only, in a 7-day constant steady state, dual tracer infusion protocol. The first group also had chronically implanted 150-mg PTU pellets (TXR-PTU); the other had implanted 0.1 N NaOH placebo pellets (TXR-EU); each delivered their product at constant rates. A third euthyroid intact group was used as the controls. The completeness of D1 inhibition was ascertained in a fourth group, identically treated with 150-mg PTU pellets, in which negligible D1 activity was found in liver and kidney using labeled rT3 as substrate for the 5'-D assays and minimal (1 mM) dithiothreitol as cofactor. In the TXR-PTU group, the percentage of T4 converted to T3 was 11.8%, compared with 23.4% (P < 0.0005) in the TXR-EU group, and 22.7% (P = NS) in controls. Thus, in euthyroid steady state, D2 contributes about half of the T3 produced from T4.

Thyroid receptor plasticity in striated muscle types: effects of altered thyroid state.

This study examined nuclear thyroid receptor (TR) maximum binding capacity (Bmax), dissociation constant (Kd), and TR isoform (alpha1, alpha2, beta1) mRNA expression in rodent cardiac, "fast-twitch white," "fast-twitch red," and "slow-twitch red" muscle types as a function of thyroid state. These analyses were performed in the context of slow-twitch type I myosin heavy-chain (MHC) expression, a 3,5,3'-triiodothyronine (T3)-regulated gene that displays varying responsiveness to T3 in the above tissues. Nuclear T3 binding analyses show that the skeletal muscle types express more TRs per unit DNA than cardiac muscle, whereas the latter has a lower Kd than the former. Altered thyroid state had little effect on either cardiac Bmax or Kd, whereas hypothyroidism increased Bmax in the skeletal muscle types without affecting its Kd. Cardiac muscle demonstrated the greatest mRNA signal of TR-beta1 compared with the other muscle types, whereas the TR-alpha1 mRNA signals were more abundant in the skeletal muscle types, especially fast-twitch red. Hyperthyroidism increased the ratio of beta1 to alpha1 and decreased the ratio of alpha2- to alpha1+beta1-mRNA signal across the muscle types, whereas hypothyroidism caused the opposite effects. The nuclear T3 affinity correlated significantly with the TR-beta1 mRNA expression but not with TR-alpha1 mRNA expression. Collectively, these findings suggest that, despite a divergent pattern of TR mRNA expression in the different muscle types, these patterns follow similar qualitative changes under altered thyroid state. Furthermore, TR expression pattern cannot account for the quantitative and qualitative changes in type I MHC expression that occur in the different muscle types.

Influence of imipramine on the hypothalamic/pituitary/thyroid axis of the rat

The effects of the tricyclic antidepressant drug imipramine at different levels of the hypothalamic/pituitary/thyroid axis were investigated in the rat. Intraperitoneal (IP) treatment for 14 days with imipramine at 10 mg/kg, but not 2 mg/kg, reduced serum total thyroxine (T4) and triiodothyronine (T3). A similar decrease in serum total T4 was observed in thyroidectomized T4-treated rats, suggesting that imipramine treatment enhances T4 clearance instead of reducing T4 secretion. There were no parallel decreases in serum free T4 and T3 concentrations, due to the simultaneous increase in the free fractions of both T4 and T3 following imipramine treatment. In vitro experiments using equilibrium dialysis indicated that neither imipramine nor its metabolite desipramine directly influenced the binding of T4 or T3 to their transport proteins following addition to normal serum, suggesting an indirect effect of imipramine or desipramine on free hormone concentrations in vivo. Concentrations of T4 and T3 in the brain, liver, and heart were unaffected by imipramine treatment, suggesting that the drug did not affect cellular uptake and metabolism of T4 and T3. Serum concentrations of thyrotropin (TSH) were unaffected by imipramine pretreatment at either dose level, compatible with the fact that serum free T4 and T3 concentrations were not reduced. Moreover, there was no difference in thyrotrope responsiveness to stimulation by TSH-releasing hormone (TRH) and to inhibition by T4 and T3 in rat anterior pituitary cells cultured ex vivo for 18 hours from control and imipramine-treated rats. Furthermore, in vitro exposure of cultured rat anterior pituitary cells to imipramine and desipramine indicated that both agents decreased TSH secretion only at concentrations greater than 10−6 mol/L. These concentrations of imipramine and desipramine in the culture medium would exceed the free concentrations of these drugs see in vivo therapeutically. In addition, no direct effects of 10−6 mol/L imipramine or desipramine on the TSH response to TRH or to T3 were observed in vitro in cultured pituitary cells. A potential indirect effect of imipramine or desipramine on TSH secretion via altered hypothalamic control of thyrotropes does not seem likely, due to the lack of effect of imipramine treatment on serum TSH concentrations in imipramine-treated rats. In conclusion, imipramine treatment reduces serum total T4 and T3 in the rat, with enhanced clearance being the most likely explanation for the effect on T4. There was no evidence for altered tissue T4 or T3 concentrations or for altered thyrotrope function. The enhanced T4 clearance may explain the reduction in total T4 reported for imipramine-treated depressed patients. However, the effects of imipramine treatment on the transport of thyroid hormones in plasma need to be examined in more detail in patients, since interspecies differences in the nature of the transport proteins preclude extrapolation of the present results from the rat.

Selenium and iodine deficiencies: effects on brain and brown adipose tissue selenoenzyme activity and expression.

Adequate dietary iodine supplies and thyroid hormones are needed for the development of the central nervous system (CNS) and brown adipose tissue (BAT) function. Decreases in plasma thyroxine (T4) concentrations may increase the requirement for the selenoenzymes types I and II iodothyronine deiodinase (ID-I and ID-II) in the brain and ID-II in BAT to protect against any fall in intracellular 3,3',5 tri-iodothyronine (T3) concentrations in these organs. We have therefore investigated selenoenzyme activity and expression and some developmental markers in brain and BAT of second generation selenium- and iodine-deficient rats. Despite substantial alterations in plasma thyroid hormone concentrations and thyroidal and hepatic selenoprotein expression in selenium and iodine deficiencies, ID-I, cytosolic glutathione peroxidase (cGSHPx) and phospholipid hydroperoxide glutathione peroxidase (phGSHPx) activities and expression remained relatively constant in most brain regions studied. Additionally, brain and pituitary ID-II activities were increased in iodine deficiency regardless of selenium status. This can help maintain tissue T3 concentrations in hypothyroidism. Consistent with this, no significant effects of iodine or selenium deficiency on the development of the brain were observed, as assessed by the activities of marker enzymes. In contrast, BAT from selenium- and iodine deficient rats had impaired thyroid hormone metabolism and less uncoupling protein than in tissue from selenium- and iodine-supplemented animals. Thus, the effects of selenium and iodine deficiency on the brain are limited due to the activation of the compensatory mechanisms but these mechanisms are less effective in BAT.

Thyroid hormones in the pathogenesis of lung hypoplasia and immaturity induced in fetal rats by prenatal exposure to nitrofen

Background/Purpose: Nitrofen is believed to act on prenatally exposed fetuses by changing maternal or fetal thyroid hormone physiology. The aim of this study was to determine whether the amounts of circulating and lung tissue T3 and T4 are decreased in rat fetuses with nitrofen-induced pulmonary hypoplasia and diaphragmatic hernia. Methods: Timed-pregnant rats were given 100 mg of nitrofen in oil on gestational day 9.5, and their fetuses were recovered on the 21st day. Lung weight to body weight ratio was determined. Hormonal studies consisted in measurement of plasma T3, T4, and TSH, and of T3, T4, and DNA in lung tissue. Suitable groups of control fetuses prenatally exposed to oil were used for comparison. Results: The lungs of nitrofen-treated fetuses were hypoplastic and those who had congenital diaphagmatic hernia were even more so. Nitrofen treatment led to decreased plasma T3 and T4 levels without TSH changes. T3 and T4 in lung tissue were apparently decreased in treated fetuses when expressed by weight, but these differences disappeared when expressed by DNA (cell content). Conclusions: Lung hypoplasia and immaturity induced by nitrofen treatment are not related to decreased levels of thyroid hormones in tissue near term. This should be kept in mind when proposing hormonal treatment for prenatal induction of lung maturation.

Effect of Chronic and Acute Thyroid Hormone Reduction on Perioperative Outcome

Effect of Chronic and Acute Thyroid Hormone Reduction on Perioperative Outcome