PubMed Health⌕ Search

Biomedical subjects

G Morreale de Escobar

Publications and source records attributed to G Morreale de Escobar.

At least 19 recordsLinked to original sources
PubMed2005

Transthyretin is not necessary for thyroid hormone metabolism in conditions of increased hormone demand.

Thyroid hormones circulate in blood mainly bound to plasma proteins. Transthyretin is the major thyroxine plasma carrier in mice. Studies in transthyretin-null mice revealed that the absence of transthyretin results in euthyroid hypothyroxinemia and normal thyroid hormone tissue distribution, with the exception of the choroid plexus in the brain. Therefore, transthyretin does not influence normal thyroid hormone homeostasis under standard laboratory conditions. To investigate if transthyretin has a buffer/storage role we challenged transthyretin-null and wild-type mice with conditions of increased hormone demand: (i) exposure to cold, which elicits thermogenesis, a process that requires thyroid hormones; and (ii) thyroidectomy, which abolishes thyroid hormone synthesis and secretion and induces severe hypothyroidism. Transthyretin-null mice responded as the wild-type both to changes induced by stressful events, namely in body weight, food intake and thyroid hormone tissue content, and in the mRNA levels of genes whose expression is altered in such conditions. These results clearly exclude a role for transthyretin in thyroid hormone homeostasis even under conditions of increased hormone demand.

Animals↗
PubMed2003

Dynamics and regulation of intracellular thyroid hormone concentrations in embryonic chicken liver, kidney, brain, and blood.

The intracellular thyroid hormone (TH) availability is influenced by different metabolic pathways. We investigated the relationship between tissue and plasma TH levels as well as the correlation with changes of deiodination and sulfation during chicken embryonic development. From day 14 until day 19, T3 remains unchanged in liver and kidney in spite of increasing plasma T4 and T3 levels and a slightly increased T4 availability in these tissues. During this period, the T3 breakdown capacity by type III deiodinase (D3) is high in liver but low in kidney. The TH inactivation capacity of type I deiodinase (D1), with production of inactive rT3 instead of T3, in kidney seems to be potentiated by the sulfation pathway. A sharp rise in T3 and T4 is detected in all tissues examined when the embryo switches to lung respiration. The same day, T4 content in liver is sharply enhanced and sulfation activity is decreased. So, T4 availability in liver is increased while a declined D3 activity allows for the accumulation of hepatic T3. The increase in renal T3 and T4 are more closely related to plasma TH profiles and a lack of correlation with the changes in renal D1 and D3 activity suggests that T4 and T3 content in this organ is strongly dependent on direct uptake from the blood. Despite much lower T4 levels, T3 levels in brain are in the same range as in liver and kidney and intracellular T3 even exceeds the T4 levels towards the end of development. The rise in TH content coincides with a drop in D3 activity, low sulfation activity and an increased T3 production capacity via type II deiodinase (D2). In conclusion, the current study describes the dynamics of intracellular TH concentrations in liver, kidney, and brain during chicken development and investigates their relationship with circulating TH levels and changes of deiodinases and sulfotransferases. The clear differences in intracellular TH profiles among the different tissues demonstrate that circulating levels are not necessarily representative for the local TH changes. Some of the changes in intracellular TH availability can be linked to changes in local deiodination and sulfation capacities, but the importance of these enzyme systems in relation to other factors, such as hormone uptake, differs between liver, kidney, and brain.

Animals↗
PubMed2003

Iodine deficiency associated with parenteral nutrition in extreme preterm infants.

Infants are in negative iodine balance on current standard regimens of total parenteral nutrition, with a mean iodine intake of 3 micro g/kg/day (150 ml/kg/day). The recommended enteral intake of iodine for preterm infants is 30 micro g/kg/day. Gastrointestinal absorption of iodine is high, suggesting that parenteral intakes should approach enteral recommendations.

Age Factors↗
PubMed2002

Thyroid hormone distribution in the mouse brain: the role of transthyretin.

Transthyretin is the major thyroxine-binding protein in the plasma of rodents, and the main thyroxine-binding protein in the cerebrospinal fluid of both rodents and humans. The choroid plexus synthesizes transthyretin and secretes it to the cerebrospinal fluid. Although it was suggested that transthyretin might play an important role in mediating thyroxine transfer from the blood into the brain across the choroid plexus-cerebrospinal fluid barrier, newer findings question this hypothesis. Because thyroid hormone passage across brain barriers is a precondition for its action in the CNS, and because brain is an important target of thyroid hormone action, we investigated the role of transthyretin in mediating thyroid hormone access to and distribution within the brain in a transthyretin-null mouse model system. In this report we describe the results derived from use of film autoradiography, a technique that yields definitive morphological results. Film autoradiograms were prepared at 3 and 19 h after intravenous injection of either high specific activity [(125)I]thyroxine or [(125)I]triiodothyronine. Image analyses were designed to demonstrate regional changes in hormone distribution, and to highlight alterations in iodothyronine delivery from ventricles to brain parenchyma. We find no qualitative or quantitative differences in these parameters between the transthyretin-null and the wild-type mouse brain after either [(125)I]thyroxine or [(125)I]triiodothyronine administration. The data presented here now provide definitive evidence that, under standard laboratory conditions, transthyretin is not required for thyroid hormone access to or distribution within the mouse brain. This study also provides the first map of iodothyronine distribution in the brain of the mouse.

Animals↗
PubMed2001

Audiogenic seizure susceptibility in thyroid hormone receptor beta-deficient mice.

As early-onset hypothyroidism produces audiogenic seizure susceptibility (AGS) in rodents, the role of TR alpha 1 and TR beta thyroid hormone receptors in AGS was investigated. AGS occurs in mice lacking specifically TR beta (Thrb(tm1/tm1)) and is marked by early onset and persistence, thereby differing from mouse strains where AGS is age-restricted. Thrb(tm1/tm1) mice display AGS whether on a mixed 129/Sv x C57BL/6J or congenic C57BL/6J background. 27% of wild-type mice on the mixed and 0% on the congenic background exhibited AGS. The inability of Thrb(tm1/tm1) mice to downregulate the response to sustained acoustic stimulation may reside in the brain or in the auditory system itself as Thrb(tm1/tm1) mice also display auditory deficits. The AGS phenotype identifies a novel neurological role for TR beta.

Age of Onset↗
PubMed2001

The role of thyroid hormone in fetal neurodevelopment.

Thyroid hormones are necessary for normal brain development during fetal and postnatal life. The stage at which the central nervous system becomes thyroid hormone sensitive, however, has not been clearly defined. There is increasing evidence from epidemiological studies and patient reports that these hormones are already needed for orderly development during the first trimester, when the fetus is entirely dependent on the maternal transfer of thyroxine, the main substrate for intracellular generation of the more active 3,5,3'-triiodothyronine for binding to the nuclear hormone receptors. A decrease in maternal circulating thyroxine during the first trimester, whether or not accompanied by increased circulating thyroid-stimulating hormone, may well result in irreversible mental and psychomotor impairments. The very frequent cause of this is an iodine intake insufficient to meet the requirements of the pregnant woman. It appears urgent to ensure the use of iodine supplements from before or very early in pregnancy, and to screen all women for hypothyroxinemia as early as possible. Maternal thyroxine continues to be important for the exposure of fetal tissues to adequate amounts of this hormone during the second and, possibly, the third trimesters. Premature birth, which interrupts this transfer, results in neonatal hypothyroxinemia. This is more severe the earlier it occurs during development, and is an important cause of the poorer mental and neuromotor development of many preterm infants. The possibility of supplying them with thyroxine during the neonatal period is being seriously tested.

Animals↗
PubMed2000

Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia?

Several recent publications have drawn attention to the role of the thyroid hormone status of the mother on the future neuropsychological development of the child. The screening of pregnant women for clinical or subclinical hypothyroidism based on second trimester elevated maternal TSH values has been proposed. Here, we have summarized present epidemiological and experimental evidence strongly suggesting that conditions resulting in first trimester hypothyroxinemia (a low for gestational age circulating maternal free T4, whether or not TSH is increased) pose an increased risk for poor neuropsychological development of the fetus. This would be a consequence of decreased availability of maternal T4 to the developing brain, its only source of thyroid hormone during the first trimester; T4 is the required substrate for the ontogenically regulated generation of T3 in the amounts needed for optimal development in different brain structures, both temporally and spatially. Normal maternal T3 concentrations do not seem to prevent the potential damage of a low supply of T4, although they might prevent an increase in circulating TSH and detection of the hypothyroxinemia if only TSH is measured. Hypothyroxinemia seems to be much more frequent in pregnant women than either clinical or subclinical hypothyroidism and autoimmune thyroid disease, especially in regions where the iodine intake of the pregnant woman is inadequate to meet her increased needs for T4. It is proposed that the screening of pregnant women for thyroid disorders should include the determination of free T4 as soon as possible during the first trimester as a major test, because hypothyroxinemia has been related to poor developmental outcome, irrespective of the presence of high titers of thyroid autoantibodies or elevated serum TSH. The frequency with which this may occur is probably 150 times or more that of congenital hypothyroidism, for which successful screening programs have been instituted in many countries.

Animals↗
PubMed1999

Tissue-specific patterns of changes in 3,5,3'-triiodo-L-thyronine concentrations in thyroidectomized rats infused with increasing doses of the hormone. Which are the regulatory mechanisms?

We have measured 3,5,3'triiodothyronine (T3) in 12 tissues from thyroidectomized (Tx) rats infused with increasing doses of T3, and related them to their corresponding plasma levels. Young adult Wistar rats were surgically Tx. After 4 weeks, the animals were infused with placebo or T3 (0.25, 0.50, 0.75, 1.00 or 2.00 microg/100 g body weight/day). Placebo-infused intact rats served as euthyroid controls. Plasma and samples of cerebral cortex, cerebellum, brown adipose tissue (BAT), pituitary, liver, heart, lung, kidney, spleen, skeletal muscle, ovary and adrenal were obtained after 12-13 days of infusion. We determined plasma T3 and thyrotropin (TSH), and tissue T3 and thyroxine (T4), the latter being virtually undetectable. Results were compared with the relationships between tissue and plasma T3 in Tx rats on T4 infusions. Most tissues presented changes which paralleled those in plasma T3, irrespective of its source (infusion of T3, or generation from infused T4). However, at similar plasma T3 concentrations, cerebral cortex, cerebellum and BAT (containing type II 5' iodothyronine deiodinase (DII) activity), reached much lower T3 levels in the T3-infused Tx rats, than in Tx rats on T4, and required elevated plasma T3 levels for normal tissue T3. In these tissues, and in the pituitary, T3 concentrations were always lower than expected from plasma T3 levels. On the contrary, the lung and ovary of the T3-infused Tx rats contained more T3 than expected from plasma T3. Unexpectedly, both the ovary and adrenal attained higher tissue T3 concentrations in Tx rats on T3 than on T4 at comparable plasma T3 levels. In conclusion, the patterns of changes of the concentrations of T3 as a function of increasing plasma T3 are not only tissue-specific when T4 is provided, but also when circulating T3 is the only source of this iodothyronine. Further studies are needed to identify the mechanisms involved in the regulation of tissue T3 concentrations.

Animals↗
PubMed1999

Exocrine pancreatic disorders in transsgenic mice expressing human keratin 8.

Keratins K8 and K18 are the major components of the intermediate-filament cytoskeleton of simple epithelia. Increased levels of these keratins have been correlated with various tumor cell characteristics, including progression to malignancy, invasive behavior, and drug sensitivity, although a role for K8/K18 in tumorigenesis has not yet been demonstrated. To examine the function of these keratins, we generated mice expressing the human K8 (hk8) gene, which leads to a moderate keratin-content increase in their simple epithelia. These mice displayed progressive exocrine pancreas alterations, including dysplasia and loss of acinar architecture, redifferentiation of acinar to ductal cells, inflammation, fibrosis, and substitution of exocrine by adipose tissue, as well as increased cell proliferation and apoptosis. Histological changes were not observed in other simple epithelia, such as the liver. Electron microscopy showed that transgenic acinar cells have keratins organized in abundant filament bundles dispersed throughout the cytoplasm, in contrast to control acinar cells, which have scarce and apically concentrated filaments. The phenotype found was very similar to that reported for transgenic mice expressing a dominant-negative mutant TGF-beta type II receptor (TGFbetaRII mice). We show that these TGFbetaRII mutant mice also have elevated K8/K18 levels. These results indicate that simple epithelial keratins play a relevant role in the regulation of exocrine pancreas homeostasis and support the idea that disruption of mechanisms that normally regulate keratin expression in vivo could be related to inflammatory and neoplastic pancreatic disorders.

Animals↗
PubMed1998

Thyroid hormones in human tumoral and normal nervous tissues.

We have studied T4 and T3 concentrations, DNA and protein concentrations and 5' and 5 deiodinases in samples of brain tumors obtained at surgery from 49 patients, and, in most cases, also from surrounding normal tissue. T4 concentrations in normal cortical tissue (6.19+/-0.45 ng/g) were lower than in white matter, but the difference disappeared when referred to the DNA content (2.26+/-0.27 ng/mg DNA). No other differences were found between cortical and white matter, or among cortical lobes. T4 in normal tissue was higher than previously reported, mostly from autopsy samples, whereas T3 (0.99+/-0.07 ng/g) was similar. 5'D-I activity was negligible as compared to 5'D-II (8.11+/-1.09 fmol/h/mg protein). When expressed in relation to the different DNA contents of normal vs. tumoral tissue, 5'D-II activities were the same for both. 5D activity was highly variable in the tumoral tissue, with negligible activities in meningiomas and pituitary adenomas. When referred to the DNA content, T4 and 5'D-II were the same, but T3 concentrations were lower in the tumor (0.24+/-0.03 ng/mg DNA) as compared to normal (0.35+/-0.04 ng/mg DNA) tissue samples. Whether or not this decrease of T3 affects the expression of T3-sensitive processes remains to be studied.

Adolescent↗
PubMed1998

Immunohistochemical and morphometric studies of the fetal pancreas in diabetic pregnant rats. Effects of insulin administration.

BACKGROUND: Maternal diabetes influences fetal pancreas development. As there are some controversial reports, we studied the morphometric changes of the fetal insular pancreas and insulin immunostain of beta cells as well as the proliferative activity of insular cells in 21-day-old fetuses from control, diabetic, and insulin-treated diabetic pregnant rats. METHODS: Streptozotocin was injected into 7-day-pregnant rats (controls were not injected). Some rats were either left untreated (diabetic) or injected with insulin. Animals were killed at 21 days of gestation. Fetal pancreas were fixed in toto for the morphometry and immunohistochemistry studies using anti-insulin, anti-Ki-67 and anti-proliferating cell nuclear antigen (PCNA) antibodies. RESULTS: Diabetic status was determined by measuring maternal and fetal serum glucose and insulin levels. The morphometric studies showed hyperplasia of the diabetic fetal insular tissue which had not been normalized by insulin therapy. Diabetes caused an increase of both insulin-positive and insulin-negative cells. The increase in insulin-positive cells was not corrected by insulin treatment, although the number of non-beta cells became normal. The nuclear area in beta cells increased in diabetic rats but was not corrected by insulin. The cytoplasmic area decreased in diabetic rats and was normalized by insulin administration. Diabetes increased the expression of the nuclear antigen Ki-67 in fetal insular pancreas, and insulin treatment returned it to the normal state. CONCLUSIONS: Maternal diabetes leads to hyperstimulation of fetal beta cells, with increased proliferative activity. Insulin administration to the dams corrects some of the changes observed.

Animals↗
PubMed1998

Synthetic flavonoids cross the placenta in the rat and are found in fetal brain.

The synthetic flavonoid EMD-49209 is a potent inhibitor of the in vivo and in vitro binding of thyroxine (T4) to transthyretin (TTR). We studied the distribution of 125I-labeled EMD-49209 in maternal tissues, intestinal contents, and fetal tissues in rats that were 20 days pregnant (from 1 to 24 h after intravenous injection). The percent dose of EMD decreased quickly with time. In maternal brain no radioactive flavonoid could be detected. EMD was excreted very rapidly from the intestines. In the fetal compartment the percent dose of EMD increased with time; after 24 h it contained 17% of the EMD. The flavonoid was found in all fetal tissues investigated and also in the fetal brain. Because TTR concentrations are high in the fetal rat, especially in the brain, the transfer of flavonoid to the fetal brain might be linked to TTR expression. The presence of flavonoid in the fetal brain raises the possibility of an essential interference of flavonoids with the availability of T4 in the fetal compartment.

Animals↗
PubMed1998

Iodothyronine deiodinase activities in fetal rat tissues at several levels of iodine deficiency: a role for the skin in 3,5,3'-triiodothyronine economy?

Iodothyronine deiodinases, types I, II, and III (D1, D2, and D3) activities were measured in tissues of fetal rats, at 18 and 21 days of gestation, at several levels of iodine deficiency (ID): mild ID diet (MID) and moderately severe ID, MID + 0.005% perchlorate (MID+P). D2 was present in fetal skin, increased between days 18 and 21, and also in MID and MID+P. In skin, D3 increased during ID at day 18, whereas there was a decrease at day 21. Skin T4 decreased in MID and MID+P, showing an inverse relationship with D2. Skin T3 decreased at day 18 in MID and MID+P but increased at day 21, probably because of the increased D2 and decreased D3, maintaining T3 concentrations. No effect of ID was observed on hepatic D1. D2 increased in brain and brown adipose tissue at day 21 in MID+P. No changes were found in maternal placental D2 and D3, but D2 and D3 increased in the fetal placenta at day 18 in MID+P. A higher level of D2 is present in fetal skin than in the brain. As the activity is increased, in even mild ID (and already at 18 days) it can be concluded that skin D2 is likely to be of considerable physiological importance, at least for fetal thyroid hormone economy, by contributing to the intracellular T3 content of the skin and, possibly, to the plasma T3.

Adipose Tissue, Brown↗