Marı́a Jesús Obregón

Instituto de Investigaciones Biomédicas Sols-Morreale

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Francisco Escobar del Rey

Consejo Superior de Investigaciones Científicas

Gabriella Morreale de Escobar

King Faisal Specialist Hospital & Research Centre

Juan Bernal

Instituto de Investigaciones Biomédicas Sols-Morreale

Rosa Calvo

Universitat de Barcelona

Ana Guadaño‐Ferraz

Consejo Superior de Investigaciones Científicas

Carmen Ruiz de Oña

Consejo Superior de Investigaciones Científicas

Raquel Martínez de Mena

Spanish National Centre for Cardiovascular Research

Soledad Bárez‐López

University of Bristol

G. Morreale de Escobar

Centre for Biomedical Network Research on Rare Diseases

Beatriz Morte

Instituto de Salud Carlos III

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Universidad Autónoma de Madrid

Consejo Superior de Investigaciones Científicas

Instituto de Salud Carlos III

Instituto de Investigaciones Biomédicas Sols-Morreale

Centro de Investigación Biomédica en Red

Universitat de Barcelona

Universidad Complutense de Madrid

Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas

Universidade do Porto

Centre for Biomedical Network Research on Rare Diseases

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Efecto del hexaclorobenceno sobre el metabolismo periferico de hormonas tiroideas

Laura María Blanco Álvarez Raquel Martínez de Mena Marı́a Jesús Obregón Diana L. Kleiman de Pisarev

Resumen del poster presentado a: XXII Reunion Anual Sociedad de Bioquimica y Biologia Molecular de Chile; XIV Reunion Anual Sociedad de Biologia Celular de Chile; XXIV Reunion Anual Sociedad Argentina de Investigacion Bioquimica y Biologia Molecular en asociacion con la Sociedad Espanola de Bioquimica y Biologia Molecular, celebrada en Vina del Mar (Chile) del 30 de octubre al 3 de noviembre del 2000.-- et al.

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Thyroid hormones and 5'-deiodinase in rat brown adipose tissue during fetal life

AJP Endocrinology and Metabolism (1989)

Marı́a Jesús Obregón Carmen Ruiz de Oña Arturo E. Hernández Rosa Calvo Francisco Escobar del Rey

Brown adipose tissue (BAT) iodothyronine 5'-deiodinase (5'D) activities are very high during fetal life but decrease 10-fold a few hours before birth. Accordingly, BAT 3,5,3'-triiodothyronine (T3) concentrations are also very high. The temporal patterns of changes in BAT 5'-D and fetal plasma insulin are similar (and differ from the pattern for catecholamines) but are not superimposable. A causal role for insulin in the activation of fetal BAT 5'-D is therefore not supported by the data. Maternal thyroidectomy leads to a decrease in the total and relative weight of fetal BAT and to a 30-50% increase in BAT 5'-D activities; BAT thyroid hormone concentrations are essentially unchanged. Fetal hypothyroidism was induced by giving methimazole and resulted in a marked decrease of BAT thyroxine (T4) and T3 concentrations. This treatment increased BAT 5'-D activity only on day 21 of gestation, but no effect was observed on day 20. The fetal 5'-D response to thyroid hormones infused into the methimazole-treated dams was studied at 21 days of gestation. The increase in BAT 5'-D induced by methimazole treatment was prevented by T4 infused into control dams but not by T3. In fetuses from thyroidectomized dams, the pattern of 5'-D regulation by thyroid hormones was impaired. It is suggested that the high concentrations of thyroid hormones present in fetal BAT might participate in the general maturation and development of fetal BAT.

Iodothyronine deiodinase

10.1152/ajpendo.1989.257.5.e625

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Iodothyronine 5′-deiodinase activity and thyroid hormone content in brown adipose tissue during the breeding cycle of the rat

Biochemical Journal (1988)

Octavi Viñas Marta Giralt Marı́a Jesús Obregón Roser Iglesias Francesc Villarroya

Brown adipose tissue iodothyronine 5'-deiodinase activity is significantly lower in 17-day pregnant rats compared with virgin controls and remains low during late pregnancy and lactation. It fully recovers with abrupt weaning, but only partially with spontaneous weaning. Even though this profile of changes is remarkably in step with the known pattern of modifications in brown fat thermogenesis during the breeding cycle, the lowered iodothyronine 5'-deiodinase activity appearing between days 15 and 17 of pregnancy occurs earlier than the reduction in brown adipose tissue thermogenesis. Brown fat 3,3',5-tri-iodothyronine content is also reduced in late pregnant, early and mid-lactating rats, most probably as a consequence of the lowered 5'-deiodination of thyroxine in situ. Acute insulin treatment increases brown fat iodothyronine 5'-deiodinase activity in virgin animals as well as in late-pregnant and lactating rats, despite the lowered basal enzyme activity levels in the latter groups. Thus an impaired response to insulin in brown fat does not appear to be a factor leading to the lowered iodothyronine 5'-deiodinase activity during late pregnancy and lactation.

Iodothyronine deiodinase

DIO2

10.1042/bj2550457

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The rat placenta and the transfer of thyroid hormones from the mother to the fetus. Effects of maternal thyroid status.

Endocrinology (1992)

Rosa Calvo Marı́a Jesús Obregón Francisco Escobar del Rey Gabriella Morreale de Escobar

We have studied the effects of maternal thyroid status on the effectiveness of the rat placenta near term as a barrier for the transfer of T4 and T3 to the fetus. Dams were given methimazole to minimize the fetal contribution to the T4 and T3 pools, so that the iodothyronines found in the conceptus are ultimately of maternal origin. The dams were infused with saline, or with T4 or T3 at doses ranging from 2.3-27.8 nmol T4 and from 0.77-20.7 nmol T3/100 g BW per day. A group of normal pregnant dams (C) was included. At 21 days of gestation T4, T3, and rT3 were measured by RIA in maternal and fetal plasma, and in maternal and fetal sides of the placenta. The total fetal extrathyroidal T4 and T3 pools were also determined. The dose-related changes in T4, T3, and rT3 levels in the placenta confirm the presence of both inner and outer ring iodothyronine deiodinase activities, and suggest increasing accumulation of the iodothyronines. Despite this, fetal extrathyroidal T4 and T3 increase progressively in T4-infused groups as a function of maternal circulating T4 levels. Fetal extrathyroidal T3 increases progressively in T3-infused groups as a function of maternal plasma T3. There was no evidence that the net maternal contribution of T4 or T3 would be proportionally less when the maternal pools became very high. It was concluded that the rat placenta is only a limited barrier for the transfer of T4 and T3 to the fetus.

Conceptus

Reverse triiodothyronine

Fetal circulation

10.1210/endo.131.1.1612015

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Presence of L-Thyroxine and 3,5,3′-Triiodo-L-thyronine in Tissues from Thyroidectomized Rats*

Endocrinology (1981)

Marı́a Jesús Obregón J. Mallol Francisco Escobar del Rey G. Morreale de Escobar

Female rats were killed 15 days, 2 months, and 4 months after surgical thyroidectomy that was followed by injection of 100 μCi 131I. The concentrations of T3 and T4 were measured in tissues (liver, kidney, brain, heart, and hindleg muscle) by specific RIAs. Results were compared to those found in intact rats. Thyroidectomy resulted in severe hypothyroidism by 2 and 4 months after the operation, as assessed by undetectable levels of T44 and T3 in unextracted plasma, high circulating TSH, hypothermia, stasis of body weight increase, and depletion of pituitary GH content. Concentrations of T44 and T3 in plasma, as determined after extraction and concentration, were very low, being less than 5% of the normal value by the earliest observation period (15 days). In contrast, although tissue concentrations and total organ contents also decreased after thyroidectomy, they were still clearly detectable 4 months after thyroidectomy. The rates of decrease of T4 and T3 concentrations in most tissues were markedly slower than expected from their rapid decrease in plasma. Some tissues still contained 20% of the normal level 2–4 months after ablation of the thyroid. Tissue levels of thyroid hormones were hardly detectable in rats thyroidectomized 6 months before, having decreased in most tissues to less than 5% of the normal value. Several animals from this group had died. It is concluded that tissues from severely hypothyroid thyroidectomized rats may contain higher concentrations of T4 and T3 than previously thought. The idea that thyroid hormone is not essential for life, based on the assumption that thyroidectomized animals survive without thyroid hormones, might have to be reevaluated.

10.1210/endo-109-3-908

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TRIAC treatment of an infant with Allan-Herndon-Dudley Syndrome (AHDS): Effects on iodothyronines in serum and cerebrospinal fluid

Ainhoa Iglesias–Ara Maria de Lourdes Briceño Palomares Beatriz Morte Marı́a Jesús Obregón Juan Bernal

Resumen del trabajo presentado al 38th Annual Meeting of the European Thyroid Association celebrado en Santiago de Compostela (Espana) del 6 al 10 de septiembre de 2014.-- et al.

TRIAC

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Crucial Role of Maternal Thyroxine but Not of 3,5,3'-Triiodothyronine in the Protection of the Fetal Brain

Rosa Calvo Marı́a Jesús Obregón Carmen Ruiz de Onha Francisco Escobar del Rey Gabriella Morreale de Escobar

To study the protective effects of maternal thyroxine (T4) and 3,5,3'-triiodothyronine (T3) in congenital hypothyroidism, we gave pregnant rats methimazole (MMI), an antithyroid drug that crosses the placenta, and infused them with three different doses of T4 or T3. The concentrations of both T4 and T3 were determined in maternal and fetal plasma and tissues (obtained near term) by specific RIAs. Several thyroid hormone-dependent biological end-points were also measured. MMI treatment resulted in marked fetal T4 and T3 deficiency. Infusion of T4 into the mothers increased both these pools in a dose-dependent fashion. There was a preferential increase ofT3 in the fetal brain. Thus, with a T4 dose maintaining maternal euthyroidism, fetal brain T3 reached normal values, although fetal plasma T4 was 40% of normal and plasma TSH was high. The infusion of T3 into the mothers increased the total fetal extrathyroidal T3 pool in a dose-dependent fashion. The fetal T4 pools were not increased, however, and this deprived the fetal brain (and possibly the pituitary) of local generation ofT3 from T4. As a consequence, fetal brain T3 deficiency was not mitigated even when dams were infused with a toxic dose of T3. The results show that (a) there is a preferential protection of the brain of the hypothyroid fetus from T3 deficiency; (b) maternal T4, but not T3, plays a crucial role in this protection, and (c) any condition which lowers maternal T4 (including treatment with T3) is potentially harmful for the brain ofa hypothyroid fetus. Recent confirmation of transplacental passage ofT4 in women at term suggests that present results are relevant for human fetuses with impairment of thyroid function. Finding signs of hypothyroidism at birth does not necessarily mean that the brain was unprotected in utero, provided maternal T4 is normal. It is crucial to realize that maintainance of maternal euthyroidism is not sufficient, as despite hypothyroxinemia, the mothers may be clinically euthyroid if their T3 levels are normal. (J. Clin. Invest. 1990. 86:889-899.) Key words: cretinism * placenta - 5' deiodinase *TSH - hypothyroxinemia

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

The Anatomical Record (1998)

Rosa-Maria Calvo Rosa Forcen Marı́a Jesús Obregón Francisco Escobar del Rey Gabriella Morreale de Escobar

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.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.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.Maternal diabetes leads to hyperstimulation of fetal beta cells, with increased proliferative activity. Insulin administration to the dams corrects some of the changes observed.

10.1002/(sici)1097-0185(199806)251:2<173::aid-ar4>3.0.co;2-

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Pendred Syndrome in Two Galician Families: Insights into Clinical Phenotypes through Cellular, Genetic, and Molecular Studies

The Journal of Clinical Endocrinology & Metabolism (2007)

F Palos María E.R. García-Rendueles David Araújo‐Vilar Marı́a Jesús Obregón Rosa Marı́a Calvo

We studied two families from Galicia (northwest Spain) with Pendred syndrome (PS) and unusual thyroid phenotypes. In family A, the proposita had a large goiter and hypothyroxinemia but normal TSH and free T3 (FT3). In family B, some affected members showed deafness but not goiter.

Pendrin

Organification

Thyroid peroxidase

10.1210/jc.2007-0539

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Iodothyronine deiodinases and thyroid hormone receptors regulation during flatfish (Solea senegalensis) metamorphosis

Journal of Experimental Zoology Part B Molecular and Developmental Evolution (2009)

Esther Isorna Marı́a Jesús Obregón Rosa Marı́a Calvo Rosa Vázquez Carlos Pendón

Abstract Thyroid hormone‐induced metamorphosis seems to represent an ancestral feature of chrordates (urochordates, cephalochordates and vertebrates), but also of nonchordate animals. Although thyroid hormones and thyroid hormone receptor profiles during metamorphosis have been analyzed in different vertebrate taxa, including fish, developmental expression and activity of type 2 ( dio2 , D2) and type 3 ( dio3 , D3) iodothyronine deiodinases, two key enzymes in anuran metamorphosis, remain unknown in any fish species. The aim of this work was to investigate the development of thyroid hormone system during the metamorphosis of a flatfish species, the Senegalese sole, focusing on the deiodinases developmental profile. We have cloned sole D2 and D3 and analyzed several parameters of thyroid hormones system in pre‐, early‐, middle‐, and late‐metamorphic larvae. Both deiodinases contain in their catalytic centers an UGA triplet encoding for a selenocystein (Sec) residue as expected. Left eye migration and rotation in body position were associated with a significant increase in both thyroid hormones and thyroid hormone receptors at the middle–late metamorphic stages. Although dio2 expression slightly increased during metamorphosis, D2 activity augmentation was much more significant. Sole dio3 expression declined only slightly, whereas the D3 activity clearly decreased at mid‐late metamorphic period. This developmental profile of deiodinases sustained the rise of thyroid hormones levels observed during sole metamorphosis. No clear cut daily rhythms were observed in the parameters analyzed although it seemed that thyroid hormone system was more active during daytime, in particular at late metamorphic stages. These developmental changes point out the importance not only of thyroid hormones and their receptors but also of dio2 and dio3 in mediating flatfish metamorphosis, as it has been described in amphibians. J. Exp. Zool. (Mol. Dev. Evol.) 312B:231–246, 2009 . © 2009 Wiley‐Liss, Inc.

DIO2

Thyroid hormone receptor

Iodothyronine deiodinase

10.1002/jez.b.21285

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Citations (51)