T3 Deficiency Research Articles

Impact of thyroid hormones on predicting the occurrence of persistent inflammation, immunosuppression, and catabolism syndrome in patients with sepsis.

The prevalence of persistent inflammation, immunosuppression, and catabolism syndrome (PICS) has an upward trend in sepsis patients and can be associated with poor outcomes. Thyroid hormones are expected to be correlated with inflammation, immunity, and metabolism. Thus, the purpose of this study was to evaluate the effect of thyroid hormones on the occurrence of PICS and then further explore the optimal level of them in sepsis. This retrospective observational study used the online database Medical Information Mart for Intensive Care (MIMIC)-IV. Univariate and multivariate logistic regression analyses were employed to determine correlations between thyroid hormone levels and PICS. A combination of independent PICS development factors was established with accuracy assessed using the area under the receiver operating characteristic curve (AUC-ROC). Patients were divided into PICS (n=205) and non-PICS (n=671) groups. The third quartiles of triiodothyronine (T3) (60-80ng/dl) and thyroxine (T4) (5.5-6.8ug/dl) had the lowest PICS incidence and the adjusted odds ratio (OR) was 0.33 (T3, p=0.009) and 0.39 (T4, p=0.006), respectively, compared with the first quartiles of T3 and T4. For patients with a pre-existing T3 deficiency, severe deficiency (T3 <60ng/dl) and a high Sequential Organ Failure Assessment (SOFA) score were significantly related to PICS incidence. The AUC for these combined parameters in predicting PICS occurrence was 0.748 (all patients) and 0.861 (patients without thyroid disease). A mild T3 deficiency (60-80ng/dl) was significantly associated with the lowest risk-adjusted PICS occurrence in patients with sepsis. A severe T3 deficiency (<60ng/dl) and a high SOFA score were independent risk factors for PICS occurrence.

Endocrinologists - Do You Remember Woltmans Sign? The Delayed Reflexes of Overt Hypothyroidism also occur with T3 Deficiency

Woltman’s Sign, the delay in the relaxation phase of the Achilles reflex, has long been recognised as the hallmark of overt hypothyroidism. It is most easily observed with the ankle jerk [1] but delayed relaxation can readily be demonstrated in all deep tendon reflexes including the biceps [2,3]. With hypothyroid patients the relaxation phase can take up to a full second. Numerous devices were devised for timing the ankle jerk [4], including the Burdick photomotogram [3,5,6], but the physical sign is so distinctive that such aids are not required in clinical practice.

Female offspring gestated in hypothyroxinemia and infected with human Metapneumovirus (hMPV) suffer a more severe infection and have a higher number of activated CD8+ T lymphocytes.

Maternal thyroid hormones (THs) are essential for the appropriate development of the fetus and especially for the brain. Recently, some studies have shown that THs deficiency can also alter the immune system development of the progeny and their ability to mount an appropriate response against infectious agents. In this study, we evaluated whether adult mice gestated under hypothyroxinemia (Hpx) showed an altered immune response against infection with human metapneumovirus (hMPV). We observed that female mice gestated under Hpx showed higher clinical scores after seven days of hMPV infection. Besides, males gestated under Hpx have higher lung viral loads at day seven post-infection. Furthermore, the female offspring gestated in Hpx have already reduced the viral load at day seven and accordingly showed an increased proportion of activated (CD71+ and FasL+) CD8+ T cells in the lungs, which correlated with a trend for a higher histopathological clinical score. These results support that T4 deficiency during gestation might condition the offspring differently in males and females, enhancing their ability to respond to hMPV.

Imprinted lncRNA Dio3os preprograms intergenerational brown fat development and obesity resistance

Maternal obesity (MO) predisposes offspring to obesity and metabolic disorders but little is known about the contribution of offspring brown adipose tissue (BAT). We find that MO impairs fetal BAT development, which persistently suppresses BAT thermogenesis and primes female offspring to metabolic dysfunction. In fetal BAT, MO enhances expression of Dio3, which encodes deiodinase 3 (D3) to catabolize triiodothyronine (T3), while a maternally imprinted long noncoding RNA, Dio3 antisense RNA (Dio3os), is inhibited, leading to intracellular T3 deficiency and suppression of BAT development. Gain and loss of function shows Dio3os reduces D3 content and enhances BAT thermogenesis, rendering female offspring resistant to high fat diet-induced obesity. Attributing to Dio3os inactivation, its promoter has higher DNA methylation in obese dam oocytes which persists in fetal and adult BAT, uncovering an oocyte origin of intergenerational obesity. Overall, our data uncover key features of Dio3os activation in BAT to prevent intergenerational obesity and metabolic dysfunctions.

Perinatal exposure to the thyroperoxidase inhibitors methimazole and amitrole perturbs thyroid hormone system signaling and alters motor activity in rat offspring

Disruption of the thyroid hormone system during development can impair brain development and cause irreversible damage. Some thyroid hormone system disruptors act by inhibiting the thyroperoxidase (TPO) enzyme, which is key to thyroid hormone synthesis. For the potent TPO-inhibiting drug propylthiouracil (PTU) this has been shown to result in thyroid hormone system disruption and altered brain development in animal studies. However, an outstanding question is which chemicals beside PTU can cause similar effects on brain development and to what degree thyroid hormone insufficiency must be induced to be able to measure adverse effects in rats and their offspring. To start answering these questions, we performed a perinatal exposure study in pregnant rats with two TPO-inhibitors: the drug methimazole (MMI) and the triazole herbicide amitrole. The study involved maternal exposure from gestational day 7 through to postnatal day 22, to MMI (8 and 16 mg/kg body weight/day) or amitrole (25 and 50 mg/kg body weight/day). Both MMI and amitrole reduced serum T4 concentrations in a dose-dependent manner in dams and offspring, with a strong activation of the hypothalamic-pituitary-thyroid axis. This reduction in serum T4 led to decreased thyroid hormone-mediated gene expression in the offspring’s brains and caused adverse effects on brain function, seen as hyperactivity and decreased habituation in preweaning pups. These dose-dependent effects induced by MMI and amitrole are largely the same as those observed with PTU. This demonstrates that potent TPO-inhibitors can induce effects on brain development in rats and that these effects are driven by T4 deficiency. This knowledge will aid the identification of TPO-inhibiting thyroid hormone system disruptors in a regulatory context and can serve as a starting point in search of more sensitive markers of developmental thyroid hormone system disruption.

Thyroid hormone deficiency during zebrafish development impairs central nervous system myelination.

Thyroid hormones are messengers that bind to specific nuclear receptors and regulate a wide range of physiological processes in the early stages of vertebrate embryonic development, including neurodevelopment and myelogenesis. We here tested the effects of reduced T3 availability upon the myelination process by treating zebrafish embryos with low concentrations of iopanoic acid (IOP) to block T4 to T3 conversion. Black Gold II staining showed that T3 deficiency reduced the myelin density in the forebrain, midbrain, hindbrain and the spinal cord at 3 and 7 dpf. These observations were confirmed in 3 dpf mbp:egfp transgenic zebrafish, showing that the administration of IOP reduced the fluorescent signal in the brain. T3 rescue treatment restored brain myelination and reversed the changes in myelin-related gene expression induced by IOP exposure. NG2 immunostaining revealed that T3 deficiency reduced the amount of oligodendrocyte precursor cells in 3 dpf IOP-treated larvae. Altogether, the present results show that inhibition of T4 to T3 conversion results in hypomyelination, suggesting that THs are part of the key signaling molecules that control the timing of oligodendrocyte differentiation and myelin synthesis from very early stages of brain development.

Absence of Thyroid Hormone Induced Delayed Dendritic Arborization in Mouse Primary Hippocampal Neurons Through Insufficient Expression of Brain-Derived Neurotrophic Factor.

Thyroid hormone (TH) plays important roles in the developing brain. TH deficiency in early life leads to severe developmental impairment in the hippocampus. However, the mechanisms of TH action in the developing hippocampus are still largely unknown. In this study, we generated 3,5,3’-tri-iodo-l-thyronine (T3)-free neuronal supplement, based on the composition of neuronal supplement 21 (NS21), to examine the effect of TH in the developing hippocampus using primary cultured neurons. Effects of TH on neurons were compared between cultures in this T3-free culture medium (-T3 group) and a medium in which T3 was added (+T3 group). Morphometric analysis and RT-qPCR were performed on 7, 10, and 14 days in vitro (DIV). On 10 DIV, a decreased dendrite arborization in -T3 group was observed. Such difference was not observed on 7 and 14 DIV. Brain-derived neurotrophic factor (Bdnf) mRNA levels also decreased significantly in -T3 group on 10 DIV. We then confirmed protein levels of phosphorylated neurotrophic tyrosine kinase type 2 (NTRK2, TRKB), which is a receptor for BDNF, on 10 DIV by immunocytochemistry and Western blot analysis. Phosphorylated NTRK2 levels significantly decreased in -T3 group compared to +T3 group on 10 DIV. Considering the role of BDNF on neurodevelopment, we examined its involvement by adding BDNF on 8 and 9 DIV. Addition of 10 ng/ml BDNF recovered the suppressed dendrite arborization induced by T3 deficiency on 10 DIV. We show that the lack of TH induces a developmental delay in primary hippocampal neurons, likely caused through a decreased Bdnf expression. Thus, BDNF may play a role in TH-regulated dendritogenesis.

Analysis of Thyroid Hormone Receptor α-Knockout Tadpoles Reveals That the Activation of Cell Cycle Program Is Involved in Thyroid Hormone-Induced Larval Epithelial Cell Death and Adult Intestinal Stem Cell Development During Xenopus tropicalis Metamorphosis.

Background: There are two highly conserved thyroid hormone (triiodothyronine [T3]) receptor (TR) genes, TRα and TRβ, in all vertebrates, and the expression of TRα but not TRβ is activated earlier than T3 synthesis during development. In human, high levels of T3 are present during the several months around birth, and T3 deficiency during this period causes severe developmental abnormalities including skeletal and intestinal defects. It is, however, difficult to study this period in mammals as the embryos and neonates depend on maternal supply of nutrients for survival. However, Xenopus tropicalis undergoes a T3-dependent metamorphosis, which drastically changes essentially every organ in a tadpole. Of interest is intestinal remodeling, which involves near complete degeneration of the larval epithelium through apoptosis. Concurrently, adult intestinal stem cells are formed de novo and subsequently give rise to the self-renewing adult epithelial system, resembling intestinal maturation around birth in mammals. We have previously demonstrated that T3 signaling is essential for the formation of adult intestinal stem cells during metamorphosis. Methods: We studied the function of endogenous TRα in the tadpole intestine by using knockout animals and RNA-seq analysis. Results: We observed that removing endogenous TRα caused defects in intestinal remodeling, including drastically reduced larval epithelial cell death and adult intestinal stem cell proliferation. Using RNA-seq on intestinal RNA from premetamorphic wild-type and TRα-knockout tadpoles treated with or without T3 for one day, before any detectable T3-induced cell death and stem cell formation in the tadpole intestine, we identified more than 1500 genes, which were regulated by T3 treatment of the wild-type but not TRα-knockout tadpoles. Gene Ontology and biological pathway analyses revealed that surprisingly, these TRα-regulated genes were highly enriched with cell cycle-related genes, in addition to genes related to stem cells and apoptosis. Conclusions: Our findings suggest that TRα-mediated T3 activation of the cell cycle program is involved in larval epithelial cell death and adult epithelial stem cell development during intestinal remodeling.

Prognosis of Hormonal Deficits in Empty Sella Syndrome Using Neuroimaging.

Aim:We have evaluated the anatomic measurements on sellar area of patients who were radiologically diagnosed with empty sella to determine the relation between the amount of pressure on the adenohypophysis and hormonal imbalances.Materials and Methods:Sixty-one cases were diagnosed with empty sella and had hormone tests and hypophysis magnetic resonance (MR). The cases were categorized into two groups – patients with hypophyseal hormone anomaly and patients without hormone anomaly. We have measured interclinoid distance, anteroposterior distance from the anterior diaphragm sella to the pituitary stalk, depth of the sella turcica, craniocaudal distance of the optic chiasm from the diaphragm sella, the heights of the right and left adenohypophysis, subcutaneous fat thickness measured orthogonal to the coronal suture and posteriorly at the level of C2–C3 for two groups on hypophysis and cranial MR imaging MRI.Results:Twenty-five hormone-positive cases (40.9%) (hormone test were abnormal) and 36 hormone-negative cases (59.1%) (hormone tests were normal) were included in the study. The most common hormone abnormality was thyroid-stimulating hormone, T3 and T4 deficiency in 12 cases (48%) and increase in prolactin level in 7 cases (28%). Right adenohypophysis height was 1.54 ± 0.840 mm for the 1st group, and 1.96 ± 0.83 mm for the 2nd group. The left adenohypophysis height was 1.66 ± 0.80 mm for the 1st group, and 1.94 ± 0.94 mm for the 2nd group. It was found out that the thickness at right and left side in the hormone-positive group diminished significantly.Conclusion:Adenohypophysis height and distance between stalk and optic nerve were good determiner for hormone defect.

Hypothyroidism and brain developmental players.

Most of our knowledge on the mechanisms of thyroid hormone (TH) dependent brain development is based on clinical observations and animal studies of maternal/fetal hypothyroidism. THs play an essential role in brain development and hormone deficiency during critical phases in fetal life may lead to severe and permanent brain damage. Maternal hypothyroidism is considered the most common cause of fetal TH deficiency, but the problem may also arise in the fetus. In the case of congenital hypothyroidism due to defects in fetal thyroid gland development or hormone synthesis, clinical symptoms at birth are often mild as a result of compensatory maternal TH supply. TH transporters (THTs) and deiodinases (Ds) are important regulators of intracellular triiodothyronine (T3) availability and therefore contribute to the control of thyroid receptors (TRs)-dependent CNS development and early embryonic life. Defects in fetal THTs or Ds may have more impact on fetal brain since they can result in intracellular T3 deficiency despite sufficient maternal TH supply. One clear example is the recent discovery of mutations in the TH transporter (monocarboxylate transporter 8; MCT8) that could be linked to a syndrome of severe and non reversible psychomotor retardation. Even mild and transient changes in maternal TH levels can directly affect and alter the gene expression profile, and thus disturb fetal brain development. Animal studies are needed to increase our understanding of the exact role of THTs and Ds in prenatal brain development.

Serum Metabolomics Reveals Cholic Acid, Chenodeoxycholic Acid, and Taurochenodeoxycholic Acid as Potential Biomarkers for Hypothyroid Rats

Hypothyroidism decreases energy metabolism including carbohydrate and lipid metabolism and protein synthesis, due to reduced serum levels of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). Although many endogenous serum metabolites are influenced by hypothyroidism, serum metabolomic profiling has rarely been applied to the study of hypothyroidism. In the present study, we investigated potential biomarkers for hypothyroidism using serum metabolomics, and then measured serum levels of these endogenous metabolites using an analytical method: ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. There was a significant difference in the metabolic profiles of thyroidectomized (Tx) and normal rats. We found that many bile acid (BA) levels were significantly changed in serum of Tx rats. Simultaneous measurement of 12 different BAs in serum revealed that cholic acid (CA), chenodeoxycholic acid (CDCA), and taurochenodeoxycholic acid (TCDCA) levels significantly increased in Tx rats by approximately 25-fold, 11-fold, and 3-fold, respectively, compared with those of control rats. In Tx rats with active hormone T3 replacement, serum T3 levels were returned to physiological levels. However, these changes in BA levels were maintained at a high level. These results indicate that T3 replacement does not normalize the thyroid hormonal milieu. Thus, increased CA, CDCA, and TCDCA levels in serum after Tx may be a homeostatic response to not only T3 but also pro-thyroid hormone T4 deficiency. This study is the first to report that CA, CDCA, and TCDCA may be potential biomarkers for hypothyroidism and the efficacy of thyroid hormone replacement therapy in hypothyroidism.

Thyroid hormone-induced cell-cell interactions are required for the development of adult intestinal stem cells

The mammalian intestine has long been used as a model to study organ-specific adult stem cells, which are essential for organ repair and tissue regeneration throughout adult life. The establishment of the intestinal epithelial cell self-renewing system takes place during perinatal development when the villus-crypt axis is established with the adult stem cells localized in the crypt. This developmental period is characterized by high levels of plasma thyroid hormone (T3) and T3 deficiency is known to impair intestinal development. Determining how T3 regulates adult stem cell development in the mammalian intestine can be difficult due to maternal influences. Intestinal remodeling during amphibian metamorphosis resembles perinatal intestinal maturation in mammals and its dependence on T3 is well established. A major advantage of the amphibian model is that it can easily be controlled by altering the availability of T3. The ability to manipulate and examine this relatively rapid and localized formation of adult stem cells has greatly assisted in the elucidation of molecular mechanisms regulating their formation and further revealed evidence that supports conservation in the underlying mechanisms of adult stem cell development in vertebrates. Furthermore, genetic studies in Xenopus laevis indicate that T3 actions in both the epithelium and the rest of the intestine, most likely the underlying connective tissue, are required for the formation of adult stem cells. Molecular analyses suggest that cell-cell interactions involving hedgehog and BMP pathways are critical for the establishment of the stem cell niche that is essential for the formation of the adult intestinal stem cells.

The flow of genetic information – the role of thyroid hormones in the regulation of gene expression

Human genome encodes about 25 000 protein coding genes, among which some are constitutively expressed in all cells of the organism while the others are activated in response to specific extra- and intracellular signaling. Gene expression is regulated on multiple levels in a spatiotemporal manner. These levels include: genome, which contains all cellular DNA sequences (nuclear and extranuclear -mitochondrial), transcriptome, which contains all sequences of RNA synthesized in the cell (including long: pre-mRNA, mRNA, ncRNA, and short: snRNA, miRNA, and piRNA), proteome, which contains all proteins synthesized in the cell, metabolome, which includes all metabolic pathways in the organism, localizome, which includes all possible subcellular localizations of macromolecules in the organism, phenome, which is defined as a set of all phenotypes of the organism, which enables establishing of the real effects of particular genes and external environment on the phenotypic variability in humans. Thyroid hormones, 3,5,3'5'-tetraiodothyronine (thyroxine) and 3,5,3'-triiodothyronine (T3) participate in the regulation of key cellular processes, including proliferation, differentiation, apoptosis and metabolism. Together with other factors they initiate variable cellular processes, starting from activation of the flow and amplification of genetic information (via DNA-RNA-protein), and ending with elicitation of specific phenotypic traits of the cell. The action of thyroid hormone, is mediated mainly by interactions with nuclear receptors (THR), which belong to the superfamily of ligand dependent nuclear transcription factors. THR bind to specific sequences of response to thyroid hormone (TRE) in promoters of target genes and regulate their expression. Apart from classic, genomic mechanism of action, THRs can also act via non-genomic mechanism in which regulation of target genes is mediated by interactions with other receptors – located in plasma membrane or cytoplasm. THR are encoded by two genes, THRA (ERBA) and THRB. These genes, located in chromosome regions 17q21 (THRA) and 3p21-3p25 (THRB), encode for three functional receptors: TRα1, TRβ1, and TRβ2, and the receptor TRα2 which does not bind T3 and acts as an antagonist of the other receptors. TRα1 and TRβ1 are expressed in all tissue types and their expression and ratios at which they are expressed depend on tissue type and developmental stage. In most tissues and organs only one of the receptors is responsible for T3 mediated regulation of gene expression. For instance, TRα1 is the main receptor acting in bones, TRβ1 acts in liver and kidney, while TRβ2 acts in pituitary and hypothalamus where it regulates HPT axis. In the genomic mechanism THR regulate expression of target genes via binding to the sequences of response to thyroid hormone (TRE) located in their promoters. Typical TRE consists of two repeats of AGGTC(C/A)A sequence. The presence of so called positive TRE results in induction of gene expression after binding of TR and T3, while binding of THR without T3 results in inhibition of gene expression. Thus, deficiency of T3 in the cell will result in inhibition of expression of a given gene, for instance GH or a gene coding for iodothyronine deiodinase type 1. The genes with negative TRE are regulated in an opposite manner: binding of T3 to the receptor results in inhibition of gene expression. The negative regulation of gene expression via T3 enables, among others, the mechanism of feedback regulation of expression of THR and TSH via T3. In consequence, all disturbances of thyroid hormone signaling pathways can directly result in deregulation of homeostasis of the organism.

Thyroid hormones and cognitive function

Iodine is essential for the synthesis of thyroxine (T4), which is critical for the maturation of the fetal brain and nervous system. Maternal circulating T4 deficiency (as in severe iodine deficien...

TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy

Thyroidal production of triiodothyronine (T(3)) is absent in patients who have undergone total thyroidectomy. Therefore, relative T(3) deficiency may occur during postoperative levothyroxine (L-T(4)) therapy. The objective of this study was to evaluate how the individual serum T(3) level changes between preoperative native thyroid function and postoperative L-T(4) therapy. We retrospectively studied 135 consecutive patients with papillary thyroid carcinoma, who underwent total thyroidectomy. Serum free T(4) (FT(4)), free T(3) (FT(3)), and TSH levels measured preoperatively were compared with those levels measured on postoperative L-T(4) therapy. serum tsh levels during postoperative L-T(4) therapy were significantly decreased compared with native TSH levels (P<0.001). serum FT(4) levels were significantly increased (P<0.001). Serum FT(3) levels were significantly decreased (P=0.029). We divided the patients into four groups according to postoperative serum TSH levels: strongly suppressed (less than one-tenth of the lower limit); moderately suppressed (between one-tenth of the lower limit and the lower limit); normal limit; and more than upper limit. Patients with strongly suppressed TSH levels had serum FT(3) levels significantly higher than the native levels (P<0.001). Patients with moderately suppressed TSH levels had serum FT(3) levels equivalent to the native levels (P=0.51), and patients with normal TSH levels had significantly lower serum FT(3) levels (P<0.001). Serum FT(3) levels during postoperative L-T(4) therapy were equivalent to the preoperative levels in patients with moderately suppressed TSH levels. Our study indicated that a moderately TSH-suppressive dose of L-T(4) is required to achieve the preoperative native serum T(3) levels in postoperative L-T(4) therapy.

Neurodevelopment in Children Born to Hypothyroid Mothers Restored to Normal Thyroxine (T4) Concentration by Late Pregnancy in Japan: No Apparent Influence of Maternal T4Deficiency

The importance of maternal T₄ for brain development prior to the onset of fetal thyroid function has been suggested in basic studies, and a correlation between mild maternal T₄ deficiency in early gestation and disturbance of neurodevelopment in progenies has been shown in large case-control studies. These findings suggest that maternal T₄ deficiency in early pregnancy potentially affects neurointellectual development. On the other hand, no apparent adverse effect in children born to mothers with overt hypothyroidism in Japan has been reported where maternal T₄ had been restored to normal by late pregnancy. We report five cases in Japan showing no apparent effect of maternal T₄ deficiency on neurodevelopment in progenies where low T₄ levels had been corrected by late pregnancy. Five women with overt hypothyroidism detected at 6-16 wk gestation initiated T₄ treatment. Four women restored euthyroidism by the 20th week. One remained in a subclinical hypothyroid state. Developmental scores of their children were evaluated between 25 months and 11 yr of age by either the Tsumori-Inage Infant's Developmental Test or the Wechsler Intelligence Scale for Children-Third Edition and compared to those of corresponding siblings with no exposure to maternal hypothyroidism. The development scores of all the children turned out to be either normal or advanced. In iodine-sufficient areas, maternal T₄ deficiency in early pregnancy does not necessarily affect neurodevelopment. Therefore, other potential factors altering neurodevelopment, such as iodine deficiency, must be investigated.

Thyroid Function and Clinical Outcomes in Kidney Failure

Thyroid hormone synthesis is finely tuned to respond to the variable energy needs of the human body ([1][1]). This process is controlled by two fundamental mechanisms. The first, based on the thyroid-stimulating hormone (TSH)–thyroxine (T4) and triiodothyronine (T3) feed-back loop, constitutes a

Maternal Thimerosal Exposure Results in Aberrant Cerebellar Oxidative Stress, Thyroid Hormone Metabolism, and Motor Behavior in Rat Pups; Sex- and Strain-Dependent Effects

Methylmercury (Met-Hg) and ethylmercury (Et-Hg) are powerful toxicants with a range of harmful neurological effects in humans and animals. While Met-Hg is a recognized trigger of oxidative stress and an endocrine disruptor impacting neurodevelopment, the developmental neurotoxicity of Et-Hg, a metabolite of thimerosal (TM), has not been explored. We hypothesized that TM exposure during the perinatal period impairs central nervous system development, and specifically the cerebellum, by the mechanism involving oxidative stress. To test this, spontaneously hypertensive rats (SHR) or Sprague-Dawley (SD) rat dams were exposed to TM (200μg/kg body weight) during pregnancy (G10-G15) and lactation (P5-P10). Male and female neonates were evaluated for auditory and motor function; cerebella were analyzed for oxidative stress and thyroid metabolism. TM exposure resulted in a delayed startle response in SD neonates and decreased motor learning in SHR male (22.6%), in SD male (29.8%), and in SD female (55.0%) neonates. TM exposure also resulted in a significant increase in cerebellar levels of the oxidative stress marker 3-nitrotyrosine in SHR female (35.1%) and SD male (14.0%) neonates. The activity of cerebellar type 2 deiodinase, responsible for local intra-brain conversion of thyroxine to the active hormone, 3',3,5-triiodothyronine (T3), was significantly decreased in TM-exposed SHR male (60.9%) pups. This coincided with an increased (47.0%) expression of a gene negatively regulated by T3, Odf4 suggesting local intracerebellar T3 deficiency. Our data thus demonstrate a negative neurodevelopmental impact of perinatal TM exposure which appears to be both strain- and sex-dependent.

Optimal bone strength and mineralization requires the type 2 iodothyronine deiodinase in osteoblasts

Hypothyroidism and thyrotoxicosis are each associated with an increased risk of fracture. Although thyroxine (T4) is the predominant circulating thyroid hormone, target cell responses are determined by local intracellular availability of the active hormone 3,5,3'-L-triiodothyronine (T3), which is generated from T4 by the type 2 deiodinase enzyme (D2). To investigate the role of locally produced T3 in bone, we characterized mice deficient in D2 (D2KO) in which the serum T3 level is normal. Bones from adult D2KO mice have reduced toughness and are brittle, displaying an increased susceptibility to fracture. This phenotype is characterized by a 50% reduction in bone formation and a generalized increase in skeletal mineralization resulting from a local deficiency of T3 in osteoblasts. These data reveal an essential role for D2 in osteoblasts in the optimization of bone strength and mineralization.

Neurodevelopmental and Neurophysiological Actions of Thyroid Hormone

For over 100 years, thyroid hormones have been known to be essential for neonatal neurodevelopment but whether they are required by the foetal brain remains a matter of controversy. For decades, the prevailing view was that thyroid hormones are not necessary until after birth because circulating levels in the foetus are very low and the placenta forms an efficient barrier to their transfer from the mother. Clinical observations of good neurological outcome following early treatment of congenital hypothyroidism were used to support the view that thyroid hormones are not required early in neurodevelopment. Nevertheless, the issue remained contentious because of findings that the severity of foetal neurological deficit due to maternal iodine deficiency correlated with the degree of maternal thyroxine (T4) deficiency. Furthermore, neurological damage in these cases could be prevented by correction of maternal T4 deficiency before mid-gestation. This observation led to the opposing view, supported by epidemiological studies of neurological cretinism, that maternal thyroid hormones are important and necessary for early foetal neurodevelopment. It is now clear that thyroid hormones are essential for both foetal and post-natal neurodevelopment and for the regulation of neuropsychological function in children and adults. In recent years, this controversial subject has progressed very rapidly following remarkable progress in understanding of the molecular mechanisms of thyroid hormone action. This article reviews the contributions of molecular biology and genetics to our new understanding of the physiological effects of thyroid hormones on neurodevelopment and in the adult brain.