Onset Of Fetal Thyroid Function Research Articles

Defending Effects of Iodide Transfer in Placental Barrier Against Maternal Iodine Deficiency.

Objective: Placental iodide transport is necessary for maintaining an adequate iodide supply to the developing fetus. We hypothesized that compounds from the placental barrier can compensate for decreases in maternal iodine intake and normalize fetal iodine levels. Methods: Pregnant rats administered different amounts of iodine (1.24, 2.5, 5, or 10 μg/day) were evaluated on gestational day (gd) 16 and 20. The iodine levels in maternal blood, amniotic fluid (AF), and placental tissue were estimated using As-Ce catalytic spectrophotometry. The protein and/or messenger RNA (mRNA) levels of sodium iodide symporter (NIS), pendrin, alpha-smooth muscle actin (α-SMA), and CD31 in the placental labyrinth, trophoblast cells isolated using laser capture microdissection (LCM), and/or fetomaternal thyroid were detected using immunoblotting, real-time polymerase chain reaction, and/or immunohistochemistry. Results: When iodine intake was reduced, iodine levels in maternal blood gradually decreased; however, placental iodine levels were not significantly different between groups on gd16 and gd20. Minimal changes were observed in AF iodine levels on gd16, and a mild decreasing trend was observed (iodine dose, 10 to 1.24 μg/day) on gd20. NIS protein, which was linearly distributed along the basolateral membrane of maternal-fetal thyroid follicles, gradually increased with decreasing iodine levels. Regarding iodine deficiency in the placental labyrinth on gd16 and gd20, pendrin and glycosylated NIS proteins were significantly upregulated in a dose-dependent manner. However, the mRNA levels were unchanged. Furthermore, the conversion of NIS protein from the nonglycosylated to the glycosylated form increased. In trophoblast cells isolated using LCM, PDS mRNA levels increased in the 1.24-μg/day group on gd16 but not NIS mRNA levels. There was a smaller α-SMA+ area in the labyrinth zone on gd16 and gd20; however, the proportional CD31+ area increased on gd16 and reduced on gd20 with decreased iodine levels. Conclusions: All mechanisms upregulating the expression of iodine transporters and changes in villous stroma and microvessel area in the placental labyrinth can promote iodide transfer from mother to fetus in iodine deficiency, especially before the onset of fetal thyroid function. Compensatory NIS protein regulation in the placenta against decreased iodine intake mainly occurs during translation and glycosylation modification after translation. Pendrin may be more important than NIS in the mediation of placental iodide transport.

Expression of Organic Anion Transporting Polypeptide 1c1 and Monocarboxylate Transporter 8 in the Rat Placental Barrier and the Compensatory Response to Thyroid Dysfunction

Thyroid hormones (THs) must pass from mother to fetus for normal fetal development and require the expression of placental TH transporters. We investigate the compensatory effect of placental organic anion transporting polypeptide 1c1 (Oatp1c1) and monocarboxylate transporter 8 (Mct8) on maternal thyroid dysfunction. We describe the expressions of these two transporters in placental barriers and trophoblastic cell populations in euthyroidism and thyroid dysfunction resulting from differential iodine nutrition at gestation day (GD) 16 and 20, that is, before and after the onset of fetal thyroid function. Immunohistochemistry revealed that in the blood-placenta barrier, these two TH transporters were strongly expressed in the villous interstitial substance and were weakly expressed in trophoblast cells. Levels of Oatp1c1 protein obviously increased in the placental fetal portion during maternal thyroid deficiency at GD16. Under maternal thyroid deficiency after the production of endogenous fetal TH, quantitative PCR analysis revealed down-regulation of Oatp1c1 occurred along with up-regulation of Mct8 in trophoblast cell populations isolated by laser capture microdissection (LCM); this was consistent with the protein levels in the fetal portion of the placenta. In addition, decreased D3 mRNA at GD16 and increased D2 mRNA on two gestational days were observed in trophoblast cells with thyroid dysfunction. However, levels of Oatp1c1 mRNA at GD16 and D3 mRNA at GD20 were too low to be detectable in trophoblast cells. In conclusion, placental Oatp1c1 plays an essential compensatory role when the transplacental passage of maternal THs is insufficient at the stage before the fetal TH production. In addition, the coordinated effects of Oatp1c1, Mct8, D2 and D3 in the placental barrier may regulate both transplacental TH passage and the development of trophoblast cells during thyroid dysfunction throughout the pregnancy.

Transient Maternal Hypothyroxinemia Potentiates the Transcriptional Response to Exogenous Thyroid Hormone in the Fetal Cerebral Cortex Before the Onset of Fetal Thyroid Function: A Messenger and MicroRNA Profiling Study

Thyroid hormone (TH) is essential for brain development both before and after birth. We have used gene expression microarrays to identify TH-regulated genes in the fetal cerebral cortex prior to the onset of fetal thyroid function to better understand the role of TH in early cortical development. TH levels were transiently manipulated in pregnant mice by treatment with goitrogens from gestational day (GD) 13-16 and/or by injection of TH 12 h before sacrifice on GD 16. The transcriptional response to exogenous TH in the GD 16 fetal cortex was potentiated by transient goitrogen treatment, suggesting that the hypothyroxinemic brain is a different substrate upon which TH can act, or that robust compensatory mechanisms are induced by transient hypothyroxinemia. Several known TH-responsive genes were identified including Klf9, and several novel TH-responsive genes such as Appbp2, Ppap2b, and Fgfr1op2 were identified in which TH response elements were confirmed. We also identified specific microRNAs whose expression in the fetal cortex was affected by TH treatment, and determined that Ppap2b and Klf9 are the target genes of miR-16 and miR-106, respectively. Thus, a complex redundant functional network appears to coordinate TH-mediated gene expression in the developing brain.

Late Maternal Hypothyroidism Alters the Expression of Camk4 in Neocortical Subplate Neurons: A Comparison with Nurr1 Labeling

Maternal thyroid hormones (THs) are essential for normal offspring's neurodevelopment even after onset of fetal thyroid function. This is particularly relevant for preterm children who are deprived of maternal THs following birth, are at risk of suffering hypothyroxinemia, and develop attention-deficit/hyperactivity disorder. Expression of neocortical Ca(2+)/calmodulin kinase IV (Camk4), a genomic target of thyroid hormone, and nuclear receptor-related 1 protein (Nurr1), a postnatal marker of cortical subplate (SP) cells, was studied in euthyroid fetuses and in pups born to dams thyroidectomized in late gestation (LMH group, a model of prematurity), and compared with control and developmentally hypothyroid pups (C and MMI groups, respectively). In LMH pups, the extinction of heavy Camk4 expression in an SP was 1-2 days delayed postnatally compared with C pups. The heavy Camk4 and Nurr1 expression in the SP was prolonged in MMI pups, whereas heavy Camk4 and Nurr1 expression in layer VIb remains at P60. The abnormal expression of Camk4 in the cortical SP and in layer VIb might cause altered cortical connectivity affecting neocortical function.

Maternal thyroid hormone deficiency affects the fetal neocorticogenesis by reducing the proliferating pool, rate of neurogenesis and indirect neurogenesis

Neuronal progenitor cell proliferation and their optimum number are indispensable for neurogenesis, which is determined by cell cycle length and cell cycle quitting rate of the dividing progenitors. These processes are tightly orchestrated by transcription factors like Tbr2, Pax6, and E2f-1. Radial glia and intermediate progenitor cells (IPC) through direct and indirect neurogenesis maintain surface area and neocortical thickness during development. Here we show that fetal neurogenesis is maternal thyroid hormone (MTH) dependent with differential effect on direct and indirect neurogenesis. MTH deficiency (MTHD) impairs direct neurogenesis through initial down-regulation of Pax6 and diminished progenitor pool with recovery even before the onset of fetal thyroid function (FTF). However, persistent decrease in Tbr2 positive IPCs, diminished NeuN positivity in layers I-III of neocortex, and reduced cortical thickness indicate a non-compensatory impairment in indirect neurogenesis. TH deficiency causes disrupted cell cycle kinetics and deranged neurogenesis. It specifically affects indirect neurogenesis governed by intermediate progenitor cells (IPCs). TH replacement in hypothyroid dams partially restored the rate of neurogenesis in the fetal neocortex. Taken together we describe a novel role of maternal TH in promoting IPCs derived neuronal differentiation in developing neo-cortex. We have also shown for the first time that ventricular zone progenitors are TH responsive as they express its receptor, TR alpha-1, transporters (MCT8) and deiodinases. This study highlights the importance of maternal thyroid hormone (TH) even before the start of the fetal thyroid function.

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.

Oxygen concentration regulates expression and uptake of transthyretin, a thyroxine binding protein, in JEG-3 choriocarcinoma cells

Maternal thyroid hormone is provided to the fetus before the onset of fetal thyroid function (at about 16 weeks) and is essential for normal neurologic development. Mechanisms of transport are uncertain but transthyretin (TTR), a thyroxine binding protein produced by the placenta may be involved. Placental oxygen concentrations in early pregnancy are low, about 1% early in the first trimester and rising to 8% over the next 12 weeks. This study investigated the regulation of TTR expression, secretion and uptake in JEG-3 placental cells cultured at different oxygen concentrations. TTR mRNA and protein expression and 125I-TTR and Alexa-Fluor594-TTR uptake were significantly higher in cells cultured at 1% and 3% O2, than at 8% O2. This suggests that increased carrier mediated T4 transport by placental TTR may be induced by the low oxygen environment of early pregnancy, a time when the fetus has its highest requirement for transport of maternal T4.

Maternal Thyroid Hormone before the Onset of Fetal Thyroid Function Regulates Reelin and Downstream Signaling Cascade Affecting Neocortical Neuronal Migration

Though aberrant neuronal migration in response to maternal thyroid hormone (TH) deficiency before the onset of fetal thyroid function (embryonic day [E] 17.5) in rat cerebral cortex has been described, molecular events mediating morphogenic actions have remained elusive. To investigate the effect of maternal TH deficiency on neocortical development, rat dams were maintained on methimazole from gestational day 6 until sacrifice. Decreased number and length of radial glia, loss of neuronal bipolarity, and impaired neuronal migration were correctible with early (E13-15) TH replacement. Reelin downregulation under hypothyroidism is neither due to enhanced apoptosis in Cajal-Retzius cells nor mediated through brain-derived neurotrophic factor-tyrosine receptor kinase B alterations. Results based on gel shift and chromatin immunoprecipitation assays show the transcriptional control of reelin by TH through the presence of intronic TH response element. Furthermore, hypothyroidism significantly increased TH receptor α1 with decreased reelin, apolipoprotein E receptor 2, very low-density lipoprotein receptor expression, and activation of cytosolic adapter protein disabled 1 that compromised the reelin signaling. Integrins (α(v) and β₁) are significantly decreased without alteration of α₃ indicating intact neuroglial recognition but disrupted adhesion and glial end-feet attachment. Results provide mechanistic basis of essentiality of adequate maternal TH levels to ensue proper fetal neocortical cytoarchitecture and importance of early thyroxine replacement.

Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity.

Hypothyroxinemia affects 35–50% of neonates born prematurely (12% of births) and increases their risk of suffering neurodevelopmental alterations. We have developed an animal model to study the role of maternal thyroid hormones (THs) at the end of gestation on offspring's cerebral maturation. Pregnant rats were surgically thyroidectomized at embryonic day (E) 16 and infused with calcitonin and parathormone (late maternal hypothyroidism [LMH] rats). After birth, pups were nursed by normal rats. Pups born to LMH dams, thyroxine treated from E17 to postnatal day (P) 0, were also studied. In developing LMH pups, the cortical lamination was abnormal. At P40, heterotopic neurons were found in the subcortical white matter and in the hippocampal stratum oriens and alveus. The Zn-positive area of the stratum oriens of hippocampal CA3 was decreased by 41.5% showing altered mossy fibers’ organization. LMH pups showed delayed learning in parallel to decreased phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression in the hippocampus. Thyroxine treatment of LMH dams reverted abnormalities. In conclusion, maternal THs are still essential for normal offspring's neurodevelopment even after onset of fetal thyroid function. Our data suggest that thyroxine treatment of premature neonates should be attempted to compensate for the interruption of the maternal supply.

The Effects of Iodine Deficiency on Thyroid Hormone Deiodination

Iodine deficiency induces multiple intrathyroidal autoregulatory changes leading to an increased triiodothyronine (T(3)) production and secretion, at the expense of thyroxine (T(4)). It is characterized by low serum T(4), normal or slightly elevated T(3), and as a consequence of the latter, normal thyrotropin (TSH). Tissues are also hypothyroxinemic, but their T(3) concentrations are mostly normal and ensure clinical euthyroidism, except for those that depend to a high degree on local generation from T(4) by extrathyroidal mechanisms involving the iodothyronine deiodinases isoenzymes. Thus, unless iodine deficiency is so severe and chronic that intrathyroidal and extrathyroidal mechanisms are no longer sufficient to maintain a normal T(3) in most tissues, individuals are clinically and biochemically euthyroid, but some tissues may be selectively hypothyroid (i.e., the brain). In adults both the intrathyroidal and the extrathyroidal mechanisms reacting to the iodine deficiency are fully operative even when the latter is mild. They contribute jointly to the maintenance of elevated or normal T(3) in those tissues deriving most of it from the plasma, until iodine deficiency becomes very severe. Those depending to a large extent from local generation from T(4), mostly by an interplay between type 2 iodothyronine deiodinase (D2) and type 3 (D3), may already be T(3)-deficient (and hypothyroid) with mild iodine deficiency. Therefore, thyroid status of the iodine-deficient individual not only depends on the degree of iodine shortage, but is mostly tissue-specific, and is difficult to define for the individual as a whole: elevated, normal, and low concentrations of T(3) are found simultaneously in different tissues of the same animal, even with severe deficiencies. Most effects of iodine deficiency are reversed in the adults with an adequate iodine prophylaxis, but the absence of T(4) during early fetal life leads to irreversible brain damage (neurologic cretinism). Thyroid hormones of maternal origin are available to the embryo early in development and continue contributing to fetal thyroid hormone status, even after onset of fetal thyroid secretion. In the case of congenital hypothyroidism and normal maternal T(4), the transfer of the latter, together with increased D2 activity, protects the fetal brain from T(3) deficiency, even when it may be insufficient to maintain euthyroidism in other fetal tissues. Practically all of the T(3) found in the fetal brain is derived locally from T(4), and not from circulating T(3). In the case of severe iodine deficiency, both the embryo and the mother are T(4)-deficient; therefore, the fetal brain is exposed to T(3)-deficiency, both before and after onset of fetal thyroid function. This leads to irreversible alterations and damage to the central nervous system (i.e. abnormal corticogenesis). Moreover, because intrathyroidal autoregulatory mechanisms are not yet operative in the fetus, both T(4) and T(3) continue to be very low until birth, and the fetus is not only hypothyroxinemic, similar to its mother, but also clinically and biochemically hypothyroid.

Prenatal exposure to thyroid hormone is necessary for normal postnatal development of murine heart and lungs

Maternal hypothyroxinemia during early pregnancy poses an increased risk for poor neuropsychological development of the fetus. We tested the hypothesis that maternal hypothyroidism before the onset of fetal thyroid function also affects postnatal development of heart and lungs. This question was addressed in transgenic mice that express herpes simplex virus thymidine kinase in their thyroidal follicle cells. Treatment with ganciclovir rendered these mice severely hypothyroid because viral thymidine kinase converts ganciclovir into a cytotoxic nucleoside analog. Since ganciclovir crosses the placenta, it also destroyed the thyroid of transgenic embryos while leaving the thyroids of nontransgenic littermates unaffected. Hypothyroidism of both mother and fetus did not affect prenatal heart and lung development. However, the postnatal switch from β- to α-myosin heavy chain (β- and α-MHC, respectively) gene expression and the increase of SERCA-2a mRNA expression did not occur in the ventricular myocardium of either the transgenic (thyroid destroyed) or nontransgenic (intact thyroid) offspring of hypothyroid mothers. Similarly, postnatal animals of the latter two groups retained elevated surfactant protein (SP) A, B, and C mRNA levels in their alveolar epithelium. In hypothyroid pups from hypothyroid mothers, these changes were accompanied by decreased alveolar septation. Our study shows that these effects of maternal hypothyroidism become manifest after birth and are aggravated by the concomitant existence of neonatal hypothyroidism.

Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny.

Epidemiological studies from both iodine-sufficient and -deficient human populations strongly suggest that early maternal hypothyroxinemia (i.e., low circulating free thyroxine before onset of fetal thyroid function at midgestation) increases the risk of neurodevelopmental deficits of the fetus, whether or not the mother is clinically hypothyroid. Rat dams on a low iodine intake are hypothyroxinemic without being clinically hypothyroid because, as occurs in pregnant women, their circulating 3,5,3'-triiodothyronine level is usually normal. We studied cell migration and cytoarchitecture in the somatosensory cortex and hippocampus of the 40-day-old progeny of the iodine-deficient dams and found a significant proportion of cells at locations that were aberrant or inappropriate with respect to their birth date. Most of these cells were neurons, as assessed by single- and double-label immunostaining. The cytoarchitecture of the somatosensory cortex and hippocampus was also affected, layering was blurred, and, in the cortex, normal barrels were not formed. We believe that this is the first direct evidence of an alteration in fetal brain histogenesis and cytoarchitecture that could only be related to early maternal hypothyroxinemia. This condition may be 150-200 times more common than congenital hypothyroidism and ought to be prevented both by mass screening of free thyroxine in early pregnancy and by early iodine supplementation to avoid iodine deficiency, however mild.

Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny

Epidemiological studies from both iodine-sufficient and -deficient human populations strongly suggest that early maternal hypothyroxinemia (i.e., low circulating free thyroxine before onset of fetal thyroid function at midgestation) increases the risk of neurodevelopmental deficits of the fetus, whether or not the mother is clinically hypothyroid. Rat dams on a low iodine intake are hypothyroxinemic without being clinically hypothyroid because, as occurs in pregnant women, their circulating 3,5,3′-triiodothyronine level is usually normal. We studied cell migration and cytoarchitecture in the somatosensory cortex and hippocampus of the 40-day-old progeny of the iodine-deficient dams and found a significant proportion of cells at locations that were aberrant or inappropriate with respect to their birth date. Most of these cells were neurons, as assessed by single- and double-label immunostaining. The cytoarchitecture of the somatosensory cortex and hippocampus was also affected, layering was blurred, and, in the cortex, normal barrels were not formed. We believe that this is the first direct evidence of an alteration in fetal brain histogenesis and cytoarchitecture that could only be related to early maternal hypothyroxinemia. This condition may be 150–200 times more common than congenital hypothyroidism and ought to be prevented both by mass screening of free thyroxine in early pregnancy and by early iodine supplementation to avoid iodine deficiency, however mild.

Pre- and Postnatal Tissue Selenium of the Rat in the Growing State

The aim of this study is to quantify the selenium (Se) content (in µg/g) during different gestational periods in rat fetal tissues, and to follow up the changes in the Se content of the placenta, fetal head, liver and lung during gestation and postpartum periods. Locally reared virgin female Wistar rats were mated. Pregnant rats were sacrificed on days 15, 18 and 21 of pregnancy. Newborn pups at the age of 3 days and rats at the age of 1 month were also investigated. There was a gradual increase in placental and whole head Se content as gestation proceeded compared to day 15; however, the differences between the groups were not statistically significant. The liver Se content at day 18 of gestation was significantly higher than at day 21 of gestation and in rats at 3 days of age, but lower than the Se content of the liver of rats at the age of 1 month and the differences were statistically significant. The lung Se content was higher at day 18 of gestation than at day 21 and in the 3-day-old rats, and all differences between all groups were statistically significant except when the lung Se content at day 18 is compared to that of 1-month-old animals. The continuous increase in the Se content of the placental tissues and the whole head, although not significant statistically, may indicate that the fetus relies heavily on its supply of Se from the maternal blood and in part on the supply of thyroid hormones which are important for brain development, as evidence exists that T₄ and T₃ are present in the fetal brain in early fetal life before the onset of fetal thyroid function. The higher content of Se on day 18 and its decline on day 21 of gestation in the liver may imply that it is stored and being utilized partly in other tissues for other functions and particularly for thyroid hormone synthesis, metabolism and functions.

Maternal hypothyroidism selectively affects the expression of neuroendocrine-specific protein A messenger ribonucleic acid in the proliferative zone of the fetal rat brain cortex.

Thyroid hormone is essential for mammalian brain development, but the mechanisms by which thyroid hormone exerts its effects, the developmental processes affected, and the timing of thyroid hormone effects are poorly understood. An important question is whether thyroid hormone of maternal origin is essential in guiding fetal brain development. In both humans and rats, thyroid hormone of maternal origin reaches the fetus before the onset of fetal thyroid function. Moreover, receptors for thyroid hormone (TRs) are present in the fetal brain and are occupied by thyroid hormone. Finally, a recent report strongly indicates that transient undiagnosed maternal hypothyroidism can lead to measurable neurological deficits in the offspring despite the lack of neonatal hypothyroidism. Considering that TRs are ligand-activated transcription factors, we recently initiated a project to identify thyroid hormone-responsive genes in the fetal cortex before the onset of fetal thyroid function. One of the thyroid hormone-responsive genes we identified, neuroendocrine-specific protein (NSP), is expressed as two separate transcripts, NSP-A and NSP-C. Only NSP-A is affected by maternal thyroid hormone. We now demonstrate that the messenger RNA encoding NSP-A is expressed exclusively in the proliferative zone of the fetal cortex, and that its expression is affected by maternal hypothyroidism. Moreover, as development proceeds, NSP-A becomes selectively expressed in Purkinje cells of the cerebellum, a well known thyroid hormone-responsive cell. These findings strongly support the concept that thyroid hormone of maternal origin exerts specific receptor-mediated effects on fetal brain development.

Thyroid Function and Thyroid Hormone Requirements of Very Preterm Infants

After completing this article, readers should be able to: 1. Describe the thyroid state of very preterm infants. 2. List the factors that influence preterm thyroid function. 3. Understand possible implications of preterm thyroid function. 4. Cite the evidence available regarding treatment with thyroxine in very preterm infants. Understanding fetal thyroid function and thyroid hormone requirements is important for comprehending pre-term thyroid function because pre-term thyroid function shares both fetal and neonatal properties. Before the onset of fetal thyroid function, the presence of thyroid hormone has been demonstrated in embryonic cavities and tissues. Nuclear thyroid hormone receptors bound to bioactive triiodothyronine (T3) have been found in human brain and lung tissue during the ninth week of fetal life. It is generally believed that the presence of thyroid hormone during early fetal life results from maternal-fetal transfer of thyroxine (T4). By 10 to 12 weeks’ gestational age, the fetal thyroid gland acquires its capacity to concentrate iodide and synthesize iodothyronines. By that same time, the pituitary can produce and secrete thyrotropin, and hypothalamic neurons can synthesize thyrotropin-releasing hormone. Thyroxine binding-globulin also can be demonstrated in fetal serum by 12 weeks. Significant thyroid hormone production, however, does not occur before the 20th week of gestation. Fetal thyroid function and the hypothalamic-pituitary-thyroid axis continue to mature throughout pregnancy; serum levels of T4, free T4, thyroglobulin, and thyrotropin increase until the end of pregnancy. Thyroid hormone metabolism is immature during fetal life. There is high activity of iodothyronine mono-deiodinase type III, which converts T4 to bioinactive reverse-triiodothyronine (rT3) and T3 to diiodothyronine. The activity of iodothyronine monodeiodinase type I, which converts T4 to T3 for the plasma T3 pool, is believed to be low. As a consequence, the secreted T4 is preferably converted to rT3, which is present in high concentrations during pregnancy and only decreases during the …

Acute Changes in Maternal Thyroid Hormone Induce Rapid and Transient Changes in Gene Expression in Fetal Rat Brain

Despite clinical evidence that thyroid hormone is essential for brain development before birth, effects of thyroid hormone on the fetal brain have been largely unexplored. One mechanism of thyroid hormone action is regulation of gene expression, because thyroid hormone receptors (TRs) are ligand-activated transcription factors. We used differential display to identify genes affected by acute T(4) administration to the dam before the onset of fetal thyroid function. Eight of the 11 genes that we identified were selectively expressed in brain areas known to contain TRs, indicating that these genes were directly regulated by thyroid hormone. Using in situ hybridization, we confirmed that the cortical expression of both neuroendocrine-specific protein (NSP) and Oct-1 was affected by changes in maternal thyroid status. Additionally, we demonstrated that both NSP and Oct-1 were expressed in the adult brain and that their responsiveness to thyroid hormone was retained. These data are the first to identify thyroid hormone-responsive genes in the fetal brain.

Maternal hypothyroxinemia influences glucose transporter expression in fetal brain and placenta.

The influence of maternal hypothyroxinemia on the expression of the glucose transporters, GLUT1 and GLUT3, in rat fetal brain and placenta was investigated. Fetal growth was retarded in hypothyroxinemic pregnancies, but only before the onset of fetal thyroid hormone synthesis. Placental weights were normal, but placental total protein concentration was reduced at 19 days gestation (dg). Immunoblotting revealed a decreased abundance of GLUT1 in placental microsomes at 16 dg, whereas GLUT3 was increased. Fetal serum glucose levels were reduced at 16 dg. In fetal brain, the concentration of microsomal protein was deficient at 16 dg and the abundance of parenchymal forms of GLUT1 was further depressed, whereas GLUT3 was unaffected. Northern hybridization analysis demonstrated normal GLUT1 mRNA levels in placenta and fetal brain. In conclusion, maternal hypothyroxinemia results in fetal growth retardation and impaired brain development before the onset of fetal thyroid function. Glucose uptake in fetal brain parenchyma may be compromised directly, due to deficient GLUT1 expression in this tissue, and indirectly, as a result of reduced placental GLUT1 expression. Though corrected by the onset of fetal thyroid hormone synthesis, these deficits are present during the critical period of neuroblast proliferation and may contribute to long term changes in brain development and function seen in this model and in the progeny of hypothyroxinemic women.

Biological activities of thyroid hormone receptors.

In recent years a large amount of data has been gathered on the biology of thyroid hormone receptors. The receptor proteins have been analyzed from the physiological and structural points of view. Most of the information has been summarized in several recent excellent reviews (1–6). The thyroid hormone receptors (TR) are ligand-modulated transcription factors which are members of a large superfamily that includes nuclear receptors for other small, hydrophobic molecules such as steroids, vitamin D3, retinoic acid, prostaglandins, terpenoids, farnesoids and fatty acids, and also the so-called orphan receptors with no recognizable ligand. They bind triiodothyronine (T3) with an affinity about 10 times higher than thyroxine (T4) and activate or repress gene expression upon ligand binding. In addition, an important property of the thyroid hormone receptors is their ability to influence gene expression in the absence of the hormone. In most cases this is reflected in a repression of the target genes which is relieved upon ligand binding, although there are also examples of ligand-independent stimulation of transcription. Little is known of the biological consequences of this intrinsic receptor property. The repressor activity of mutated T3 receptors that have lost the ability to bind hormone is considered to play a role in the pathogenesis of the thyroid hormone resistance syndromes. Receptor expression during development precedes the onset of fetal thyroid function and, with the reservations imposed by placental transfer of maternal thyroid hormone, the unliganded receptor might influence fetal development through mechanisms that are at present unknown. To shed light on this problem, we and others have analyzed the influence of exogenous T3 receptor expression on the phenotype of cultured cells which express no or little T3 receptors unless engineered to do so. The purpose of this review is to summarize the available data in this direction and to try to formulate an hypothesis concerning receptor function.

Maternal hypothyroxinaemia during the first half of gestation in an iodine deficient area with endemic cretinism and related disorders

Iodine deficiency is well known as the cause of several disorders such as endemic goitre and cretinism, along with a wide spectrum of psychoneurological development disorders including endemic mental deficiency and endemic cognitive deficiency, which are generally correlated to damage to the fetus. Such damage is, by inference, deemed a consequence either directly of iodine deficiency or of insufficient availability of thyroxine at the feto-placental unit level. Early pregnancy represents the crucial period for neurogenesis in the embryo. Several experimental studies have emphasized the direct role of maternal T4 in neurological embryogenesis, before the onset of fetal thyroid function and, therefore, its protective role in fetal thyroid failure. The objective of this study was to evaluate whether iodine deficiency may influence thyroid status of pregnant women throughout the first half of pregnancy. Thyroid function tests including total and free T4 and T3, TBG and TSH along with urinary iodine excretion were measured in the serum of pregnant women from an iodine deficient endemic goitre area in north-eastern Sicily, at 8, 13 and 20 weeks of gestation. The times of sampling were chosen to correspond approximately to a period prior to, coincident with and after the onset of fetal thyroid function, respectively. The longitudinal study was undertaken in 16 euthyroid pregnant women from the iodine deficient area in which major iodine deficiency disorders such as endemic cretinism and endemic cognitive deficiency in schoolchildren still persist (area A) and in 7 age matched volunteer pregnant women from a marginally iodine sufficient area (area B). Hormones and TBG were measured using commercial kits. Urinary iodine was measured by an automated method. The divergent changes in serum T4 and TBG with pregnancy progression induced a progressive TBG desaturation by T4 during the whole study period (from 22 to 17% in area A, ANOVA two-way F = 18.9, P < 0.0001; from 33 to 20% in area B, F = 20.7, P < 0.0005) in both areas. At 20 weeks, average FT4 levels were lower in area A than in area B (11.5 +/- 2.5 vs 14.3 +/- 2.4 pmol/l, t = 2.7 P < 0.01) and were below the normal range in 2/16 and borderline-low in 6/16 pregnant women. FT4 serum levels were inversely related to TSH concentrations (r = -0.54, P < 0.0001) which progressively increased, in area A, during the whole study period (F = 6.0, P < 0.01) and were abnormally high in the two women with low FT4, but not in area B. Also in area A (F = 3.4, P < 0.05) a significant T3/T4 molar ratio increase was observed. Iodine deficiency induces in early pregnancy a series of events (reduced synthesis of maternal T4, TBG desaturation by T4, critical decrease of FT4 levels with consequent TSH increase) responsible for overt or marginal biochemical hypothyroidism in about 50% of pregnant women. It is hypothesized that the imbalance of maternal thyroid hormone homeostasis during pregnancy as a consequence of endemic iodine deficiency may be responsible for the impaired psychoneurological development observed in children from that area so appropriate iodine and/or thyroxine prophylaxis to women in that region may prevent the neurobehavioural, cognitive and motor compromise of the population.