The present comments are restricted to the role of maternal thyroid hormone on early brain development, and are based mostly on information presently available for the human fetal brain. It emphasizes that maternal hypothyroxinemia - defined as thyroxine (T4) concentrations that are low for the stage of pregnancy - is potentially damaging for neurodevelopment of the fetus throughout pregnancy, but especially so before midgestation, as the mother is then the only source of T4 for the developing brain. Despite a highly efficient uterine-placental 'barrier' to their transfer, very small amounts of T4 and triiodothyronine (T3) of maternal origin are present in the fetal compartment by 4 weeks after conception, with T4 increasing steadily thereafter. A major proportion of T4 in fetal fluids is not protein-bound: the 'free' T4 (FT4) available to fetal tissues is determined by the maternal serum T4, and reaches concentrations known to be of biological significance in adults. Despite very low T3 and 'free' T3 (FT3) in fetal fluids, the T3 generated locally from T4 in the cerebral cortex reaches adult concentrations by midgestation, and is partly bound to its nuclear receptor. Experimental results in the rat strongly support the conclusion that thyroid hormone is already required for normal corticogenesis very early in pregnancy. The first trimester surge of maternal FT4 is proposed as a biologically relevant event controlled by the conceptus to ensure its developing cerebral cortex is provided with the necessary amounts of substrate for the local generation of adequate amounts of T3 for binding to its nuclear receptor. Women unable to increase their production of T4 early in pregnancy would constitute a population at risk for neurological disabilities in their children. As mild-moderate iodine deficiency is still the most widespread cause of maternal hypothyroxinemia in Western societies, the birth of many children with learning disabilities may already be preventable by advising women to take iodine supplements as soon as pregnancy starts, or earlier if possible.

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An inadequate supply of iodine during gestation results in damage to the foetal brain that is irreversible by mid-gestation unless timely interventions can correct the accompanying maternal hypothyroxinemia. Even mild to moderate maternal hypothyroxinemia may result in suboptimal neurodevelopment. This review mainly focuses on iodine and thyroid hormone economy up to mid-gestation, a period during which the mother is the only source for the developing brain of the foetus. The cerebral cortex of the foetus depends on maternal thyroxine (T 4 ) for the production of the 3 0 ,3,5-tri-iodothyronine (T 3 ) for nuclear receptor-binding and biological effectiveness. Maternal hypothyroxinemia early in pregnancy is potentially damaging for foetal brain development. Direct evidence has been obtained from experiments on animals: even a relatively mild and transient hypothyroxinemia during corticogenesis, which takes place mostly before mid-gestation in humans, affects the migration of radial neurons, which settle permanently in heterotopic locations within the cortex and hippocampus. Behavioural defects have also been detected. The conceptus imposes important early changes on maternal thyroid hormone economy that practically doubles the amount of T 4 secreted something that requires a concordant increase in the availability of iodine, from 150 to 250-300 mg I day 21 . Women who are unable to increase their production of T 4 early in pregnancy constitute a population at risk for having children with neurological disabilities. As a mild to moderate iodine deficiency is still the most widespread cause of maternal hypothyroxinemia, the birth of many children with learning disabilities may be prevented by advising women to take iodine supplements as soon as pregnancy starts, or earlier if possible, in order to ensure that their requirements for iodine are met.

Thyroid hormone plays an essential role in mammalian brain maturation and function, in large part by regulating the expression of specific neuronal genes. In this tissue, the type 2 deiodinase (D2) appears to be essential for providing adequate levels of the active thyroid hormone 3,5,3-triiodothyronine (T3) during the developmental period. We have studied the regional and cellular localization of D2 mRNA in the brain of 15-day-old neonatal rats. D2 is expressed in the cerebral cortex, olfactory bulb, hippocampus, caudate, thalamus, hypothalamus, and cerebellum and was absent from the white matter. At the cellular level, D2 is expressed predominantly, if not exclusively, in astrocytes and in the tanycytes lining the third ventricle and present in the median eminence. These results suggest a close metabolic coupling between subsets of glial cells and neurons, whereby thyroxine is taken up from the blood and͞or cerebrospinal f luid by astrocytes and tanycytes, is deiodinated to T3, and then is released for utilization by neurons.Thyroid hormone controls a number of metabolic and developmental processes and, in particular, is an essential factor for normal mammalian brain maturation (1). In humans and other species, thyroid deficiency during the perinatal period results in irreversible brain damage and mental retardation (1, 2). The effects of thyroid hormone result primarily from changes in gene expression mediated through the binding of the active compound 3,5,3Ј-triiodothyronine (T3) to specific nuclear receptors of the steroid-retinoic acid-thyroid hormone superfamily. Previous studies have demonstrated that T3 nuclear receptors are expressed in a complex temporal pattern in specific regions of the brain that include the cerebral cortex, hippocampus, striatum, cerebellum, and hypothalamus (3, 4). These receptors are found predominantly in neurons and oligodendrocytes (5-7), and a number of neuronal genes have been shown to be regulated by thyroid hormone during development (8, 9).The majority of T3 in the brain is produced locally within the central nervous system by the 5Ј-deiodination of thyroxine (T4) (10). The type 2 deiodinase (D2) appears to be of particular importance in catalyzing the conversion of T4 to T3 in the brain during fetal and early neonatal life (11)(12)(13). During this period in the rat, the expression of D2 activity in brain increases at the end of gestation and is highest at 15-20 days of postnatal life (14). This pattern of activity corresponds temporally to the period when the developing brain is most dependent on thyroid hormone and correlates with increasing brain T3 concentrations, which peak at 2 weeks of age (13).An important property of the D2 is that its activity is markedly increased by thyroid hormone deficiency (15). This enhanced D2 activity serves to maintain T3 production in the brain in the face of limiting amounts of the prohormone T4 (16). Brain T3 levels thus appear to be protected to a considerable extent by alterations in circulating thyroid hormone levels (12...

Abstractsue-specific and dose-related changes in tissue T3 concentra-We have studied whether, or not, tissue-specific regulatory mechanisms provide normal 3,5,3'-triiodothyronine (T3) concentrations simultaneously in all tissues of a hypothyroid animal receiving thyroxine (T4), an assumption implicit in the replacement therapy of hypothyroid patients with T4 alone. 1. Abbreviations used in this paper: 5 'D-I, type I 5'-iodothyronine deiodinase; 5 'D-II, type II 5 '-iodothyronine deiodinase; SD-III, 5-deiodinase; BAT, brown adipose tissue (interscapular pads); BW, body weight; Cb, cerebellum; Cx, cerebral cortex; d.f., degrees of freedom; H, heart; K, kidney; L, liver; Lu, lung; Mu, skeletal muscle (musculus quadriceps femoris); P1, plasma; PTU, 2-N-propyl-6-thiouracil; R2, coefficient of determination; rT3, reverse 3,5 ',3 '-triiodothyronine; S, spleen; T3, 3,5,3 '-triiodothyronine; T3S, 3,5,3 '-triiodothyronine sulfate; T4, thyroxine; TSH, thyroid-stimulating hormone.tions.In conclusion, euthyroidism is not restored in plasma and all tissues of thyroidectomized rats on T4 alone. These results may well be pertinent to patients on T4 replacement therapy. (J. Clin. Invest. 1995Invest. . 96:2828Invest. -2838

Thyroid hormone is a critical determinant of cellular metabolism and differentiation. Precise tissue-specific regulation of the active ligand 3,5,3′-triiodothyronine (T3) is achieved by the sequential removal of iodine groups from the thyroid hormone molecule, with type 3 deiodinase (D3) comprising the major inactivating pathway that terminates the action of T3 and prevents activation of the prohormone thyroxine. Using cells endogenously expressing D3, we found that hypoxia induced expression of the D3 gene DIO3 by a hypoxiainducible factor-dependent (HIF-dependent) pathway. D3 activity and mRNA were increased both by hypoxia and by hypoxia mimetics that increase HIF-1. Using ChIP, we found that HIF-1α interacted specifically with the DIO3 promoter, indicating that DIO3 may be a direct transcriptional target of HIF-1. Endogenous D3 activity decreased T3-dependent oxygen consumption in both neuronal and hepatocyte cell lines, suggesting that hypoxia-induced D3 may reduce metabolic rate in hypoxic tissues. Using a rat model of cardiac failure due to RV hypertrophy, we found that HIF-1α and D3 proteins were induced specifically in the hypertrophic myocardium of the RV, creating an anatomically specific reduction in local T3 content and action. These results suggest a mechanism of metabolic regulation during hypoxic-ischemic injury in which HIF-1 reduces local thyroid hormone signaling through induction of D3.

Thyroid hormones are required for human brain development, but data on local regulation are limited. We describe the ontogenic changes in T(4), T(3), and rT(3) and in the activities of the types I, II, and III iodothyronine deiodinases (D1, D2, and D3) in different brain regions in normal fetuses (13-20 wk postmenstrual age) and premature infants (24-42 wk postmenstrual age). D1 activity was undetectable. The developmental changes in the concentrations of the iodothyronines and D2 and D3 activities showed spatial and temporal specificity but with divergence in the cerebral cortex and cerebellum. T(3) increased in the cortex between 13 and 20 wk to levels higher than adults, unexpected given the low circulating T(3). Considerable D2 activity was found in the cortex, which correlated positively with T(4) (r = 0.65). Cortex D3 activity was very low, as was D3 activity in germinal eminence and choroid plexus. In contrast, cerebellar T(3) was very low and increased only after midgestation. Cerebellum D3 activities were the highest (64 fmol/min.mg) of the regions studied, decreasing after midgestation. Other regions with high D3 activities (midbrain, basal ganglia, brain stem, spinal cord, hippocampus) also had low T(3) until D3 started decreasing after midgestation. D3 was correlated with T(3) (r = -0.682) and rT(3)/T(3) (r = 0.812) and rT(3)/T(4) (r = 0.889). Our data support the hypothesis that T(3) is required by the human cerebral cortex before midgestation, when mother is the only source of T(4). D2 and D3 play important roles in the local bioavailability of T(3). T(3) is produced from T(4) by D2, and D3 protects brain regions from excessive T(3) until differentiation is required.

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 of T3 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 of T3 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 of a hypothyroid fetus. Recent confirmation of transplacental passage of T4 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.)