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.

Most mammals have two types of cone photoreceptors, which contain either medium wavelength (M) or short wavelength (S) opsin. The number and spatial organization of cone types varies dramatically among species, presumably to fine-tune the retina for different visual environments. In the mouse, S-and M-opsin are expressed in an opposing dorsal-ventral gradient. We previously reported that cone opsin patterning requires thyroid hormone ␤2, a nuclear hormone receptor that regulates transcription in conjunction with its ligand, thyroid hormone (TH). Here we show that exogenous TH inhibits S-opsin expression, but activates M-opsin expression. Binding of endogenous TH to TR␤2 is required to inhibit S-opsin and to activate M-opsin. TH is symmetrically distributed in the retina at birth as S-opsin expression begins, but becomes elevated in the dorsal retina at the time of M-opsin onset (postnatal day 10). Our results show that TH is a critical regulator of both S-opsin and M-opsin, and suggest that a TH gradient may play a role in establishing the gradient of M-opsin. These results also suggest that the ratio and patterning of cone types may be determined by TH availability during retinal development.photoreceptor ͉ retinal development ͉ nuclear hormone receptor T hyroid hormone (TH) is secreted mostly as thyroxine (T4) from the thyroid gland and converted locally to a transcriptionally active form, 3,5,3Ј-triiodothyronine (T3), by iodothyronine deiodinating enzymes (1). T3 receptors bind to DNA regulatory elements, often as heterodimers with retinoid X receptors (RXRs), to activate or repress transcription of target genes (for review, see refs. 2 and 3). T3 regulates diverse developmental processes in multiple regions of the central nervous system including the hippocampus, cerebral cortex, inner ear, and cerebellum (4-8). Numerous developmental processes are TH-dependent, including cell differentiation, migration, and dendritic growth (2, 3, 9-11). Perturbations in maternal or fetal TH in humans can lead to clinical syndromes ranging from severe mental retardation and hearing loss to mild or moderate deficits in motor skills, language, memory, and attention (12)(13)(14).In the retina, the TH ␤2 receptor isoform (TR␤2) is restricted to cone photoreceptors (15, 16), and we previously showed that it is a critical regulator of late-stage cone differentiation. In the first stage of cone differentiation, cones exit the cell cycle and begin to express specific transcription factors, including cone rod homeobox (CRX), TR␤2,. In the second stage of differentiation, cones express opsin and form specific synaptic connections. Most mammalian cones express short wavelength (S-opsin) or medium wavelength (M-opsin) opsin. However, the spatial arrangement of cone types varies considerably among species. In mice, S-opsin expression begins just before birth and is expressed predominantly in ventral cones. By contrast, M-opsin expression begins at the end of the first postnatal week and is expressed predominantly in dorsal cones (21, 22...

Background: Maternal hypothyroxinemia, due to gestational iodine deficiency, causes neurological dysfunctions in the progeny. Our aim was to determine the effects of delayed iodine supplementation (200 mg KI per day) to mildly hypothyroxinemic pregnant women at the beginning of gestation (i.e., having circulating free thyroxine [FT 4 ] within the 0th-10th percentile interval and normal thyrotropin [TSH]) on the neurobehavioral development of their children. Methods: Using the Brunet-Lézine scale, we evaluated the neurocognitive performance at 18 months of age in three groups of children. Group 1 included children of women with FT 4 above the 20th percentile at 4-6 gestational weeks and at full-term. Group 2 included children of mildly hypothyroxinemic women diagnosed during the first 12-14 gestational weeks and with FT 4 above the 20th percentile at full-term. Group 3 included children born to mildly hypothyroxinemic women at full-term, without iodine supplementation during gestation. Women of all groups were iodine supplemented from the day of enrollment until the end of lactation. Results: Before iodine supplementation, 33.0% of the women (114 out of 345) were hypothyroxinemic, with FT 4 below normal in 28 of them (8.1%). None were found to be hypothyroxinemic at full-term after supplementation. The mean (AESD) developmental quotient of children was 101.8 AE 9.7 in group 1 (n ¼ 13) vs. 87.5 AE 8.9 in group 3 (n ¼ 19; p < 0.001) and 92.2 AE 5.4 in group 2 (n ¼ 12; p < 0.05). The difference between groups 2 and 3 was not statistically significant. Delayed neurobehavioral performance was observed in 36.8% and 25.0% of children in groups 3 and 2, respectively, compared with no children in group 1. Differences ( p < 0.001) were found on gross and fine motor coordination and socialization quotients. No statistically significant differences were found on language quotients. Conclusions: A delay of 6-10 weeks in iodine supplementation of hypothyroxinemic mothers at the beginning of gestation increases the risk of neurodevelopmental delay in the progeny. Public health programs should address the growing problem of iodine deficiency among women of gestational age in developing and industrialized nations.

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Epidemiological studies and case reports show that even a relatively minor degree of maternal hypothyroxinemia during the first half of gestation is potentially dangerous for optimal fetal neurodevelopment. Our experimental approach was designed to result in a mild and transient period of maternal hypothyroxinemia at the beginning of corticogenesis. Normal rat dams received the goitrogen 2-mercapto-1-methyl-imidazole for only 3 d, from embryonic d 12 (E12) to E15. Maternal thyroid hormones decreased transiently to 70% of normal serum values, without clinical signs of hypothyroidism. Dams were injected daily with 5-bromo-2'-deoxyuridine (BrdU) during 3 d, from E14-E16 or E17-E19. Their pups were tested for audiogenic seizure susceptibility 39 d after birth (P39) and killed at P40. Cells that had incorporated BrdU were identified by immunocytochemistry, and quantified: numerous heterotopic cells were found, whether labeled at E14-E16 or E17-E19, that were identified as neurons. The cytoarchitecture and the radial distribution of BrdU-labeled neurons was significantly affected in the somatosensory cortex and hippocampus of 83% of the pups. The radial distribution of gamma-aminobutyric acidergic neurons was, however, normal. The infusion of dams with T4 between E13 and E15 avoided these alterations, which were not prevented when the T4 infusion was delayed to E15-E18. In total, 52% of the pups born to the goitrogen-treated dams responded to an acoustic stimulus with wild runs, followed in some by seizures. When extrapolated to man, these results stress the need for prevention of hypothyroxinemia before midpregnancy, however moderate, and whichever the underlying cause.

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.

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

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