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Mount Sinai School of Medicine Department of Human Genetics New York, New York 10029
Address all correspondence and requests for reprints to: Douglas Forrest, Mount Sinai School of Medicine, Department of Human Genetics, 1425 Madison Avenue, New York, New York 10029. E-mail: douglas.forrest{at}mssm.edu.
It is well known that thyroid hormone is necessary for the correct development of the brain and the mental function of the child. A question that we know less about, however, concerns the developmental time periods during which the brain is sensitive to thyroid hormone. The need for thyroid hormone at and after birth is well established: routine neonatal screening can identify infants with thyroid deficiencies, and very importantly this information allows treatment with replacement hormone in time to reduce subsequent neurological impairment. In countries with the resources for comprehensive screening, congenital hypothyroidism is detected in about 1 in 3500 newborns (1). Studies in animal models have identified a number of cellular migration and differentiation events in the postnatal brain that depend upon thyroid hormone (2). This postnatal brain maturation requires a functioning thyroid gland in the offspring and adequate iodine nutrition for the biosynthesis of the hormone. However, what remains less clear is the sensitivity of the fetal brain to thyroid hormone and the role of maternal thyroid hormone in promoting brain development in utero.
The clarification of the role of maternal thyroid hormone in the fetal brain poses a challenge in developmental biology and also has possible relevance to human health. One implication is whether there are prenatal measures that should be considered with a view to preventing potential mental damage in the offspring of women who have thyroid deficiencies during pregnancy. Evidence to define a role for maternal thyroid hormone in the early fetal brain is not necessarily easy to obtain given the complexity of maternal-fetal interactions and the changing sources of hormone during gestation and the postnatal period (Fig. 1
). Some suggestive evidence is found in regions of the world where endemic iodine deficiency is a persistent problem. Iodine deficiency can impose a chronic, combined maternal-fetal hypothyroidism from the earliest stages after conception with the offspring being at risk of severe mental retardation and deaf-mutism (3, 4). However, the final symptoms observed in such children reflect a cumulative deficiency of maternal, fetal, and neonatal thyroid hormone sources over a prolonged period.
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The consequences of the transient thyroid impairment in utero were assessed in young adult offspring at 40 d of age. In the forebrain, some histological markers were permanently altered in the somatosensory cortex and hippocampus. The layered structure of the neocortex is formed by progressive phases of neuronal migration beginning before midgestation. In the offspring of treated dams, the migration was retarded such that significant numbers of misplaced neurons were found in deep-lying layers. The time of generation of these cells was correlated with the period of thyroid deficiency in utero by concomitant treatment with bromodeoxyuridine, which marked dividing cells at that time. The offspring were also susceptible to audiogenic seizures, a known consequence of more chronic thyroid impairment in rodents (6). It is noteworthy that the treatment caused only a modest drop in thyroid hormone levels in the dams to 70% of normal. Thus, the findings suggest that a transient and moderate deficiency of maternal thyroid hormone during pregnancy can have deleterious consequences on brain morphology and behavior in the offspring.
Do the findings of Auso et al. (5) have implications for the human population? The authors support the view that thyroid function should be monitored carefully from the earliest stages of pregnancy to avoid the possibility of defects in brain development resulting from maternal thyroid deficiency (7, 8). Moderate thyroid hormone abnormalities are more common, and unless specifically tested for, are less likely to be noticed than are overt thyroid disorders. Although severe iodine deficiency is not a major concern in countries where iodine is supplemented in salt or other foods, iodine intake has shown some decline since 1974, probably through changing diets (9). Are borderline or slightly low iodine levels therefore a possible risk factor? The American Thyroid Association has issued a statement addressing these health issues and has advocated research to investigate the incidence of thyroid imbalances such as subclinical hypothyroidism and hypothyroxinemia and their possible consequences in pregnant women (http://www.thyroid.org).
What are the underlying mechanisms that control the transfer of maternal thyroid hormone to the fetus and to the fetal brain tissues? Further research is needed to identify the genes that regulate these events and where and when these genes are expressed in the fetus. Thyroid hormone transporters are presumably involved at some stages, and there has been some encouraging progress in this area (10, 11). The deiodinase enzymes that metabolize thyroid hormone into active and inactive forms are also likely to play a role (12). Type 2 deiodinase, which converts T4, the main circulating form of thyroid hormone into T3, the major active form of the hormone, is thought to assist in maintaining thyroid hormone levels in the brain (13, 14). To some extent, a deficiency of thyroid hormone may be compensated for by increased activity of type 2 deiodinase and a resultant increase in generation of T3. However, the data of Auso et al. (5) imply that even with a mild thyroid hormone deficiency, deiodinases cannot afford full protection to the fetal brain. Some functions evidently remain sensitive to moderate fluctuations of maternal hormone.
A paradox of thyroid hormone is that, although we know it is critical for the correct function of the brain, the developmental mechanisms by which it achieves this end remain rather poorly defined. This is especially true in the embryonic brain. Auso et al. (5) describe a few, selected histological markers in the cortex, but other functions await identification. Thyroid hormone receptors, particularly those encoded by the Thra/THRA gene are widely expressed in the fore-, mid-, and hindbrain regions of the early embryo (15). Mutation of Thra in mouse embryonic stem cells has been shown to impair the capacity of these cells for neuronal differentiation in culture (16). In keeping with the potent but somewhat stealthy actions of thyroid hormone as a maturation factor in other systems (15), its role in the early brain may not involve gross morphogenesis. Rather, thyroid hormone may promote subtle but critical events in neuronal differentiation and function. Although these events may be programmed in the early brain, they may not ultimately become evident until later in the maturing brain.
To piece together the cellular and molecular basis of the functions of thyroid hormone in the early developing brain will probably require cross-disciplinary approaches including anatomical as well as behavioral (17, 18) and electrophysiological (19) analyses. The identification of downstream target genes in the fetal brain should provide another important piece of the puzzle. Some thyroid hormone-responsive genes have been found in the brain in the mid-gestational rat embryo (20). Perhaps with further advances, the early embryonic brain need no longer be viewed as a black box of suspected but ill-defined responses to thyroid hormone.
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Acknowledgments |
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Footnotes |
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Received May 11, 2004.
Accepted for publication May 11, 2004.
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References |
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gene dominant-negative mutation (P398H) selectively impairs gene expression in differentiated embryonic stem cells. Endocrinology 143:2664–26721 is associated with selective alterations in behavior and hippocampal circuits. Mol Psychiatry 8:30–38[CrossRef][Medline]
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