This article is based on a presentation at the 20th Rochester Conference on Environmental Toxicity titled "The Role of Environmental Neurotoxicants in Developmental Disabilities" held 23-25 September 1998 in Rochester, New York.
Address correspondence to S.P. Porterfield, CB #1841, Medical College of Georgia, Augusta, GA 30912 USA. Telephone: (706) 721-3217. Fax: (706) 721-7244. E-mail: sporterf@mail.mcg.edu
Received 5 November 1999; accepted 28 February 2000.
Thyroid hormones are essential for normal brain development in animals and humans and either excess or deficient hormone levels produce significant neurologic impairment if abnormal exposure to environmental chemicals occurs during specific developmental windows. The relationship between polyhalogenated biphenyls and neurologic function is complex. Prenatal exposure to specific biphenyls has been associated with abnormalities in neurologic function. Because toxicant exposure can alter brain thyroid hormone availability and the effects of toxicant exposure frequently resemble those of prenatal hypothyroidism (
1), there is a need to establish more definitive relationships between toxicant exposure and neurologic function. The complexity of the developing nervous system makes this a difficult task. Because many of these toxicants can produce neurotoxicity independently of any action on the thyroid system, it is important that both those actions mediated independently of the thyroid, perhaps through the aryl hydrocarbon (Ah) receptor, and those mediated through the thyroid system be defined. This requires further research at the cellular and molecular levels. These studies are complicated by the fact that transport of either hormones or the toxicants into brain is complex and involves multiple pathways with multiple potential regulatory points.
The thyroid, pituitary, and hypothalamus begin development early in gestation (
2). Thyroid hormone synthesis begins at 10-12 weeks gestation (
3), and serum thyroid hormone levels rise progressively throughout the remainder of gestation (
4). The hypothalamic-pituitary-thyroid axis is functional by the latter half of gestation, and maturation continues until approximately 2 months postpartum in humans (
5). Ligand-bound thyroid hormone receptors are seen by 10 weeks gestation in humans (
6).
Thyroid hormones are important regulators of brain development during the fetal and neonatal periods. They control neuronal and glial proliferation in definitive brain regions and regulate neuronal migration and differentiation. Differentiation includes the development of neuronal connectivity and myelination. Because neurologic development occurs in discrete developmental windows, the role of thyroid hormones in orchestrating the timing of specific developmental events and signals is crucial and even transient disorders in thyroid hormone availability can have profound effects on brain development.
Endemic Cretinism
The most severe neurologic impairment resulting from a thyroid deficiency is in endemic cretinism caused by iodine deficiency. In fact, iodine deficiency represents the single most preventable cause of neurologic impairment and cerebral palsy in the world today (7,8). These individuals suffer from hypothyroidism that begins at conception because the dietary iodine deficiency prevents synthesis of normal levels of thyroid hormones. It is more severe than that seen in congenital hypothyroidism because the deficiency occurs much earlier in development and results in decreased brain thyroid hormone exposure both before and after the time the fetal thyroid begins functioning. Problems with endemic cretins include mental retardation that can be profound, spastic dysplasia, and problems with gross and fine motor control resulting from damage to both the pyramidal and the extrapyramidal systems. These problems include disturbances of gait, and in the more extreme forms, the individuals cannot walk or stand (8-10). If postnatal hypothyroidism is present, there is growth retardation and delayed or absent sexual maturation (3). Damage occurs both to structures such as the corticospinal system that develop relatively early in the fetus and structures such as the cerebellum that develop predominantly in the late fetal and early neonatal period. The damage is inversely related to maternal serum thyroxine (T4) levels but not to triiodothyronine (T3) levels (3,8,11). Delong (12) suggests that the neurologic damage occurs primarily in the second trimester, which is an important period for formation of the cerebral cortex, the extrapyramidal system, and the cochlea, areas damaged in endemic cretins. Maternal T3 levels are often normal and the mother therefore may not show any overt symptoms of hypothyroidism. Early development of the auditory system appears to be dependent upon thyroid hormones (13). The greater impairment characterized by endemic cretinism relative to congenital hypothyroidism is thought to result from the longer period of exposure of the developing brain to hypothyroidism in endemic cretinism (3,7,8).
Congenital Hypothyroidism
Untreated congenital hypothyroidism (sporadic cretinism) produces neurologic deficits having predominantly postnatal origins. Although mental retardation can occur, it typically is not as severe as that seen in neurologic cretinism. Untreated infants with severe congenital hypothyroidism can lose 3-5 IQ points per month if untreated during the first 6-12 months of life (14). If the children are treated with thyroid hormones soon after birth, the more severe effects of thyroid deficiency are alleviated. However, these children are still at risk for mild learning disabilities. They may show subtle language, neuromotor, and cognitive impairment (15). They are more likely to show attention deficit hyperactivity disorder (ADHD), have problems with speech and interpretation of the spoken word, have poorer fine motor coordination, and have problems with spatial perception (16). The severity of these effects is correlated with the retardation of bone ossification seen at birth. This would suggest that the damage is correlated with the mild hypothyroidism they experience in utero. Rovet and Ehrlich (17) have proposed that the sensitive periods for thyroid hormones vary for verbal and nonverbal skills. The critical period for verbal and memory skills appears to be in the first 2 months postpartum, whereas for visuospatial or visuomotor skills it is prenatal.
Thyroid hormone deficiency impairs learning and memory, which depend on the structural integrity of the hippocampus. Maturation and synaptic development of the pyramidal cells of the hippocampus are particularly sensitive to thyroid hormone deficiency during fetal/perinatal development (18). Early in fetal development (rats), thyroid hormone deficiency decreases radial glial cell maturation and therefore impairs cellular migration (19), which can lead to irreversible changes in the neuronal population and connectivity in this region. Animals with experimentally induced congenital hypothyroidism show delayed and decreased axonal and dendritic arborization in the cerebral cortex, a decrease in nerve terminals, delayed myelination, abnormal cochlear development, and impaired middle ear ossicle development (3).
Resistance to Thyroid Hormones
Resistance to thyroid hormones (RTH) is a genetic disorder typically resulting from a point mutation of the gene producing the thyroid hormone beta receptor (TRß). The presence of the mutant gene can exert a dominant negative effect on thyroid hormone receptor alpha (TR
)-directed transactivation (20). People with RTH commonly show neurologic deficiencies that include a higher incidence of auditory deficiencies and a relatively high incidence of ADHD (21). This impairment has been confirmed through behavioral testing and magnetic resonance imaging of the sylvian fissure show discrete structural abnormalities in the cerebral cortex (22). The latter damage would most likely result from a deficient action of thyroid hormones in utero and the early postnatal period.
Data from Animals
If pregnant rats are treated with the goitrogen propylthiouracil (PTU) early in pregnancy, it delays neuronal proliferation in both the motor and the mesencephalic nuclei of the trigeminal nerve. These neurons normally form relatively early in gestation at a period that would correspond to the first half of gestation in humans (23). Eventually these neurons are produced, but the timing of neuronal birth, migration, and synaptogenesis is finely tuned and if neurons are not formed at the appropriate time, they may never reach the right cell layer of the brain and form normal neuronal synapses. Disorganization of the cellular layers of the cerebellar cortex has been shown to occur in postnatal hypothyroidism in rats (24). The cellular changes reported by Narayanan and Narayanan (23) are reflected in behavioral effects. The trigeminal nerve is important for suckling and the PTU-treated pups had difficulty suckling. Rat fetuses exposed to slightly lower brain thyroid hormone levels in utero have problems with learning and memory and are hyperactive as adults, even though thyroid hormone levels are normal as adults (25) (Figure 1).
Figure 1. Errors in a Lashley Maze by progeny of hypothyroid (Tx) rats versus progeny of control rats. The progeny of Tx dams are exposed to low levels of thyroid hormones during most of fetal development. While the control progeny learn the maze over 10 trials (trials 2-10 < 1; 4-10 < 2; 8-10 < 3; p = 0.05), the progeny of Tx dams never learn the maze during that period. Data from Hendrich et al. (25).
Thyroid hormone deficiency during a critical developmental period can impair cellular migration and development of neuronal networks. Neuronal outgrowth and cellular migration are dependent on normal microtubule synthesis and assembly and these latter processes are regulated by thyroid hormones (
26). During cerebral development, postmitotic neurons forming near the ventricular surface must migrate long distances to reach their final destination in the cortical plate where they form a highly organized 6-layer cortical structure. Appropriate timing of this migration is essential if normal connectivity is to be established. This migration depends not only upon specialized cells such as the radial glial cells that form a scaffolding system but also on specific adhesion molecules in the extracellular matrix that are associated with the focal contacts linking migrating neurons with radial glial fibers (
27). These neurons migrate along radial glial fibers, and following neuronal migration, the radial glial cells often degenerate or become astrocytes (
28). Migration also depends on adhesive interactions involving extracellular matrix proteins such as laminin and the cell-surface receptor integrin. Laminin is synthesized by astrocytes and bound to the astrocyte surface by the transmembrane receptors integrin and the integrins are held in place by the intracellular astrocyte microfilament network. These macromolecular complexes are called focal contacts and provide directional clues for elongating neurons. T
4 regulates focal contact formation by astrocytes by promoting actin polymerization (
26,
29). T
4 but not T
3 regulates the appearance and regional distribution of laminin in the developing rat cerebellum (
30), as well as the microfilament network associated with integrins, and T
4 but not T
3 directly alters neurite outgrowth and neuronal migration on laminin in cerebellar explants. Disorders of neuronal migration are considered to be major causes of both gross and subtle brain abnormalities (
28). Hypothyroidism during fetal and neonatal development results in delayed neuronal differentiation and decreased neuronal connectivity (
26).
Thyroid hormones regulate development of certain cholinergic and dopaminergic neurotransmitter systems (
31,
32). The cholinergic fibers projecting from the hippocampus to the basal forebrain, including the striatum, are particularly sensitive to thyroid hormone deficiency (
32). These cholinergic fibers are important in memory and learning, and a well-functioning cholinergic system is a prerequisite for performance on spatial learning tasks in rodents (
33). This cholinergic system has also been proposed as a site for damage in ADHD). These brain regions (hippocampus, basal forebrain) have particularly high levels of thyroid hormone receptors during development and are sites where thyroid hormones regulate nerve growth factor (NGF) production (
34-
36). Thyroid hormones and NGF cooperate in the development of specific cholinergic systems in the central nervous system (
37), and thyroid hormones could regulate neurotransmitter development through their action on NGF production in these specific regions. Hypothyroidism decreases choline acetyltransferase (ChAT) quantities in brain regions innervated by these neurons (
32) because thyroid hormones serve as positive regulatory factors for the ChAT gene (
38). This drop in ChAT quantity is preceded by a drop in nerve growth factor receptor (NGFR) levels, suggesting that thyroid hormone actions could be mediated by its action on NGFR production (
32). The development of both dopaminergic and cholinergic systems is delayed in hypothyroidism (
39). In addition, T
3 regulates expression of the neuron-specific gene for synapsin I, an important protein regulating neurotransmitter release and synaptic plasticity (
40). Gliogenesis is delayed as is myelination in hypothyroidism (
3,
26). In this case, the impairment represents a developmental delay rather than a block.
Thyroid hormone synthesis does not begin until 10-12 weeks of gestation in humans and 17 days of gestation in the rat (
3). While many important aspects of brain development occur either before the time of fetal thyroid hormone synthesis or at least before synthesis of high levels of fetal hormone, thyroid hormones are available from the mother during early gestation (
3,
7). Thyroid hormones are present in small quantities in rat and human fetal tissue at the earliest ages that it is feasible to measure tissue hormone levels (
3,
41). These low levels of maternal thyroid hormones might be important for developmental events such as cerebral and brain-stem neurogenesis that occur relatively early in development. The importance of maternal thyroid hormones in fetal brain development is seen in the recently published data of Haddow et al. (
42), showing that maternal thyroid deficiency during pregnancy can impair subsequent neuropsychologic development in children. Later in gestation, both maternal and fetal thyroid hormones are important for fetal brain development. At the time of birth, as much as 17.5% of the thyroid hormones found in the newborn are of maternal origin in rats (
43) and maternal thyroid hormones can produce neonatal thyroid hormone levels approaching the low normal level in congenitally hypothyroid children with a complete inability to synthesize thyroglobulin and therefore thyroid hormones (
44).
Thyroid hormones enter the brain through two routes. The predominant route is via the blood-brain barrier involving direct transport through the capillary endothelium and into the brain cells. Hormone transport via this route depends on the serum hormone levels (influenced by serum protein-binding relationships), the transport systems through the endothelium, and the transport systems into the brain cells. The second and less significant route is via the choroid plexus-cerebrospinal fluid (CSF). The thyroid hormone-binding protein transthyretin (TTR) binds T
4 but not T
3. It is produced by the choroid plexus and secreted into the CSF. The TTR then binds to T
4 that enters CSF through the choroid plexus and may play an important role in T
4 transport to the brain cells. Hydroxylated PCBs have a stronger binding affinity for TTR than even T
4 and therefore the presence of these PCBs could compete with T
4 for transport on TTR. In addition, the transport systems for thyroid hormones across cell membranes involve saturable, stereospecific carrier-mediated transport systems (
45,
46). It is possible that these structurally similar toxicants could also compete with thyroid hormones for transport across cell membranes. Although the T
3 has the higher affinity for the thyroid hormone nuclear receptor, T
4 is the predominant form transported into brain. Most of the brain intracellular T
3 pool is derived from local deiodination of T
4 to T
3 by the enzyme iodothyronine 5´-deiodinase (type II).
Thyroid hormone receptor binding is present in both the fetal rat brain by 13 days of gestation and the fetal human brain by 10 weeks of gestation (
6,
47). Fetal thyroid hormone secretion begins at 17 days postconception in rats and 8-10 weeks in humans (
3,
47). The fetal rat brain contains predominantly TR
1 and TR
2. While small quantities of TRß1 are expressed early in gestation in specific regions such as the fetal rat otic vesicles (the precursor to the cochlea) (
13), most TRß1 expression occurs late in gestation and the rise in expression corresponds with the rise in fetal/neonatal T
4 secretion (
47). The highest concentrations of T
3-binding sites in the adult brain are found in the hippocampus, amygdala, and the cerebral cortex, regions of the brain known to be particularly sensitive to thyroid hormone action (
31).
Thyroid hormone receptors are transcription factors requiring interactions with multiple proteins to regulate gene expression. There are at least three functional thyroid hormone receptors formed from two gene transcripts, TR
1, TRß1, and TRß2. The TR
2 isotype does not bind ligand. However, the presence of the TR
2 isotype is thought to inhibit gene regulation mediated through the other isotypes (
20). Recent data from TR
and TRß null transgenic mice suggest that functions regulated by one receptor type can at least partially be compensated for by the other receptor type (
48).
Work is currently under way characterizing the respective roles of the and ß receptor types. Studies of this nature are complicated by the fact that mutant forms of the gene can exert a dominant negative effect on functions of the other gene, thereby magnifying the severity of the deficiency (20). Thyroid hormone receptors, unlike steroid receptors, do not require ligand to bind to the receptor. In fact, the unliganded alpha receptor present in early fetal development may be an important inhibitor of transcription of certain thyroid hormone-regulated genes. Thyroid hormone receptors dimerize, and they can either form a homodimer with another thyroid hormone receptor or they can form a heterodimer with proteins such as the retinoic acid receptor or retinoid X receptor. The ability of thyroid hormones to turn on or turn off a specific gene is controlled by various proteins acting as corepressors or coactivators. The thyroid hormone receptor is a member of the thyroid hormone-retinoic acid-steroid hormone receptor superfamily and as such shows considerable homology with the retinoic acid and the steroid hormone receptors. Excess retinoic acid can act as a neurologic teratogen.
Thyroid hormones regulate gene expression of a limited number of genes. Genes regulated by thyroid hormones in brain include purkinje cell protein, myelin basic protein, nerve growth factor 1-A, NADH dehydrogenase subunit 3, and rat cortex clone 3 (RC3) (neurogranin or calbindin) (37,49-52). The gene for the phosphocreatine kinase C substrate RC3 is the only gene shown to be regulated by thyroid hormones in the adult, as well as the fetal brain (47). These other genes are developmentally regulated in brain.
Although thyroid hormones have extensive effects on brain development both in vivo and in vitro, only a few genes appear to be directly regulated by thyroid hormones. This disparity could result from multiple potential factors. It is possible that there are intervening factors regulating thyroid hormone-controlled brain development. These could include the potential impact of other hormones, growth factors, or transcription factors. Thyroid hormones are thought by many to be capable of having both genomic and nongenomic actions. Perhaps some of the actions of thyroid hormones on brain development involve nongenomic actions. Farwell and Leonard (53) have shown that thyroid hormone regulation of glial type II iodothyronine 5´-deiodinase, the enzyme converting T4 to T3, results from a direct action of T4 on cellular actin filaments.
Certain PCBs and chlorinated dibenzo-
p-dioxin congeners are structurally similar to the active thyroid hormones (
54). These structural similarities could theoretically lead to endocrine disruption if the compounds act as agonists or antagonists to the naturally occurring hormone. These compounds include many of the 209 congeners of PCBs and many of the 75 possible congeners of the dioxins. Maier et al. (
55) have demonstrated that the
ortho-substituted PCB congeners are more neuroactive than the non-
ortho-substituted congeners and those compounds with lateral halogen substitution exert many of their biologic actions by acting through the Ah receptor. In addition, there are multiple possible mechanisms of action of these compounds on the thyroid system. These compounds are structurally similar to thyroid hormones and therefore have the potential of binding to proteins that characteristically bind thyroid hormones such as the serum-binding proteins or the thyroid hormone receptor. Laterally substituted chlorinated aromatic compounds such as the
meta and
para PCBs, particularly when hydroxylated, are ideally suited to serve as binding ligands for T
4-binding proteins (
54,
56). Because environmental persistence is correlated with lateral substitution, many of the congeners accumulating in the environment are likely to impact the thyroidal system (
55).
These organohalogens could have direct toxic effects on the thyroid, as suggested by the observed histologic changes reported in the glands of animals exposed to certain PCB and 2,3,7,8-TCDDcongeners that are suggestive of the histologic changes occurring in Hashimoto's thyroiditis in humans (
57). These histologic changes are often associated with normal or high serum thyroid-stimulating hormone (TSH) levels with low serum T
4 levels (
58), suggesting a primary thyroidal disorder. Morse et al., (
59) have shown that maternal exposure to Aroclor 1254 significantly decreases fetal and neonatal plasma T
4 levels in a dose-dependent manner and decreases forebrain and cerebellar T
4 concentrations in fetal rats on day 20. The predominant metabolite accumulating in fetal plasma and forebrain was the hydroxylated congener 2,3,3´,4´,5-pentachloro-4-biphenylol. The hydroxylated congeners of PCBs have a high affinity for TTR (
1,
56,
60-
62). Cheek et al. (
62) have shown that half the hydroxylated PCBs they tested had higher affinities than did T
4 for TTR. Only two of the hydroxylated PCBs bound thyroxine-binding globulin, the major transport protein in humans. Only the hydroxylated PCBs inhibited T
3 binding to TRß; binding affinity was less than 1/10,000 that of T
4 (
65). The lower serum T
4 levels in PCB-exposed rats could probably result in part from increased metabolism of thyroid hormones. PCB exposure of perinatal rats (
61) and adult rats (
63) increases biliary excretion of T
4 by inducing the enzyme T
4-uridine diphosphoglucuronyltransferase, thereby increasing hepatic T
4 glucuronidation (
1).
Neurologic Effects of Organohalogens
In many species, including humans, perinatal exposure to certain PCB and dioxin congeners can produce neurologic impairment. Children in Taiwan accidentally exposed prenatally to high levels of PCBs (Yu-Cheng, "oil disease") tended to have impaired cognitive development, with these children at 4-5 years of age scoring an average of approximately 5 points lower than unexposed children on the Stanford-Binet test (64). Because most of these children were not breast fed, their predominant exposure occurred in utero. Jacobson and Jacobson (65) have followed the children of a cohort of women who had eaten the equivalent of at least 11.8 kg of PCB-contaminated Lake Michigan fish during the 6-year period prior to giving birth. Prenatal exposure of these children to PCBs was associated with lower full-scale and verbal IQ scores, with the strongest effects seen on short-term and long-term memory and focused and sustained attention. Verbal skills and reading comprehension were impaired. Even though more PCB exposure occurs during lactation than in utero, the deficits were associated with prenatal not lactational exposure, suggesting the greatest vulnerability to PCB toxicity of the developing brain occurs in utero.
Rodents exposed in utero to PCBs have impaired active avoidance acquisition, hyperactivity, and impaired discrimination learning (1,66). Hyperactivity in mice following fetal exposure to the congener 3,3´,4,4´-tetrachlorobiphenyl has been attributed to decreased levels of dopamine and dopamine receptor in strial synapses (67). Schantz and Bowman (68) and Schantz et al. (69) have shown that monkeys perinatally exposed to PCBs have problems with learning and memory (70). Rat pups exposed to PCBs show delayed development of negative geotaxis, auditory startle, and righting reflexes (66), developmental problems were also noted in congenitally hypothyroid rats (71). Mice pups exposed to PCBs in utero show hyperactivity, and the increased activity is correlated with decreases in dopamine and dopamine-binding sites in the caudate nuclei as well as long-lasting changes in the development of striatal synapses (66). The striatum is highly sensitive to the actions of thyroid hormones (72).
The developing auditory system is known to be sensitive to thyroid hormones, and hearing disorders including deaf mutism are common in endemic cretinism, with less severe auditory disturbances occurring in congenital hypothyroidism (73). In addition, an increased incidence of sensorineural deafness has been noted in RTH (74). Bradley et al. (13) have shown a correlation between neurologic deafness and expression of Trß1 and Trß2 in the region of the embryonic ear (ventral otocyst) giving rise to the cochlea. When Long-Evans rats are given Aroclor 1254 during gestation through lactation, the pups (through day 30 postpartum) had low serum T4 levels and permanent auditory deficits that most likely resulted from impaired cochlear development (75). In turn, rats given the goitrogen PTU during this same period had similar auditory deficits, the severity of which correlates with the decreased thyroid hormone secretion (76).
Alterations in neurotransmitter levels in discrete brain regions have been associated with behavioral problems. Both thyroid hormones and certain organohalogens such as some of the PCB congeners and dioxins alter biogenic amines in regions of the brain such as the basal forebrain and hippocampus that are associated with learning and memory. Rat pups exposed
in utero to
ortho-substituted but not coplanar PCB congeners have lower-than-normal dopamine levels in the basal forebrain in a manner analogous to what occurs in hypothyroidism (
1,
77). Rat pups either prenatally or lactationally exposed to PCBs have low ChAT activity in the hippocampus and basal forebrain (
78). The results are the same as those seen in neonatally hypothyroid rats. Because PCB exposure lowered serum T
4 levels, Juarez et al. (
78) treated some of the pups with T
4 or T
3 and found that T
4, but not T
3, returned ChAT activity almost to control levels, thereby suggesting that PCB-induced ChAT suppression could be mediated through the thyroidal system.
Polychlorinated biphenyls and dioxins exert their neurotoxic effects through multiple mechanisms. The classical mechanism is through interactions with the Ah receptor. In addition, many of the congeners of PCBs and dioxins alter thyroid function. Because thyroid hormones are essential for normal brain development, it is possible that the xenobiotics could produce neurotoxicity indirectly by altering thyroid-regulated brain development. Many of the neurotoxic effects of organohalogens reported in humans and experimental animals resemble those seen in fetal/neonatal hypothyroidism. Because brain development occurs in very discrete windows, transient exposure of the developing brain to either abnormal thyroid hormone levels or to excessive organohalogens could potentially have lasting neurologic effects. Potential mechanisms of neurotoxicity that could be induced by organohalogens acting through the thyroidal system include the following:
a) The toxicants could alter thyroid hormone synthesis and secretion, either by acting directly on the thyroid gland or through acting on the pituitary or hypothalamic control of TSH secretion.
b) The toxicants could compete with thyroid hormone for serum-binding proteins, thereby potentially impairing tissue hormone delivery.
c) The toxicants could compete with thyroid hormones for membrane carrier systems and therefore inhibit tissue uptake of the hormones.
d) The toxicants could be either agonists or antagonists for thyroid hormone receptor binding.
e) The toxicants could alter production of proteins such as coactivators or corepressors that regulate transcription of thyroid hormone-regulated genes. This field remains a fertile area for further investigation.
REFERENCES AND NOTES
1. Brouwer A, Ahlborg UG, Van den Berg M, Birnbaum LS, Boersma ER, Bosveld B, Denison MS, Gray LE, Hagmar L, Holene E, et al. Functional aspects of developmental toxicity of polyhalogenated aromatic hydrocarbons in experimental animals and human infants. Eur J Pharmacol Environ Toxicol Pharmacol Section 293:1-40 (1995).
2. Fuse Y. Development of the hypothalamic-pituitary-thyroid axis in humans. Reprod Fertil Dev 8:1-21 (1996).
3. Porterfield SP, Hendrich CE. The role of thyroid hormones in prenatal and neonatal neurological development--current perspectives. Endocr Rev 14:94-106 (1993)
4. Fisher DA. Fetal thyroid function: diagnosis and management of fetal thyroid disorders. Clin Obstet Gynecol 40:16-31 (1997).
5. Klein AH, Oddie TH, Parslow M, Foley TP Jr, Fisher DA. Developmental changes in pituitary-thyroid function in the human fetus and newborn. Early Hum Dev 6:321-330 (1982).
6. Puymirat J. Thyroid receptors in the rat brain. Prog Neurobiol 39:281-294 (1992).
7. Morreale de Escobar G, Obregon MJ, Calvo R, Pedraza P, Escobar del Rey F. Iodine deficiency, the hidden scourge: the rat model of human neurological cretinism. In: Recent Research Developments in Neuroendocrinology--Thyroid Hormone and Brain Maturation (Hendrich CE, ed). Kerala State, India: Research Signpost, 1997;66-70.
8. Donati L, Antonelli A, Bertoni F, Moscogiuri D, Andreani M, Venturi S, Filippi T, Gasperinin L, Neri S, Baschieri L. Clinical picture of endemic cretinism in central Apennines (Montefeltro). Thyroid 2:283-290 (1992).
9. Stanbury JB. The pathogenesis of endemic cretinism. J Endocrinol Invest 7:409-419 (1997).
10. Pharoah P, Connolly K, Hetzel B, Ekins R. Maternal thyroid function and motor competence in the child. Dev Med Child Neurol 23:76-82 (1981).
11. Calvo R, Obregon MJ, Ruiz de Ona C, Escobar del Rey F, Morreale de Escobar G. Congenital hypothyroidism as studied in rats. J Clin Invest 86:889-899 (1990).
12. DeLong R. Neurological involvement in iodine deficiency disorders. In: The Prevention and Control of Iodine Deficiency Disorders (Hetzel BS, Dunn JT, Stanbury JB, eds). Amsterdam:Elsevier, 1987;49-63.
13. Bradley DJ, Towle HC, Young WS III. and ß thyroid hormone receptor (TR) gene expression during auditory neurogenesis: evidence for TR isoform-specific transcriptional regulation in vivo. Proc Natl Acad Sci USA 91:439-443 (1994).
14. Burrow, GN, Fisher, DA, Larsen, PR. Maternal and fetal thyroid function. N Engl J Med 331:1072-1078 (1994).
15. Rovet J, Ehrlich R, Altmann D. Psychoeducational outcome in children with early-treated congenital hypothyroidism. Abstract #167. American Thyroid Association, 1996.
16. Rovet JF, Ehrlich Rm, Sorbara DL. Neurodevelopment in infants and preschool children with congenital hypothyroidism: etiological and treatment factors affecting outcome. J Pediatr Psychol 2:187-213 (1992).
17. Rovet JF, Ehrlich RM. Long-term effects of l-thyroxine therapy for congenital hypothyroidism. J Pediatr 126:380-386 (1995).
18. Madeira MD, Sousa N, Lima-Andrade MT, Calheiros F, Cadete-Leite A, Paula-Barbosa MM. Selective vulnerability of the hippocampal pyramidal neurons to hypothyroidism in male and female rats. J Comp Neurol 322:501-518 (1992).
19. Rami A, Rabie A. Effect of thyroid deficiency on the development of glia in the hippocampal formation of the rat: an immunocytochemical study. GLIA 1:337-345 (1988).
20. Lazar MA. Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr Rev 14:184-193 (1993).
21. Hauser P, Zametkin AJ, Martinez P, Vitiello B, Matochik JA, Mixson AJ, Weintraub BD. Attention deficit-hyperactivity disorder in people with generalized resistance to thyroid hormone. N Engl J Med 328:997-1001 (1993).
22. Leonard CM, Martinez P, Weintraub BD, Hauser P. Magnetic resonance imaging of cerebral anomalies in subjects with resistance to thyroid hormone. Am J Med Genet 60:238-243 (1995).
23. Narayanan CH, Narayanan Y. Cell formation in the motor nucleus and mesencephalic nucleus of the trigeminal nerve of rats made hypothyroid by propylthiouracil. Exp Brain Res 59:257-266 (1985).
24. Hamburgh M, Mendoza LA, Burkart JF, Weil F. The thyroid as a time clock in the developing nervous system. In: Cellular Aspects of Neural Growth and Differentiation (Pease DC, ed). Berkeley, CA:University of California Press, 1971;321-328.
25. Hendrich CE, Jackson WJ, Porterfield SP. Behavioral testing of progenies of Tx (hypothyroid) and growth hormone-treated rats: animal model for mental retardation. Neuroendocrinology 38:429-437 (1984).
26. Nunez J, Couchie D, Aniello F, Bridoux AM. Regulation by thyroid hormone of microtubule assembly and neuronal differentiation. Neurochem Res 16:975-982 (1991).
27. Mione MC, Parnavelas JG. How do developing cortical neurones know where to go? Trends Neurosci 17:443-445 (1994).
28. Rakic P. Principles of neural cell migration. Experientia 46:882-891 (1990).
29. Farwell AP, Tranter MP, Leonard JL. Thyroxine-dependent regulation of integrin-laminin interactions in astrocytes. Endocrinology 136:3909-3915 (1995).
30. Farwell AP, Dubord SA. Thyroid hormone regulates neurite outgrowth and neuronal migration onto laminin. Abstract #P53. American Thyroid Association Annual Meeting,1996.
31. Puymirat J, Barret A, Picart R, Vigny A, Loudes C, Faivre-Bauman A, Tixier-Vidal A. Triiodothyronine enhances the morphological maturation of dopaminergic neurons from fetal mouse hypothalamus cultured in serum-free medium. Neuroscience 10:801-810 (1983).
32. Oh, JD, Butcher, LL, Woolf, NJ, Thyroid hormone modulates the development of cholinergic terminal fields in the rat forebrain: relation to nerve growth factor receptor. Dev Brain Res 59:133-142 (1991).
33. Schwegler H, Crusio WE. Correlations between radial-maze learning and structural variations of septum and hippocampus in rodents. Behav Brain Res 67:29-41 (1995).
34. Charrasse S, Jehan F, Confort C, Brachet P, Clos J. Thyroid hormone promotes transient nerve growth factor synthesis in rat cerebellar neuroblasts. Dev Neurosci 14:282-289 (1992).
35. Figueiredo BC, Otten U, Strauss S, Volk B, Maysinger D. Effects of perinatal hypo- and hyperthyroidism on the levels of nerve growth factor and its low-affinity receptor in cerebellum. Brain Res 72:237-244 (1993).
36. Alvarez-Dolado M, Iglesias T, Rodriguez-Pena A, Bernal J, Munoz A. Expression of neurotrophins and the trk family of neurotrophin receptors in normal and hypothyroid rat brain. Mol Brain Res 27:249-257 (1994).
37. Munoz A, Wrighton C, Seliger B, Bernal J, Beug H. Thyroid hormone receptor/c-erbA: control of commitment and differentiation in the neuronal/chromaffin progenitor line PC12. J Cell Biol 121:423-438 (1993).
38. Quirin-Stricker C, Nappey V, Simoni P, Toussaint JL, Schmitt M. Trans-activation by thyroid hormone receptor the 5' flanking region of the human ChAT gene. Mol Brain Res 23:253-265 (1994).
39. Vaccari A, Rossetti ZL, De Montis G, Stefanini E, Martino E, Gessa GL. Neonatal hypothyroidism induces striatal dopaminergic dysfunction. Neuroscience 35:699-706 (1990).
40. Di Liegro I, Savettieri G, Coppolino M, Scaturro, M, Monte, M, Nastasi T, Salemi G, Castiglia D, Cestelli A. Expression of synapsin I gene in primary cultures of differentiating rat cortical neurons. Neurochem Res 20:239-243 (1995).
41. Porterfield SP, Hendrich CE. Tissue iodothyronine levels in fetuses of control and hypothyroid rats at 13 and 16 days of gestation. Endocrinology 131:195-200 (1992).
42. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O'Heir CE, Mitchell ML, Hermos RJ, Waisbren SE, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 341:549-555 (1999).
43. Morreale de Escobar G, Calvo RM, Obregon MJ, Escobar del Rey F. Contribution of maternal thyroxine to fetal thyroxine pools in normal rats near term. Endocrinology 126:2765-2767 (1990).
44. Vulsma T, Gons MH, de Vijlder J. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect of thyroid agenesis. N Engl J Med 321:13-16 (1989).
45. Chantoux F, Blondeau JP, Francon J. Characterization of the thyroid hormone transport system of cerebrocortical rat neurons in primary culture. J Neurochem 65:2549-2554 (1995).
46. Kastellakis A, Valcana T. Characterization of thyroid hormone transport in synaptosomes from rat brain. Mol Cell Endocrinol 67:231-241 (1989).
47. Bernal J, Perez-Castillo A, Pans T, Ferreiro B. Developmental patterns of thyroid hormone nuclear receptor. In: Iodine Nutrition Thyroxine and Brain Development (Kochupillar N, Karmarkar MG, Ramalingaswami V, eds). New Delhi:Tate McGraw-Hill, 1985;132-137.
48. Forrest D, Hanebuth E, Smeyne RJ, Everds N, Stewart CL, Wehner JM, Curran T. Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor ß: evidence for tissue-specific modulation of receptor function. EMBO J 15:3006-3015 (1996).
49. Bernal J, Rodriguez-Pena A, Iniguez MA, Ibarrola N, Munoz A. Influence of thyroid hormone on brain gene expression. Acta Med Austriaca 19 (suppl 1):32-35 (1992).
50. Iglesias T, Caubin J, Zaballos A, Bernal J, Munoz A. Identification of the mitochondrial NADH dehydrogenase subunit 3 (ND3) as a thyroid hormone regulated gene by whole genome PCR analysis. Biochem Biophys Res Commun 210:995-1000 (1995).
51. Xue-Yi C, Xin-Min J, Zhi-Hong D, Rakeman MA, Ming-Li Z, O'Donnell K, Tai M, Amette K, DeLong N, DeLong GR. Timing of vulnerability of the brain to iodine deficiency in endemic cretinism. N Engl J Med 331:1739-1744 (1994).
52. Mellstrom B, Pipaon C, Naranjo JR, Perez-Castillo A, Santos A. Differential effect of thyroid hormone on NGFI-A gene expression in developing rat brain. Endocrinology 135:583-588 (1994).
53. Farwell AP, Leonard JL. Dissociation of actin polymerization and enzyme inactivation in the hormonal regulation of type II iodothyronine 5'-deiodinase activity in astrocytes.Endocrinology 131:721-728 (1992).
54. McKinney JD, Waller CL. Polychlorinated biphenyls as hormonally active structural analogues. Environ Health Perspect 102:290-297 (1994).
55. Maier WE, Kodavanti PR, Harry GJ, Tilson HA. Sensitivity of adenosine triphosphatases in different brain regions to polychlorinated biphenyl congeners. J Appl Toxicol 14:225-229 (1994).
56. McKinney JD, Chae K, Oatley SJ, Blake CCF. Molecular interactions of toxic chlorinated dibenzo-p-dioxins and dibenzofurans with thyroxine binding prealbumin. J Med Chem 28:375-381 (1985).
57. Ness DK, Schantz SL, Moshtaghian J, Hansen LG. Effects of perinatal exposure to specific PCB congeners on thyroid hormone concentrations and thyroid histology in the rat. Toxicol Lett 68:311-323 (1993).
58. Koopman-Esseboom C, Morse DC. Weisglas-Kuperus, Lutkeschipholt IJ, Van der Paauw CG, Tuinstra LGMT, Brouwer A, Sauer PJJ. Effects of dioxins and polychlorinated biphenyls on thyroid hormone status of pregnant women and their infants. Pediatr Res 36:468-473 (1994).
59. Morse DC, Wehler EK, Wesseling W, Koeman JH, Brouwer A. Alterations in rat brain thyroid hormone status following pre- and postnatal exposure to polychlorinated biphenyls (Aroclor 1254). Toxicol Appl Pharmacol 136:269-279 (1996).
60. Sauer PJ, Huisman M, Koopman-Esseboom C, Morse DC, Smits-van Prooije AE, Van de Berg KJ, Tuinstra LG, van der Paauw CG, Boersma ER, Weisglas-Kuperus N. Effects of polychlorinated biphenyls (PCBs) and dioxins on growth and development. Hum Exp Toxicol 13:900-906 (1994).
61. Morse DC, Groen D, Veerman M, van Amerongen CJ, Koeter HB, Smits van Prooije AE, Visser TJ, Koeman JH, Brouwer A. Interference of polychlorinated biphenyls in hepatic and brain thyroid hormone metabolism in fetal and neonatal rats. Toxicol Appl Pharmacol 122:27-33 (1993).
62. Cheek AO, Kow K, Chen J, McLachlan JA. Potential mechanisms of thyroid disruption in humans: interaction of organochlorine compounds with thyroid receptor, transthyretin, and thyroid-binding globulin. Environ Health Perspect 107:273-278 (1999).
63. Bastomsky CH. Enhanced thyroxine metabolism and high uptake goiters in rats after a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin, Endocrinology 101:292-296 (1977).
64. Chen YC,Guo YL, Hsu CC, Rogan WJ. Cognitive development of Yu-Cheng ("oil disease") children prenatally exposed to heat-degraded PCBs. JAMA 268:3213-3218 (1992).
65. Jacobson JL, Jacobson SW. Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N Engl J Med 335:783-789 (1996).
66. Tilson HA, Jacobson JL, Rogan WJ. Polychlorinated biphenyls and the developing nervous system: cross-species comparisons. Neurotoxicol Teratol 12:239-248 (1990).
67. Agrawal AK, Tilson HA, Bondy SC. 3,4,3',4'-Tetrachlorobiphenyl given to mice prenatally produces long-term decreases in striatal dopamine and receptor binding sites in the caudate nucleus. Toxicol Lett 7:417-424 (1981).
68. Schantz SL, Bowman RE. Learning in monkeys exposed perinatally to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Neurotoxicol Teratol 11:12 (1989).
69. Schantz SL, Levin ED, Bowman RE. Long-term neurobehavioral effects of perinatal polychlorinated biphenyl (PCB) exposure in monkeys. Environ Toxicol Chem 10:747-756 (1991).
70. Schantz, SL, Moshtaghian J, Ness DK. Long-term effects of perinatal exposure to PCB congeners and mixtures on locomotor activity of rats. Teratology 45:524 (1989).
71. Adams PM, Stein SA, Palnitkar M, Anthony A, Gerrity L, Shanklin DR. Evaluation and characteriztion of the hypothyroid hyt/hyt mouse. I: somatic and behavioral studies. Neuroendocrinology 49:138-143 (1989).
72. Piosik PA, van Groenigen M, Ponne NJ, Bolhuis PA, Baas F. RC3/neurogranin structure and expression in the caprine brain in relation to congenital hypothyroidism. Mol Brain Res 29:119-130 (1995).
73. Hebert R, Langlois JM, Dussault JH. Permanent defects in rat peripheral auditory function following perinatal hypothyroidism: determination of a critical period. Dev Brain Res 23:161-170 (1985).
74. Brucker-Davis F, Pikus A, Ishizawar D, Skarulis M. Incidence and mechanisms of hearing loss in patients with resistance to thyroid hormone (RTH+). Abstract 135. American Thyroid Association, 1996.
75. Goldey ES, Kehn LS, Lau C, Rehnberg GL, Crofton KM. Developmental exposure to polychlorinated biphenyls (Aroclor 1254) reduces circulating thyroid hormone concentrations and causes hearing deficits in rats. Toxicol Appl Pharmacol 135:77-88 (1995).
76. Goldey ES, Kehn, LS, Rehnberg GL, Crofton KM. Effects of developmental hypothyroidism on auditory and motor function in the rat. Toxicol Appl Pharmacol 135:67-76 (1995).
77. Kodavanti PR, Shin DS, Tilson HA, Harry GJ. Comparative effects of two polychlorinated biphenyl congeners on calcium homeostasis in rat cerebellar granule cells. Toxicol Appl Pharmacol 123:97-106 (1993).
78. Juarez de Ku LM, Sharma-Stokkermans M, Meserve LA. Thyroxine normalizes polychlorinated biphenyl (PCB) dose-related depression of choline acetyltransferase (ChAT) activity in hippocampus and basal forebrain of 15-day-old rats. Toxicology 94:19-30 (1994).
Last Updated: May 25, 2000
