Introduction
The importance of thyroid hormone in brain development has been extensively
documented and reviewed for animals (1-13) and humans (14-22).
These reviews leave no doubt that thyroid hormone deficit or excess during development
can have permanent, pervasive, and profound effects on adult neurological function.
Recent studies also demonstrate that relatively subtle changes in circulating
levels of thyroid hormone in pregnant women can affect the neurological outcome
of their children (23-27). Thus, it is clear that the fetus and
neonate are quite sensitive to thyroid hormone. However, despite the known importance
of thyroid hormone for normal brain development, and new insight into the sensitivity
of neural development to maternal thyroid status, there are critical gaps in
our understanding of thyroid hormone and brain development. These gaps compromise
our ability to accurately determine whether environmental chemicals interact
with the thyroid system and, if they do, whether the consequence of exposure
is adverse. This is particularly important considering that a large number of
chemicals are known to interfere with thyroid functioning and perhaps thyroid
hormone action (28-32).
Our goal in this article is to briefly review the data that have led us to
make the novel proposal that some environmental chemicals can disrupt thyroid
hormone signaling without affecting circulating levels of thyroid hormone, including
data from our laboratory. An important theme in this article is that measures
of thyroid function such as blood levels of hormones and the processes regulating
these levels are not equivalent to measures of thyroid hormone action at the
receptor, such as the regulation of gene expression and the developmental processes
on which they act. To provide context for this proposition, we review the literature
on thyroid hormone and brain development and the effects of polychlorinated
biphenyls (PCBs) on this system.
Thyroid Hormone and Brain Development in Humans
The neonatal period of development in humans is known to be sensitive to thyroid
hormone, especially as revealed in the disorder known as congenital hypothyroidism
(CH) (16,18,19,21,22,33-37). CH occurs at a rate of approximately
1 in 3,500 live births (16). Because CH infants do not present a specific
clinical picture early, their diagnosis based solely on clinical symptoms was
delayed before neonatal screening for thyroid hormone. In fact, only 10% of
CH infants were diagnosed within the first month, 35% within 3 months, 70% within
the first year, and 100% only after age 3 (38,39). The intellectual deficits
as a result of this delayed diagnosis and treatment were profound. One meta-analysis
found that the mean full-scale intelligence quotient (IQ) of 651 CH infants
was 76 (20). Moreover, the percentage of CH infants with an IQ above
85 was 78% when the diagnosis was made within 3 months of birth, 19% when it
was made between 3 and 6 months, and 0% when diagnosed after 7 months of age
(20,40). Studies now reveal that the long-term consequences of CH are
subtle if the diagnosis is made early and treatment is initiated within 14 days
of birth (36,37,41-43), which can be accomplished only by mandatory
screening for thyroid function at birth. This medical profile has become the
principal example illustrating the importance of thyroid hormone for normal
brain development.
Recent studies indicate that thyroid hormone is also important during fetal
development. Thyroid hormones are detected in human coelomic and amniotic fluids
as early as 8 weeks of gestation, before the onset of fetal thyroid function
at 10-12 weeks (44). In addition, human fetal brain tissues express
thyroid hormone receptors (TRs), and receptor occupancy by thyroid hormone is
in the range known to produce physiological effects as early as 9 weeks of gestation
(45,46). Finally, the mRNAs encoding the two known TR classes exhibit
complex temporal patterns of expression during human gestation (47),
and the mRNAs encoding these TR isoforms are expressed in the human oocyte (48).
These data indicate that maternal thyroid hormone is delivered to the fetus
before the onset of fetal thyroid function, and that the minimum requirements
for thyroid hormone signaling are present at this time.
Two kinds of pathological situations reveal the functional consequences of
deficits in thyroid hormone during fetal development. The first is that of cretinism,
a condition usually associated with severe iodine insufficiency in the diet
(15). There are two forms of cretinism based on clinical presentation:
neurological cretinism and myxedematous cretinism (15,17). Neurological
cretinism is characterized by extreme mental retardation, deaf-mutism, impaired
voluntary motor activity, and hypertonia (15). In contrast, myxedematous
cretinism is characterized by less severe mental retardation and all the major
clinical symptoms of persistent hypothyroidism (15). Iodide administration
to pregnant women in their first trimester eliminates the incidence of neurological
cretinism. However, the initiation of iodine supplementation by the end of the
second trimester does not prevent neurological damage (15,49). Several
detailed studies of endemias occurring in different parts of the world have
led to the proposal that the various symptoms of the two forms of cretinism
arise from thyroid hormone deficits occurring at different developmental windows
of vulnerability (15,17,49). Therefore, thyroid hormone appears to play
an important role in fetal brain development, perhaps before the onset of fetal
thyroid function.
The second type of pathological situation is that of subtle, undiagnosed maternal
hypothyroxinemia. The concept and definition of maternal hypothyroxinemia were
developed in a series of papers by Man et al. (50-56). Low thyroid
hormone was initially defined empirically--those pregnant women with the lowest
butanol-extractable iodine among all pregnant women (55,57). This work
was among the first to document an association between subclinical hypothyroidism
in pregnant women and neurological function of the offspring. After the development
of radioimmunoassay for thyroid hormone, Pop et al. (58) found that the
presence of antibodies to thyroid peroxidase in pregnant women, independent
of thyroid hormone levels per se, is associated with significantly lower IQ
in the offspring. Subsequent studies have shown that children born to women
with thyroxine (T4) levels in the lowest 10th percentile
of the normal range had a higher risk of low IQ and attention deficit (25).
Excellent recent reviews discuss these studies in detail (24,57,59).
Taken together, these studies present strong evidence that maternal thyroid
hormone plays a role in fetal brain development before the onset of fetal thyroid
function, and that thyroid hormone deficits in pregnant women can produce irreversible
neurological effects in their offspring (18,19,22,37,60-62).
Thyroid Hormone and Brain Development in Experimental Animals
Considerable research using experimental animals has provided important insight
into the mechanisms and consequences of thyroid hormone action in brain development.
The body of this work is far too extensive to review here but has been reviewed
at critical times during the past 50 years (4,6,11,12,18,57,63-66).
Several themes have emerged that provide a framework in which to begin to understand
the role of thyroid hormone in brain development. First, the majority of biological
actions of thyroid hormone appear to be mediated by TRs, which are ligand-dependent
transcription factors (67,68). There are two genes, encoding TR
and TRß, although these two receptors do not exhibit different binding
characteristics for T4 and for triiodothyronine (T3).
Second, based on considerable work in the cerebellum, there appear to be critical
periods of thyroid hormone action during development. As originally defined
(69), the critical period was that developmental stage where thyroid
hormone replacement to CH children could improve their intellectual outcome.
This definition was also applied to experimental studies to identify the developmental
period during which thyroid hormone exerts a specific action. It is now generally
accepted that there is no single critical period of thyroid hormone action on
brain development, either in humans (15) or in animals (70). Rather,
thyroid hormone acts on a specific development process during the period that
the process is active. For example, thyroid hormone effects on cellular proliferation
would necessarily be limited to the period of proliferation for a specific brain
area. Because cells in different brain regions are produced at different times
(71), the critical period for thyroid hormone action on cell proliferation
would differ for cells produced at different times.
Maternal Thyroid Hormone and Fetal Brain Development
We recently initiated a series of studies to test the broad hypothesis that
thyroid hormone of maternal origin can exert direct effects on brain development
before birth. Fetal thyroid function begins in the rat at approximately embryonic
day 17.5 (E17.5) (72,73); therefore, thyroid hormone effects exerted
before this time would indicate a role for thyroid hormone of maternal origin
in fetal brain development. Because thyroid hormone is known to influence many
cellular and developmental processes (11,12), the specific genes regulated
by thyroid hormone are not possible to predict a priori. Therefore, we
used the nonbiased method of differential display (74) to identify putative
thyroid hormone-responsive genes in the fetal cerebral cortex. Moreover, to
increase the likelihood of identifying genes that are directly regulated by
thyroid hormone, we used a model of acute thyroid hormone exposure (70).
We identified several putative thyroid hormone-responsive genes in the
fetal cortex, including neuroendocrine-specific protein A (NSP-A), Oct-1, and
RC3/neurogranin (70,75,76). Identification of these genes as thyroid
hormone responsive in the fetal cortex before the onset of fetal thyroid function
represents important evidence that maternal thyroid hormone can directly affect
brain development. Interestingly, all of these genes are selectively expressed
in the ventricular zone of the G16 cortex, where cells undergo proliferation
before committing to a specific fate (77-80). Therefore, we tested
whether thyroid hormone affects cell proliferation in the ventricular zone using
bromodeoxyuridine (BrdU). This compound is incorporated into newly synthesized
DNA and can be localized immunocytochemically (81). We found that manipulation
of maternal thyroid status did not alter the number of BrdU-labeled cells in
the ventricular zone (82); therefore, we concluded that thyroid hormone
does not affect the number of cells being produced in the developing cortex.
Recently, we found that thyroid hormone enhanced contact-dependent signaling
among cells in the ventricular zone of the E16 cerebral cortex. (83).
This signaling system is mediated by the Notch receptor. Originally identified
in Drosophila, the Notch receptor is a membrane-bound protein whose extracellular
domain can bind to a ligand such as Delta or Jagged, proteins that also are
membrane bound (84). Upon ligand binding, the Notch receptor is cleaved
by a gamma-secretase activity, which liberates the Notch intracellular domain
to translocate to the nucleus and regulate gene expression (85). An important
gene regulated by Notch signaling is the basic helix-loop-helix gene HES-1 [Hairy-Enhancer
of Split (86)]. Because HES expression appears to inhibit neurogenesis
and favor gliogenesis (87-90), we are presently pursuing the working
hypothesis that thyroid hormone of maternal origin is involved in controlling
the balance in production of neurons and glia in the ventricular zone of the
early cerebral cortex. This hypothesized role of thyroid hormone in fate specification
of neural stem cells is similar to the role of thyroid hormone in the control
of oligodendrocyte differentiation (91,92).
Taken together, our studies demonstrate that maternal thyroid status is important
to the neurological outcome of the offspring, and that thyroid hormone of maternal
origin can selectively affect gene expression in the fetal cortex, perhaps by
modifying Notch signaling. It is also important to recognize that the actions
of thyroid hormone will depend on the developmental events occurring at the
time under investigation. For example, cerebellar granule cells are generated
after birth in the rat, but cerebral cortical neurogenesis occurs between E13
and E17 (71). Therefore, it is predictable that thyroid hormone does
not play a significant role in cerebellar granule cell proliferation on E16
or in cortical neurogenesis on postnatal day 5 (P5). Thus, the concept of a
"critical period" of thyroid hormone action on brain development should be restricted
to specific developmental events and not be viewed as a single window of brain
development to which thyroid hormone action is limited.
Thyroid Hormone Action and PCBs
Considering that thyroid hormone of maternal origin is important in fetal
brain development and neurological outcome of the offspring, environmental factors
that affect maternal thyroid function, or thyroid hormone action directly, may
affect fetal brain development and neurological outcome. Although a number of
environmentally relevant compounds are known to affect thyroid status (93),
we focus on PCBs in this review because their effects on the thyroid system
illustrate several important concepts of thyroid toxicology that may not be
generally appreciated.
Polychlorinated biphenyls are a class of industrial compounds consisting of
paired phenyl rings with various degrees of chlorination (94-96).
They are now ubiquitous, persistent environmental contaminants routinely found
in samples of human and animal tissues. Exposure to PCBs is associated with
cognitive and behavioral changes in humans (97-100). The effects
of PCBs on brain development may be attributable, at least in part, to their
ability to affect the thyroid system (101). This hypothesis is supported
in part by the overlap in neurological deficits observed in humans associated
with PCB exposure and those deficits observed in the offspring to hypothyroxinemic
women (36,41,102,103).
PCB body burden also has been associated with measures of thyroid hormones
in humans, although these data are complex. For example, Hagmar et al. (103)
found a significant inverse association between serum levels of PCB 153 and
total T3 in fishermen's wives from the Swedish east coast. However,
this association was not observed in men (104). Furthermore, Sala et
al. (105) found that serum levels of both hexachlorobenzene and PCBs
were inversely related to serum total T4. Persky et al. (106)
recently found that serum PCB levels were inversely related to serum total T4
and free T4 in women but only to total T4 in men. Osius
et al. (107) studied 7- to 10-year-old school children in three German
municipalities and found a significant positive correlation between serum concentration
of the mono-ortho congener PCB 118 and serum thyrotropin (TSH). Moreover,
they found a significant negative correlation between several PCB congeners
and free T3. They found no correlation between circulating levels
of PCBs and T4. In contrast, Koopman-Esseboom et al. (108)
measured dioxins and PCBs in human cord blood and breast milk and found that
PCB exposure, estimated by toxic equivalents, was negatively correlated with
circulating T4 in infants.
It is important to recognize that the differences in circulating levels of
thyroid hormones associated with PCBs are still within the normal range. Therefore,
there is no formal evidence for background exposure to PCBs causing overt hypothyroidism.
Because different studies reveal different associations between body burden
of PCBs and various measures of thyroid hormone levels, it is possible that
these associations are spurious. However, it is also possible that the environmental
mixture to which different populations are exposed can produce slightly different
effects.
All studies to date that focus on the relationship between PCBs and the thyroid
use circulating levels of thyroid hormone as the sole indicator of an effect
on the thyroid system, or focus on mechanisms by which PCBs affect thyroid hormone
levels. Therefore, the prevailing view is that PCBs interfere with thyroid hormone
signaling by reducing circulating levels of thyroid hormone, thereby limiting
the hormone available to act on tissues (109-111). However, the
developmental effects of PCB exposure in experimental animals are not fully
consistent with a mechanism attributable to hypothyroidism. For example, PCB
exposure induces hearing loss in rats (109) that is similar to that observed
in hypothyroid rats (112). Moreover, this PCB-induced hearing loss can
be at least partially restored in PCB-treated rats by thyroid hormone replacement
(110). However, circulating levels of TSH were not elevated by PCB exposure
as it is after exposure to the goitrogen propylthiouracil (109,113).
Moreover, the timing of eye opening was advanced by PCB exposure, rather than
delayed after exposure to the goitrogen 6-n-propyl-2 thiouracil (109).
These and other observations suggest that the combination of PCB congeners present
in the commercial Aroclor mixtures produces heterogeneous effects on the thyroid
system (101).
There are 209 PCB congeners based on the number and placement of the chlorine
atoms in the biphenyl backbone (114). Some investigators categorize PCB
congeners according to their dioxinlike activity (96). PCBs with zero
or one ortho chlorine, two para chlorines, and at least two meta
chlorines can adopt a planar structure similar to that of 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD) and can bind to and activate the aryl hydrocarbon receptor (AhR) (96,115).
In contrast, some ortho-substituted PCBs may adopt a non-coplanar conformation
that does not act through the AhR but can nevertheless produce neurotoxic effects
(115-117).
In general, congener-specific studies demonstrate that both coplanar and non-coplanar
PCB congeners can reduce circulating levels of T4. However, the mechanism(s)
by which different congeners lead to changes in circulating levels of thyroid
hormones appears to differ. At least three independent, but perhaps interacting,
mechanisms may account for the ability of PCBs to reduce circulating levels
of thyroid hormone [see Brouwer et al. (111) for full discussion]. First,
PCBs have been reported to alter the structure of the thyroid gland, perhaps
directly affecting thyroid function (118-120). These observations,
although not extensively investigated, are consistent with the report of Byrne
et al. (121) that PCB exposure reduces the ability of TSH to increase
serum T4 in vivo. Thus, PCBs may directly interfere with the
ability of the thyroid gland to respond to TSH. Second, PCBs can alter thyroid
hormone metabolism. Early work demonstrated that PCB exposure increased the
rate of bile flow and increased the biliary excretion of 125I-T4
(122). Moreover, PCB exposure induces the expression and activity of
UDP-glucuronosyltransferase (123) and increases T4 glucuronidation
(124). In addition, PCB exposure selectively activates the glucuronidation
of T4 but not T3 (113), suggesting that this mechanism
may account in part for the failure of PCBs to alter circulating T3.
Thus, PCB exposure may facilitate T4 clearance from serum through
liver metabolism, reducing the half-life of T4 in the blood. Finally,
specific PCB congeners can bind to thyroid hormone-binding proteins in
the blood and potentially can displace T4 from the protein in
vivo (111,125). These three mechanisms may combine to reduce the
carrying capacity of the blood for T4, reduce the serum half-life
of T4, and reduce the ability of the thyroid gland to respond to
TSH. Although it is not clear which among these potential mechanisms are most
important for mediating the effects of PCBs on circulating levels of thyroid
hormone, it is likely that all are important to some extent in experimental
systems.
A number of studies have focused on the structural requirements of individual
PCB congeners required for binding to the T4-binding protein transthyretin
(125-128). These studies demonstrate that individual PCB congeners
can displace T4 from these proteins with high affinity. In addition,
several investigators have speculated that certain PCB congeners may affect
brain development by directly interacting with TRs (129-132), although
the TRs are T3-binding proteins that are structurally and evolutionarily
unrelated to transthyretin. However, this concept is important to consider,
because many studies have demonstrated the ability of environmental chemicals
to bind directly to estrogen and androgen receptors (133), and direct
interaction with the TR is possible. In addition, although the two TR types
bind to T3 and to T4 similarly, a number of analogs can
differentiate between the two receptors. For example, 3,5,3´-triiodithyroacetic
acid has a much higher affinity for the TRß1 than does T3 (134).
In addition, the compound GC-1 is a TRß-selective agonist (134,135).
Moreover, the therapeutic agent desethylamiodarone is a noncompetitive inhibitor
of T3 binding to TRß1 but a competitive inhibitor of T3
binding to TR1
(136,137). These studies demonstrate that the two classes of TRs (TR
and TRß) can discriminate between ligands that may include compounds such
as PCBs. Moreover, it is possible in principle that individual PCB congeners
could produce allosteric effects on TR action, modifying their ability to interact
with dimerization partners or cofactors (131). These interactions are
not simple to fully evaluate but are important to address.
Because very few thyroid hormone-responsive end points have been evaluated
to test whether PCBs act on the thyroid hormone system solely by reducing circulating
levels of thyroid hormone, we tested this hypothesis in the early postnatal
rat brain. During the first 3 postnatal weeks in the rat and mouse, two genes
have been most extensively studied for their responsiveness to thyroid hormone:
RC3/neurogranin in the forebrain and myelin basic protein (MBP) in the cerebellum
(138-141). The expression of both of these genes is up-regulated
by thyroid hormone (139,142). Interestingly, MBP expression in the cerebellum
and RC3/neurogranin expression in the forebrain are affected by thyroid hormone
during a specific period from about P7 to P25 (64). Therefore, we employed
RC3/neurogranin and MBP gene expression during this developmental period as
end points of thyroid hormone action to test the effects of PCB exposure.
For this experiment, we fed pregnant rats doses of Aroclor 1254 (A1254), from
E6 to P21, as initially reported by Goldey et al. (109). These doses
(1, 4, and 8 mg/kg) reduced circulating levels of thyroid hormones in the pups
during the first 3 postnatal weeks in a dose-dependent manner. The highest dose,
8 mg/kg, reduced circulating T4 to undetectable levels; however,
RC3/neurogranin and MBP mRNA levels were both significantly increased by PCB
exposure in a dose-dependent manner (143). Importantly, this effect of
A1254 on RC3/neurogranin and MBP expression was observed on P15 but not on P5
or P30. Moreover, A1254 increased RC3/neurogranin expression only in brain areas
in which it is increased by thyroid hormone (144). Finally, A1254 increased
cellular levels of RC3/neurogranin mRNA, suggesting a transcriptional mechanism
similar to that induced by thyroid hormone (144). These data are consistent
with the interpretation that specific PCB congeners exert a thyroid hormonelike
effect on the expression of these genes. These data cannot be explained by the
ability of PCBs to reduce circulating levels of thyroid hormone.
We then tested whether A1254 could affect gene expression in the fetus, using
genes previously identified as thyroid hormone responsive [(70,75,76),
and reviewed here]. We found that A1254, provided to the dam from E6 to E16,
increased RC3/neurogranin expression in the E16 fetal cortex (145). In
addition, A1254 increased the expression of Oct-1 mRNA in the fetal brain but
had no effect on the expression of NSP-C (145). NSP-C is a splicing variant
of NSP-A, which we have shown is not regulated by thyroid hormone in the E16
cortex (70,76). Importantly, the same doses of A1254 that significantly
reduced circulating levels of thyroid hormone in neonatal animals had no effect
on circulating levels of thyroid hormones in the dams. Thus, the ability of
PCBs to affect circulating levels of thyroid hormone is not related to their
ability to affect thyroid hormone-responsive gene expression. This observation
is consistent with the interpretation that PCB congeners responsible for reducing
circulating levels of thyroid hormone in the rat are not the same congeners
producing thyroid hormonelike effects on gene expression in the developing brain.
It will be important to determine the functional consequences of PCB effects
on thyroid hormone-responsive genes in the fetal brain. For this reason,
we have begun to explore the effects of PCB exposure on Notch signaling and
have found that A1254 produces thyroid hormonelike effects on HES-1 expression
in the E16 brain (146). Our working hypothesis is that PCBs increase
HES-1 expression in the fetal cortex, which increases gliogenesis at the expense
of neurogenesis. Clearly, the presence of an environmental contaminant that
affects the balance of production of neurons and glia in the absence of effects
on circulating levels of thyroid hormone is an important observation with implications
for screening programs that use circulating levels of thyroid hormone as the
sole index of thyroid toxicology.
The parsimonious explanation for these findings is to propose that individual
PCB congeners, or classes of congeners, can directly activate the TR either
as parent congeners or after metabolic activation. If true, then individual
PCB congeners should be able to bind to the TR (or TRs) with high affinity.
Presently, only one study has tested this hypothesis formally (128),
and although the investigators found that individual hydroxylated PCB congeners
can bind to the TRß1 with low affinity (Ki ~ 32 mM),
it is questionable that this level of binding is physiologically meaningful.
Thus, this prediction remains to be fully tested.
Conclusions
Thyroid hormone is essential for brain development both before and after birth.
Therefore, it is important to effectively evaluate whether environmental factors
can interfere with maternal or neonatal thyroid function, or thyroid hormone
action. We need to improve upon our ability to identify thyroid-disrupting environmental
chemicals for several reasons. First, we know surprisingly little about the
molecular and cellular mechanisms by which thyroid hormone affects brain development.
Moreover, we know even less about the developmental events affected by thyroid
hormone at any one time in brain development. Therefore, we have few clear and
quantitative end points of thyroid hormone action in brain development that
can be validated as end points of thyroid toxicity. Toxicological studies underlying
risk assessment for thyroid toxicity must rely on measures of thyroid function
such as hormone levels and thyroid histopathology (147). Therefore, environmental
chemicals are tested for their ability to disrupt thyroid hormone action by
measuring whether they are able to affect circulating levels of thyroid hormone.
The example of PCB exposure on thyroid hormone-responsive genes described
here demonstrates that thyroid hormone action may well be disrupted without
changes to overt measures of thyroid function. Thus, we must develop biomarkers
of thyroid hormone action in brain development that can be employed in toxicological
studies for risk assessment (147).
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Last Updated: May 27, 2002
