1 Thyroid Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston 02115; and 2 Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, Department of Medicine, New England Medical Center-Tufts University School of Medicine, Boston, Massachusetts 02111
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ABSTRACT |
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The goal of the present investigation was to analyze the types 2 (D2) and 3 (D3) iodothyronine deiodinases in various structures within the central nervous system (CNS) in response to iodine deficiency. After 5-6 wk of low-iodine diet (LID) or LID + 2 µg potassium iodide/ml (LID+KI; control), rats' brains were processed for in situ hybridization histochemistry for D2 and D3 mRNA or dissected, frozen in liquid nitrogen, and processed for D2 and D3 activities. LID did not affect weight gain or serum triiodothyronine, but plasma thyroxine (T4) was undetectable. In the LID+KI animals, D3 activities were highest in the cerebral cortex (CO) and hippocampus (HI), followed by the olfactory bulb and was lowest in cerebellum (CE). Iodine deficiency decreased D3 mRNA expression in all CNS regions, and these changes were accompanied by three- to eightfold decreases in D3 activity. In control animals, D2 activity in the medial basal hypothalamus (MBH) was similar to that in pituitary gland. Of the CNS D2-expressing regions analyzed, the two most responsive to iodine deficiency were the CO and HI, in which an ~20-fold increase in D2 activity occurred. Other regions, i.e., CE, lateral hypothalamus, MBH, and pituitary gland, showed smaller increases. The distribution of and changes in D2 mRNA were similar to those of D2 activity. Our results indicate that decreases in the expression of D3 and increases in D2 are an integral peripheral component of the physiological response of the CNS to iodine deficiency.
thyroid; selenium; goiter; nutrition; trace element; development; growth
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INTRODUCTION |
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IODINE IS AN ESSENTIAL COMPONENT of thyroid hormones. The thyroglobulin-derived iodothyronine molecules contain three or four iodine atoms that are covalently bound during iodide organification. This process, also known as iodination, is catalyzed by thyroid peroxidase and requires that the thyroid cell concentrate iodide from plasma (19). Iodine is readily available from the ocean, and salt-water vertebrates, the first life forms to develop a thyroid gland, are not at risk for iodine deficiency. However, in terrestrial vertebrates, including humans, iodine availability can be rate limiting depending on the proximity to the ocean and the iodine content of the soil. Fortunately, a multiplicity of physiological mechanisms has evolved to mitigate the consequences of iodine deficiency on thyroid hormone synthesis. In fact, these mechanisms can be so efficient that a recent survey indicates that nearly 2.3 billion people can live in geographical areas with low-iodine soil content (8). In areas of extreme deficiency, however, iodine intake is so low that the compensation mechanisms are inadequate. The consequence of this is the iodine deficiency disorders, including hypothyroidism, irreversible mental retardation, goiter, reproductive failure, increased infant mortality, and socioeconomic hardships.
When rats are placed on a low-iodine diet (LID), the
hypothalamic-pituitary-thyroid axis undergoes a series of rapid
physiological adaptations to maintain the delivery of thyroid hormones
to tissues. The changes in thyroidal iodothyronines have been well
described and are designed to maintain plasma triiodothyronine
(T3) in the normal range (1, 12, 26, 27). This
assures that most target tissues are only mildly affected during
moderate iodine deficiency. As an example, no differences in
O2 consumption or thermal homeostasis were detected in
iodine-deficient rats (33). In addition, growth and
relative weight of various organs are not affected in rats with
moderate iodine deficiency despite an ~10-fold higher
thyroid-stimulating hormone (TSH) and nearly undetectable plasma
thyroxine (T4) (25). Not surprisingly,
however, if iodine deficiency is severe and prolonged, signs of
hypothyroidism will develop, i.e., reduced O2 consumption
(24) and liver -glycerophosphate dehydrogenase
(24) and malic enzyme activities (23, 31), indicating a finite capacity of adaptive physiological mechanisms.
In addition to the thyroidal changes, in some tissues including brain, pituitary gland, and brown adipose tissue (BAT), intracellular T3 may be regulated in a more complex manner, since the intracellular production of T3 from T4 catalyzed by type 2 iodothyronine deiodinase (D2) occurs in these tissues. The activity of this enzyme is increased during iodine deficiency or hypothyroidism (5, 13, 20, 22), thus increasing the fractional conversion of T4 to T3. We (40) and others (14, 28) have demonstrated that D2 activity and mRNA are heterogeneous within the rat central nervous system (CNS) and that D2 is especially concentrated in the hypothalamus, particularly in the tanycytes and the arcuate nucleus-median eminence region. Recently, D2 mRNA was also shown to peak dramatically around postnatal day 7 in the mouse cochlea, a structure known to be exquisitely sensitive to thyroid hormones (4). All of these results point to the potential for region-specific regulation of intracellular T3 production in the CNS.
The CNS has yet another potential physiological mechanism for adaptation to iodine deficiency. A second deiodinase, type 3 (D3), which inactivates T4 and T3, is also expressed in this tissue. D3 is a T3-dependent gene (37, 41) and is positively correlated with thyroid status (16). Despite its critical role, it was only recently demonstrated that its distribution in the CNS, like that of D2, is heterogeneous with high focal expression in the hippocampal pyramidal neurons, granule cells of the dentate nucleus, and layers II-VI of the cerebral cortex (9, 41). These data imply that there may also be region-specific regulation of D3.
Much of our understanding of adaptive regulation of selenodeiodinases is derived from studies in animals with altered thyroid status. During hypothyroidism, there is an increase in D2 activity in various regions of the CNS (28), and the opposite is observed for D3 mRNA levels (41). However, hypothyroidism is observed only in moderate-to-severe iodine deficiency (31). In addition, given the exquisite sensitivity of D2 to reductions in plasma T4, it is likely that an increase would occur long before the onset of hypothyroidism (21). From a teleological point of view, primary hypothyroidism due to autoimmune disease is extremely rare compared with iodine deficiency and is unlikely to be the condition for which these peripheral physiological adaptive mechanisms evolved.
The goal of the present investigation was to document changes in D2 and D3 mRNA levels and activities within specific structures of the CNS of iodine-deficient rats. Our results show marked regional alterations in the expression of both enzymes, illustrating that increases in D2 combined with compensatory decreases in D3 are an integral peripheral component of the tissue physiological response of the vertebrate to iodine deficiency.
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MATERIAL AND METHODS |
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Animals and diets. Unless specified otherwise, all drugs and reagents were purchased from Sigma Chemical (St. Louis, MO). Experiments were performed on male Sprague-Dawley rats weighing 100-125 g obtained from Harlan (Madison, WI). Studies were conducted in accordance with the highest standards of humane animal care under a protocol approved by the Standing Committee on Animal Research. Animals were maintained on a 12:12-h light-dark cycle at 21°C and had free access to diet and water. Some animals were placed on a Remington low-iodine diet (LID; Harlan) during 5-6 wk with supplemental 0.5% sodium perchlorate in the drinking water during the 1st wk to induce rapid depletion of thyroidal iodine. The control group [LID supplemented with potassium iodide (LID+KI)]received the same diet with supplemental 2 µg KI/ml in the drinking water.
In situ hybridization histochemistry.
All animals (n = 7 in each group) were deeply
anesthetized with pentobarbital sodium (50 mg/kg) and perfused through
the heart first with saline followed by 4% paraformaldehyde in PBS for
20 min. The brains were removed and immersed in 20% sucrose in PBS overnight. Blocks of the forebrain were frozen on dry ice and sectioned
in the coronal plane at 18 µm on a cryostat. Sections were mounted
onto Superfrost Plus glass slides (Fisher) and stored at 80°C until
subjected to hybridization. The hybridization protocols were based on
methods previously reported from our laboratories (40,
41). For D2 mRNA, tissue sections were hybridized with a single
stranded [35S]UTP-labeled cRNA probe generated from
pHT-1575. The rD2 fragment contains a portion of 5' flanking region
(FR) and the entire 798 nt of coding region (kindly provided by Drs. D. St. Germain and V. A. Galton, Dartmouth Medical School, Lebanon,
NH). As a control, the same plasmid was used to generate sense
RNA with T3 RNA polymerase. Hybridization was performed
under plastic coverslips in buffer containing 50% formamide, a twofold
concentration of standard sodium citrate (2× SSC), 10% dextran
sulfate, 0.25% BSA, 0.25% Ficoll 400, 0.25% polyvinylpyrolidone 360, 250 mM Tris (pH 7.5), 0.5% sodium pyrophosphate, 0.5% sodium dodecyl
sulfate, 250 µg/ml denatured salmon sperm DNA, and 6 × 105 cpm of the radiolabeled probe for 16 h at 55°C.
Slides were dipped into Kodak NTB2 autoradiography emulsion
(Eastman Kodak, Rochester, NY), and the autoradiograms were developed
after 7 days of exposure at 4°C.
Analytical procedures. At the end of the experimental period, rats were killed by decapitation, the brains were rapidly removed, and specific regions were dissected and frozen in liquid nitrogen, as previously described (28). D2 activity was measured as previously described (29) using two different protein concentrations (4-fold difference for each sample), depending on the cerebral structure, i.e., 2-30 µg for medial basal hypothalamus (MBH), 90-500 µg for lateral hypothalamus, 60-400 µg for hippocampus, 60-350 µg for cerebral cortex, 75-370 µg for cerebellum, and 2-10 µg for pituitary gland. For D3 activity, 80-100 µg of protein was assayed during 2 h at 37°C as described (30). The reaction was stopped by the addition of 200 µl of normal horse serum and 100 µl of TCA, and the supernatant was used for determination of the [125I]T2 and [125I]T1 produced. This was done after the supernatant was loaded onto a 2-ml LH-20 column and washed subsequently with water and 20 ([125I]T1) and 50% ([125I]-T2) ethanol. Nonspecific deiodination was estimated similarly as for D2 and was always <1.5%.
Blood was collected, and serum concentrations of T4 and T3 were measured by RIA by the Clinical Research Center at the Brigham and Women's Hospital.Statistical analysis. Results are expressed as means ± SD throughout the text, table, and figures. Comparisons were done by Student's t-test.
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RESULTS |
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Animals from both groups, LID and LID+KI, gained ~100 g body wt
during the 5- to 6-wk experimental period, with body weights that were
not significantly different (305 ± 13 vs. 286 ± 25 g; P > 0.05) at the completion of the study. On the other
hand, rats on LID without supplemental KI increased their thyroid gland
weight about threefold (Table 1). Iodine
deficiency reduced serum T4 to undetectable levels, but the
30% decrease in serum T3 was not significant (Table
1; P > 0.05). In both groups, D2 and D3 activities were quantified in cerebral cortex, hippocampus, cerebellum, and pituitary gland. In addition, D3 activity was measured in olfactory bulb, and D2 activity was quantified in the MBH and lateral
hypothalamus. Other animals from the same groups were also studied for
changes in D2 and D3 mRNA by in situ hybridization histochemistry to
allow qualitative estimates of the changes in the mRNAs encoding these proteins.
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In control animals supplemented with KI, D3 activities (Fig.
1A) were highest in the
cerebral cortex and hippocampus, followed by the olfactory bulb and
cerebellum. No D3 activity was detected in the pituitary gland. Iodine
deficiency caused a marked decrease in the expression of D3 in all CNS
regions analyzed. As shown in Fig. 1B, D3 activity
in the iodine-deficient animals was reduced five- to eightfold relative
to that in LID+KI animals, except in the olfactory bulb, where it was
decreased to ~40% of control.
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The pattern of distribution of D3 mRNA, as detected by in situ
hybridization, paralleled the expression of D3 activity. D3 mRNA was
distributed in a diffuse pattern over the forebrain in control animals
but was particularly apparent in the hippocampal pyramidal cells,
granule cells of the dentate (Fig.
2A), and layer II of the
pyriform cortex (Fig. 2C). In the iodine-deficient rats, the
D3 mRNA hybridization signal was reduced throughout (Fig. 2,
B and D). However, the regional distribution was
maintained.
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D2 activity was ~10-fold higher in MBH than in any other CNS region
analyzed, including the immediately adjacent lateral hypothalamus (Fig.
3A), due to the presence of
the tanycytes in the region (40). D2 activity in MBH was
not different from that in the pituitary gland. Of the brain regions
examined for D2 activity, the two most responsive D2-expressing
structures to iodine deficiency were the cerebral cortex and
hippocampus, in which an ~20-fold increase in D2 activity occurred.
Five- to tenfold increases in D2 activity were detected in cerebellum,
lateral hypothalamus, MBH, and pituitary gland of the animals with
iodine deficiency (Fig. 3B).
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By in situ hybridization histochemistry, silver grains denoting
the location of D2 mRNA were distributed widely but in low abundance
throughout the forebrain and were only marginally greater than
background. In the tuberal region of the hypothalamus, however, hybridization was intense and primarily concentrated between the rostral pole of the hypothalamic median eminence and the infundibular recess. Three different rostrocaudal sections of the
hypothalamus are shown in Fig. 4.
Hybridization of the D2 mRNA is seen in the most rostral region at the
external zone of the median eminence (Fig. 4A), whereas a
midsection shows D2 mRNA hybridization in the floor of the third
ventricle (Fig. 4C). In the most caudal region, silver
grains accumulated over cells lining the infralateral wall and floor of
the third ventricle and extended into the stalk median eminence,
closely associated with portal vessels (Fig. 4E).
Interestingly, hybridization was also found in the adjacent arcuate nucleus-encircling blood vessels, and at the base of the hypothalamus and in a zone overlying the tuberoinfundibular sulci of
the median eminence. Similar rostrocaudal hypothalamic sections were
prepared from iodine-deficient rats (Fig. 4, B, D, and
F). At each level examined, the intensity of the D2 mRNA
hybridization was increased in the iodine-deficient rats. However, as
with D3, the regional distribution of D2 mRNA did not change.
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DISCUSSION |
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This is the first comparative analysis of the effects of moderately severe iodine deficiency on the physiological response of the iodothyronine deiodinases in discrete subregions of the CNS. The expression of D2 and D3 in brain is well documented as are the changes induced by alterations in thyroid status in this organ as a whole (15, 16). The results indicate that the physiological response to iodine deprivation in the cerebral cortex and hippocampus is a combination of 8- to 20-fold increases in D2 activity and 3- to 8-fold decreases in that of D3 (Figs. 1-4). Parallel, but less dramatic, changes occur in cerebellum, and qualitatively similar effects are observed in the mRNAs encoding these two enzymes by in situ hybridization. These changes are in the same direction but much greater than the approximately threefold alterations observed in the whole brain (22).
The regional specificity of the changes indicates that deiodinase regulation is a specific physiological adaptation of the CNS to this challenge. Previous data obtained by in situ hybridization show that D3 mRNA is expressed at its highest levels in the cerebral cortex and hippocampus. In fact, of the brain regions examined, these are the regions where the highest D3 activities were found in the iodine-deficient rats, indicating that the D3 message is being translated into active protein. Furthermore, it is known that D3 mRNA and activities are regulated by thyroid status being markedly increased in hyperthyroid rats and decreased relative to euthyroid levels in hypothyroid rats (16, 41). In addition, iodine deficiency has been shown to modulate D3 activity in the CNS. Both total fetal (32) and adult (22) rat brains respond to iodine deficiency by decreasing D3 activity, but only modest (2-fold) reductions were observed. By focusing on specific subregions of the CNS, we found that D3 activity is decreased by 80-90% in the cerebral cortex, hippocampus, and cerebellum, changes of a much higher magnitude than occur in the brain in general. The consequences of the marked fall in D3 activity are twofold. First, there will be an increase in the residence time of T3 within the tissue, because the rate of T3 degradation via inner-ring deiodination will be reduced. Second, because T4 is also a substrate for this enzyme, relatively more of this prohormone will remain within the tissue for conversion to T3 by D2. Particularly in tissues such as brain, where the exchange of T3 with plasma is slow and where most of the T3 is generated in situ, it is likely that fluctuations in the rate of T3 degradation will have a greater influence on tissue levels of T3 than will occur in tissues that are in rapid equilibration with plasma, such as liver and kidney (7). This prediction has been borne out using dual-labeling in vivo techniques in which the disappearance of tracer T3 from cerebral cortex and cerebellum was found to be significantly slower in hypothyroid rats, a situation where CNS D3 is also decreased (36).
As can be appreciated from the in situ hybridization results (Fig. 4), there was an increase in D2 mRNA in iodine-deficient animals, especially within those subregions of the brain expressing high D2 activity. An increase in D2 mRNA would be expected from the negative regulation of transcription of D2 by T3 (17). However, the increases in D2 activity of 20-fold in the cerebral cortex and hippocampus appear to be much greater than those in D2 mRNA (Fig. 3 vs. Fig. 4). This discrepancy is analogous to results recently reported in hypothyroid rat cerebral cortex in which a 1.7-fold increase in D2 mRNA was associated with a 4.6-fold increase in D2 activity (3). The much greater increase in D2 activity than in D2 message can be explained by the hypothyroxinemia of iodine deficiency per se acting at a posttranslational level. The mechanism by which T4, the preferred substrate for D2, reduces D2 protein levels is a consequence of a substrate-induced increase in the rate of D2 ubiquitination and subsequent proteasomal degradation (11, 38, 39). When plasma T4 falls, D2 half-life is prolonged, leading to an increase in the D2 protein-to-mRNA ratio. During modest reductions in iodine intake, the increased D2 will increase the fractional rate of T4 to T3 conversion, thus maintaining T3 production despite a decrease in T4.
The differences in the magnitude of the changes in D2 and D3 activities in different subregions (Figs. 1-4) suggest that the responses to iodine deficiency within the CNS are region specific. Previous studies in iodine-deficient rats have examined only the global changes in these activities in the entire brain, which may mask large changes in small regions. For example, we confirmed that the MBH has the highest level of D2 activity of any CNS structure analyzed, comparable to that in pituitary (28). However, the increases in D2 activity during iodine deficiency in both of these tissues are of far less magnitude than are those in cerebral cortex and hippocampus (Fig. 3B). This suggests either differential sensitivity of these regions to the same stimulus or regional differences in the supply of T4 or T3 within the CNS. Teleologically, one might argue that, because the hypothalamus and pituitary are critical for the control of TSH secretion, which must be increased as part of the central physiological response to iodine deficiency, the lower magnitude of the D2 response is appropriate. In addition, Koenig et al. (18) have shown that D2 activity in populations of pituitary cells relatively enriched in thyrotrophs is the least responsive to the absence of T3.
The increased fractional production of T3 from T4 by D2 combined with the prolonged residence time of T3 will mitigate the effects of iodine deficiency, as has been demonstrated in mild-to-moderate hypothyroidism by tracer studies (34). These predictions were confirmed directly by Campos-Barros et al. (5), who measured thyroid hormone concentrations in various regions of the CNS in iodine-deficient rats. As expected, tissue T4 was markedly decreased, whereas tissue T3 concentrations were reduced by only 50%. This illustrates the effectiveness of these compensatory mechanisms.
The CNS is an unusual tissue with respect to thyroid function, since the occupancy of the nuclear T3 receptors in these tissues is ~80-90% (7). Similar high T3 receptor saturation provided by the action of D2 is seen in pituitary and also in BAT during cold stress (6, 35). However, nuclear T3 receptors in the remainder of peripheral tissues are only 50% saturated, since plasma T3 is the primary source of receptor-bound T3 in those tissues. The decrease of ~50% in CNS T3 in the aforementioned iodine-deficient animals would reduce nuclear T3 receptor occupancy to ~45%. Thus, despite all of the compensatory mechanisms that occur, the CNS is modestly hypothyroid. This is the cause of the decrease in D3 mRNA and activity. However, this reduction in D3 can also be viewed as a second line of defense for an amelioration of the hypothyroidism. The requirement for high T3 receptor saturation for normal D3 synthesis in brain can explain this increase. It suggests that, at least for this T3-dependent parameter, the partial desaturation of the receptors decreases D3 gene transcription. Interestingly, a similar phenomenon occurs for the uncoupling protein 1 gene in BAT, for which high T3 receptor occupancy must be achieved for optimal gene expression (2). The analysis of T3-dependent enzymes in the cerebral cortex of neonatal rats mentioned earlier (33) suggests that certain T3-dependent events in the cerebral cortex can be preserved even with a reduction of nuclear T3 receptor saturation to only 40%.
In iodine deficiency, the onset of generalized hypothyroidism will depend on the severity of the challenge and the success of compensation, which may vary from tissue to tissue. The present results indicate that, even within the CNS, the adaptive mechanisms for maintaining T3 concentrations are not generalized. Although an increase in D2 and a decrease in D3 activities occur throughout the CNS, there is a regional specificity in the magnitude of this response that has not been previously recognized. The increase in D2 activity arises, in part, from an increase in D2 mRNA but, predominantly, by an increase in D2 protein half-life. The decrease in D3, however, appears to parallel the fall in D3 mRNA. These changes will mitigate the effects of modest iodine deficiency on intracellular T3 concentrations in these tissues. Although it is difficult to examine the long-term consequences of this in experimental animals, the syndrome of endemic cretinism in geographical regions with severe iodine deficiency suggests that the residual nuclear T3 saturation in the brain of severely iodine-deficient infants and children is not adequate to permit normal intellectual development. Thus stringent efforts must continue to increase the level of iodine intake to amounts that can provide sufficient T4 for D2-catalyzed T3 production. This would allow individuals in these regions to benefit from the intrinsic physiological compensatory mechanisms in this critical tissue.
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ACKNOWLEDGEMENTS |
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Serum concentrations of thyroid hormones were measured by the Clinical Research Center at the Brigham and Women's Hospital.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants RO1-DK-44128 and DK-37021. A. C. Bianco was partially supported by the University of Saõ Paulo. R. Peeters was supported by the Dr. Saal van Zwanenbergstichting, Stichting Bekker-la Bastide-Fonds, and Stichting Dr. Hendrik Muller's Vaderlandsch Fonds.
Address for reprint requests and other correspondence: P. R. Larsen, Brigham and Women's Hospital, 77 Ave. Louis Pasteur, HIM Bldg. Rm. 550, Boston MA 02115 (E-mail: rlarsen{at}rics.bwh.harvard.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 13 September 2000; accepted in final form 15 February 2001.
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