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Departments of Medicine (A.H., M.E.M., D.L.S.G.) and Physiology (V.A.G., D.L.S.G.), Dartmouth Medical School, Lebanon, New Hampshire 03756; Departments of Medicine (X.-H.L., S.R.) and Pediatrics (S.R.) and the Committees on Genetics and Molecular Medicine, The University of Chicago, Chicago, Illinois 60637; and Institute de Recherche Interdisciplinaire (J.V.S.), Faculte de Medicine, Universite Libre de Bruxelles, 1070 Bruxelles, Belgium
Address all correspondence and requests for reprints to: Arturo Hernandez, Ph.D., Research Assistant Professor of Medicine, Dartmouth Medical School, Lebanon, New Hampshire 03756. E-mail: Arturo.Hernandez{at}Dartmouth.edu.
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Introduction |
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Two TH are secreted by the thyroid: T4, which is considered to be a prohormone, and the more active hormone T3. Their concentrations in the plasma are tightly regulated by the hypothalamic-pituitary-thyroid (HPT) axis. TRH generated in the hypothalamus induces the secretion from the pituitary of TSH, which in turn stimulates the thyroid gland to release TH into the circulation. Serum TH provide additional regulatory control by exerting negative feedback effects on the axis at both the pituitary and hypothalamic levels. Given the pleiotropic and profound biological effects of TH, the proper regulation of the HPT axis is of great importance to numerous biological processes.
Systemic and intracellular TH concentrations are also regulated at a prereceptor level by the three selenodeiodinases, whose actions result either in the activation or inactivation of TH (6, 7, 8). Whereas the type 1 and 2 deiodinases (D1 and D2, respectively) activate T4 by converting it to T3, the type 3 deiodinase (D3) can convert both T4 and T3 into inactive metabolites by removing an iodine atom from the inner ring of these molecules (6, 9). In mammals, the D3 is highly expressed in the placenta and pregnant uterus (10, 11, 12, 13, 14), fetal and neonatal tissues (15, 16) as well as in the developing and adult brain (17, 18).
Recently we generated a D3-deficient (D3KO) mouse by inactivation of the Dio3 through homologous recombination (19, 20). The lack of D3 activity in these mice results in perinatal thyrotoxicosis as indicated by the marked increase in the serum T3 level observed during development. As adults, D3KO mice develop a moderate hypothyroidism characterized by a low serum T4 level and a modest decrease in the serum T3 level that persists throughout life (20). The hypothyroidism observed in D3KO mice appears to be due primarily to central impairment of the HPT axis, because the serum TSH level is only minimally elevated in the face of the low levels of serum TH. In the present study, we have analyzed the physiology of the HPT axis in the D3KO mouse and have identified functional defects at all levels of the axis. These findings help explain the altered thyroid parameters in this mouse model and highlight the important role of D3 in the establishment and function of the HPT axis.
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Materials and Methods |
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Wild-type (WT) and D3KO mice were generated by breeding animals heterozygous for the D3 mutation. Genotyping was performed by genomic PCR on DNA samples isolated from tail snips as previously described (20).
Hyperthyroidism was induced by providing the animals with T3 in the drinking water for a period of 1 month. The concentrations of T3 used were 0.1 and 0.25 µg/ml. During these treatments, no significant difference in the amount of water consumed was observed between WT and D3KO mice. Hypothyroidism was induced for the same period of time by treating the mice with drinking water containing 0.1% methimazole (MMI) plus 0.2% potassium perchlorate (ClO4–). After 1 month of treatment, the mice were euthanized, and blood samples were taken from the inferior vena cava. Unless otherwise stated, tissues were immediately harvested and frozen on dry ice. Sera and tissues were stored at –40 C and –80 C, respectively, until further analysis.
TRH and TSH response tests
To measure pituitary responsiveness to TRH, a blood sample was taken from the orbital sinus of the animals just before TRH injection (time = 0); 100 ng TRH (Sigma Chemical Co., St. Louis, MO) was then injected ip into each, and 20 min later, a second blood sample was taken from the opposite orbital sinus. Two hours and 20 min after TRH injection, mice were euthanized, and blood was collected from the inferior vena cava.
To analyze the thyroidal response to TSH, mice were provided with T3 in the drinking water (0.1 µg/ml) for 2 wk. A blood sample was then taken from the orbital sinus to confirm that the T4 level was suppressed. Animals were then injected ip with either 2 mU or 10 mU bovine TSH (Sigma). Blood samples were taken 3 h after TSH injection using the same procedure.
In situ hybridization of TRH mRNA
After harvesting, whole brains were placed in ice-cold PBS (pH 7.4) containing 4% paraformaldehyde and incubated at 4 C overnight, followed by incubation for 16 h at 4 C in the same solution plus sucrose (30% wt/vol). Brains were then embedded in OCT compound (Triangle Biomedical Science, Durham, NC), frozen in dry ice, and stored at –70 C for subsequent sectioning and analysis. Tissue sections (25 mm) were cut at –20 C in a cryostat, thaw-mounted onto Superfrost slides (Fisher Scientific Co., Pittsburgh, PA), and dried at 37 C overnight. To improve the accessibility of the probes to the mRNA, the thaw-mounted sections were placed in PBS containing 0.3% Triton X-100 for 10 min and then in 0.2 N HCl for 10 min. They were then acetylated in 0.1 M triethanolamine containing 0.25% acetic anhydride for 10 min, postfixed in 4% paraformaldehyde for 10 min, and dehydrated in a series of ethanol solutions (30, 50, 70, and 90%) for 2 min each, followed by 100% ethanol for 10 sec. Between each treatment, slides were washed in PBS for 5 min. Slides were air dried at room temperature. TRH sense and antisense RNA probes were prepared by in vitro transcription using the T3 and T7 polymerases (Maxi-Script kit from Ambion, Austin, TX). In each case, an appropriately linearized pBluescript plasmid (Stratagene, La Jolla, CA) containing 0.8 kb mouse TRH cDNA was used as a template. The probes were purified using the ammonium acetate/ethanol precipitation protocol provided with the Maxi-Script kit. The hybridization solution contained 50% formamide, 10% dextran sulfate, 5x Denhardt’s solution (1x Denhardt’s solution contains 0.02% BSA, 0.02% Ficoll 400, and 0.02% polyvinylpyrrolidone), 0.62 M NaCl, 50 mM dithiothreitol, 10 mM EDTA, 20 mM PIPES-Na (pH 6.8), 0.2% SDS, 250 µg/ml salmon sperm DNA, and 250 mg/ml yeast tRNA. The appropriate [35S]RNA probe, at a final concentration of 2 x 107 cpm/ml, was added to 0.5 ml of the hybridization buffer, and 20 µl of this solution was pipetted onto each slide and a coverslip applied. Slides were incubated in humid chambers at 55 C overnight. After incubation, coverslips were removed by dipping slides into a beaker containing 100 ml 1x standard saline citrate (SSC) (0.05 M NaCl and 0.0015 M Na citrate.) Excess probe was removed by placing slides in 2x SSC containing 10 mM ß-mercaptoethanol for 30 min, followed by incubation with 4 µg/ml ribonuclease A in 0.5 M NaCl, 50 mM Tris (pH 7.5), and 5.0 mM EDTA for 1 h at 37 C. Slides were then washed, first in 0.5x SSC containing 50% formamide and 10 mM ß-mercaptoethanol at 55 C for 2 h and then in 0.1x SSC containing 10 mM ß-mercaptoethanol at 68 C for 1 h. After a final wash in PBS for 5 min, sections were dehydrated in a series of ethanol solutions (40, 60, 80, and 90%) containing 0.3 M NH4OAc for 90 sec each, followed by 100% ethanol for 10 sec, and allowed to dry at room temperature. Sections were exposed for 5 d to BioMax MR film (Eastman Kodak, Rochester, NY) and then dipped in NTB autoradiographic emulsion (Eastman Kodak). After exposure for 3 wk at 4 C, the slides were developed with Kodak D19 developer (Eastman Kodak), fixed, and counterstained with nuclear fast red. Slides were examined using light-field microscopy.
Hormone determinations and TSH bioactivity
Total T4 concentration in serum was determined using the Total T4 Coat-a-Count RIA kit (Diagnostic Products Corp., Los Angeles, CA) according to the manufacturer’s instructions. The sensitivity of the assay as determined experimentally ranged from 0.1–0.2 µg/dl. The serum T3 level was determined using a sensitive RIA method established in our laboratory (21), with the modification that the T3 antibody used was obtained from a commercial source (Fitzgerald Industries International, Inc., Concord, MA). The cross-reactivity of T4 with the T3 antibody was less than 0.38%.
The serum TSH level was measured in 50 µl serum using a sensitive, heterologous, disequilibrium double-antibody precipitation RIA as previously described by Pohlenz et al. (22). Samples containing more than 1000 mU/liter were diluted with a TSH-deficient rat serum.
The bioactivity of TSH in serum was determined as described (22) by measurement of cAMP generation after the addition of serum to the medium of cultured Chinese hamster ovary (CHO) cells (clone JP26) stably transfected with a human TSH receptor cDNA (23). Briefly, 50,000 cells were seeded in individual test tubes and incubated for 24 h in 100 µl Ham’s F-12 nutrient mixture supplemented with 10% fetal calf serum, 100 IU/ml penicillin, 100 µg/ml streptomycin, 1 mM sodium pyruvate, and 2.5 µg/ml Fungizone. The cells were washed with 500 µl Krebs Ringer HEPES buffer (pH 7.4) supplemented with 8 mM glucose and 0.5 g/liter BSA and then preincubated for 30 min in 200 µl of the same medium. The medium was removed and 200 µl fresh buffer containing the standards or samples for TSH measurement were added along with 25 µM Rolipram (Sigma), a cAMP phosphodiesterase inhibitor. The incubation was continued for 1 h, and then the medium was replaced with 0.1 M HCl. cAMP was measured in the dried cell extract by RIA according to the method of Brooker et al. (24). Standards consisted of bovine TSH serially diluted in TSH-deficient mouse serum. To measure the bioactivity of TSH in the serum samples containing a high level of TSH, the samples were also serially diluted with TSH-deficient mouse serum. Thus, all incubations, including the basal value, were carried out in a medium containing a final concentration of 10% mouse serum. The cAMP results were correlated with those of the TSH RIA by linear regression. To calculate the intrinsic TSH bioactivity, i.e. the ratio of biological activity to the amount of immunoreactive TSH, the cAMP results were corrected for TSH-independent cAMP generation by subtracting the y-intercept of the (uncorrected) standard regression line as described (23).
Histological analysis
Thyroid glands with the trachea attached were collected from adult mice, placed in formalin, and embedded in paraffin. Mid-thyroid sections (4 µm thick) were stained with hematoxylin and eosin using standard procedures. Estimates of thyroid gland size and the area of individual follicular size were obtained using ImageJ (NIH image software) in several tissue sections through the mid-portion of the gland.
Statistical analysis
Statistical significance between two groups was determined by the Student’s t test. Statistical significance among multiple groups was determined by ANOVA followed by Fisher’s least significant difference analysis using the GB STAT computer software on a Macintosh computer.
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Results |
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given the scale of the y-axis (baseline values were 61.0 ± 5.6 and 95.2 ± 8.9 mU/liter in WT and D3KO mice, respectively, P < 0.01). Twenty minutes after TRH injection, a marked elevation (15-fold) in the serum TSH level was observed in WT mice (Fig. 1A). In D3KO mice, the serum TSH level was also stimulated by TRH but significantly less (only a 5-fold elevation), and the absolute level of TSH reached was considerably lower (D3KO, 475 ± 43 vs. WT, 742 ± 82 mU/liter, P < 0.01). In both groups of mice, the serum TSH level had returned to baseline 140 min after the injection.
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, B and C). In contrast, T3 and T4 levels were not increased in the D3KO mice (Fig. 1, B and C, bars on the right), despite the observed 5-fold increase in the serum TSH level. In fact, the serum T3 level was slightly and significantly reduced. These results indicate an impaired responsiveness of the pituitary of D3KO mice to TRH. In addition, the D3KO thyroid gland responds poorly to endogenously secreted TSH.
TSH bioactivity
To investigate the possibility of altered TSH bioactivity in the D3KO mice, we collected serum from both WT and D3KO mice under basal and hypothyroid conditions and examined these samples for TSH bioactivity in a cultured TSH-responsive CHO cell line (23). As shown in Fig. 2, TSH bioactivity expressed as cAMP production relative to TSH immunoreactivity was not significantly different in the serum samples taken from WT and D3KO mice. The similarity in TSH bioactivity was observed both under control conditions and in animals treated with MMI/ClO4–, where the TSH level was elevated. These results indicate that there is no significant abnormality in the bioactivity of the TSH produced by D3KO mice.
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) suggested that the thyroid does not respond appropriately to TSH. To explore this possibility directly, we performed a TSH stimulation test. WT and D3KO mice were treated with 0.1 µg/ml T3 in the drinking water for 2 wk to suppress TSH and serum T4 levels. With this treatment, the serum T4 level was just above the limits of detectability (Fig. 3A). The mice were then injected with 2 mU bovine TSH. Three hours later, the serum T4 level was approximately 3-fold higher in WT mice than in D3KO mice after TSH injection (Fig. 3A). Similar results were observed with a higher dose of TSH (10 mU).
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, C vs. B), and in the average follicular size (Fig. 3, E vs. D) in the D3KO animal. Using computer-assisted quantification of midsections of the thyroid, we estimate that the D3KO thyroid is only one third the size of the WT gland and half the normal size when adjusted for body weight (Fig. 3F). In addition, average thyroid follicular size was reduced 50% in D3KO mice.
Response to induced hyper- and hypothyroidism
To evaluate how the HPT axis of D3KO mice adjusts to altered TH levels, we measured serum T3, T4, and TSH in WT and D3KO mice after induction of hyper- and hypothyroidism. In WT animals, the addition of T3 to the drinking water at two different concentrations (0.1 and 0.25 µg/ml) resulted, respectively, in 2- and 6-fold increases in the serum T3 level (Fig. 4A, white bars). In D3KO mice, these treatments produced much larger increases (16- and 34-fold elevation) in this parameter (Fig. 4A, black bars). These results suggest that the absence of D3 activity significantly compromises T3 clearance.
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). As shown previously (20), the serum TSH level was elevated 50% in untreated D3KO mice (Fig. 4C). Treatment with T3 (0.1 µg/ml) resulted in an undetectable level of TSH in the serum of both WT and D3KO mice (dotted line in Fig. 4C represents the sensitivity of the assay).
As reported previously (20), the baseline serum T3 level in D3KO mice was 20% lower than that in WT animals (Fig. 5A, bars on the left). Hypothyroidism induced by MMI/ClO4– treatment decreased the serum T3 level to approximately 60% of baseline level in both WT and D3KO animals (Fig. 5A, bars on the right) and markedly suppressed serum T4 to a level that was less than 5% of the normal value (Fig. 5B). The same level of T4 suppression appeared to be achieved in both WT and D3KO mice. It is notable that MMI/ClO4– treatment resulted in a marked increase (180-fold) of the serum TSH level in WT mice (Fig. 5C), whereas this rise was significantly blunted in D3KO animals (30-fold increase) and reached an absolute value that was less than 20% of that observed in WT mice. This marked discrepancy in TSH responsiveness occurred despite serum levels of T4 and T3 that were comparably low in both groups. These data demonstrate a defect in the HPT axis of the D3KO mouse that results in a blunting of the TSH response to hypothyroidism.
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). After T3 treatment, WT mice given the lower T3 dose had the same weight as the WT control animals, whereas D3KO mice given the same treatment showed significant weight loss. This weight change in response to T3 treatment was greater with the higher T3 dose and more pronounced in the D3KO animals. Thus, after high-dose T3 treatment, WT mice exhibited a 10% increase in weight, whereas D3KO mice lost 20% of body weight.
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). In contrast to WT mice, where no deaths were observed in 34 animals treated with either dose of T3, 45% of D3KO mice (29 of 64) died during the month of treatment (P < 0.001). Lethality was 39% (11 deaths in 28 mice) and 50% (18 deaths in 36 mice) after treatment with, respectively, 0.1 and 0.25 µg/ml T3, suggesting a correlation between morbidity and the T3 concentration achieved. No deaths were observed in the 16 WT animals treated with MMI/ClO4–, but five D3KO mice of 27 (18.5%) died during the antithyroid treatment. Regarding untreated animals, no deaths were observed during this period in 20 WT animals, but two D3KO mice of 12 (17%) died.
Hypothalamic TRH expression
An integral part of the regulation of the thyroid axis is the TH-dependent expression of TRH in the hypothalamus.
Studies by other investigators (25) have demonstrated that TRH expression in the hypothalamus is significantly influenced by TH status only in the paraventricular nucleus (PVN). We performed in situ hybridization in coronal brain sections of WT and D3KO mice under control conditions and in mice that were rendered hypothyroid with MMI/ClO4– treatment. The expression of prepro-TRH mRNA was largely confined to the hypothalamus. The hybridization signal was specific, because no signal was detected when using a sense riboprobe (Fig. 7). We analyzed in detail the brain sections encompassing the PVN. The autoradiographs revealed that in this area, TRH expression is very similar in WT and D3KO mice (Fig. 7, B vs. C). As expected, antithyroid treatment resulted in a marked increase in TRH expression in WT mice (Fig. 7, B vs. F); however, no increase was observed in D3KO mice (Fig. 7, C vs. G). None of the hypothalamic sections from MMI/ClO4–-treated D3KO mice showed any significant increase in TRH expression relative to control animals, whereas several consecutive sections of the corresponding WT animals showed a level of expression as high as the one shown in Fig. 7F. We obtained similar results when in situ hybridization of prepro-TRH mRNA was performed in sections from another set of animals and the signal was detected using photographic emulsion (data not shown). These results indicate that the normal TH-dependent regulation of TRH expression in the hypothalamic PVN is impaired in the D3KO mouse.
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Discussion |
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We speculated previously that central mechanisms might play a principal role in the hypothyroidism of the D3KO mouse (20). Thus, we suggested that the decreases in serum T3 and T4 levels in the face of a mild elevation in TSH resulted from the secretion of a TSH molecule with reduced bioactivity. Such a phenomenon has been observed in other mouse models of central hypothyroidism, where the TSH level is also minimally elevated (26, 27). However, the results reported herein demonstrate that this is not the case. As directly assessed using cultured cells expressing the TSH receptor, the TSH in the serum of D3KO mice, under both basal and hypothyroid conditions, manifests normal bioactivity.
This unexpected result suggests that a defect in the thyroid gland itself is responsible for the observed decreases in serum T4 and T3 levels in this animal model. This thesis was confirmed by the results of the TSH stimulation test, whereby the increase in the serum T4 level in response to the administration of exogenous TSH was markedly blunted in the D3KO animal. Similarly, the secretory response of the thyroid to a 5-fold increase in endogenous TSH, as occurred during the TRH stimulation test, was also markedly blunted; indeed, no increases in serum T4 and T3 levels were noted in the D3KO mouse despite the reduced clearance of these compounds that occurs in these animals. Histological analysis of the thyroid gland suggests that the reduced size of the D3KO thyroid gland as well as the reduced follicular size contribute to the impaired thyroid gland function in these animals.
It could be argued that the interpretation of the results of these stimulation tests is complicated to some extent by the fact that serum T4 and T3 levels are decreased in the D3KO animal under basal conditions. However, the combination of low serum TH levels in the face of a mildly elevated level of TSH of normal bioactivity serves to reinforce the concept that the hypothyroid phenotype results from an impaired response of the thyroid to its trophic hormone. The profile of hormones in serum also renders irrelevant any concern that the impaired response to exogenous TSH results from an enhanced rate of clearance of the injected hormone.
Thus, regulatory or synthetic defects in the thyroid gland of the adult D3KO mouse appear to be a major consequence of D3 deficiency. Because D3 has not been detected in the adult rodent thyroid gland (28), this abnormality in thyroid function likely results from indirect effects of the D3 deficiency that alter the developmental or functional program of this organ.
This demonstration of defective thyroid function does not negate the possibility that central defects in the HPT axis also impact the thyroid status of the adult D3KO mouse. Indeed, our original observation that the TSH level, although mildly elevated, is relatively low for the degree of hypothyroidism as judged by serum T4 and T3 levels suggests that abnormalities are present in hypothalamic and/or pituitary function in this animal. This does indeed appear to be the case. The expected rise in the TRH mRNA level in the PVN as a result of hypothyroidism is significantly blunted in the D3KO mouse. We also demonstrated a very significant blunting of the TSH response to exogenously administered TRH, indicating abnormal responsiveness of the pituitary gland as well.
The response of the HPT axis to hypothyroidism in the D3KO mouse provides additional evidence of central defects in this animal. After treatment with MMI/ClO4–, serum T3 and T4 were suppressed to similar levels in both WT and D3KO mice. However, the serum TSH response in the face of this hypothyroid challenge was markedly impaired in the D3KO mice; the serum level of TSH rose to only 15% of the level observed in WT animals. Although it is likely that the blunted response of TRH in the hypothalamus and of TSH to TRH stimulation in the pituitary may be playing important roles in the impaired HPT axis response to hypothyroidism, other factors such as the effectiveness of TH feedback need to be examined in future studies. In this regard, we did administer T3 at two dose levels on a chronic basis to WT and D3KO animals in the present studies. However, the TSH level was undetectable in all treated animals, precluding any assessment of differential sensitivity of the HPT axis in WT vs. D3KO mice to feedback inhibition by TH.
Important information was obtained from experiments in which mice were administered T3 and rendered hyperthyroid. At both dosages of T3, the serum level of this hormone was markedly higher in the D3KO animals than in WT mice. This observation demonstrates that in the setting of T3 excess, D3 plays a critical role in the clearance of this hormone and thus in protecting tissues from thyrotoxicosis. It is important to note that this conclusion applies to adult animals, in which D3 expression is generally more limited than during development, and the brain and the skin are the only large adult tissues with high D3 expression. As expected, D3 expression in brain was markedly increased in WT mice treated with T3 (data not shown). The lower serum T3 levels in the D3KO mouse seem inconsistent with impairment in T3 clearance. However, the latter may be due to the reduced serum T4 and liver D1 activity previously observed (20) as well as to the impairment in thyroid function reported here.
This protective effect of D3 in adult hyperthyroidism is substantiated by the significant weight loss and notable lethality of D3KO mice during T3 administration. Although chronic hyperthyroidism is known to result in weight loss, no such observation was made in T3-treated WT animals compared with untreated controls. This could be explained by the fact that the T3 was administered in the drinking water, which is a slow but steady method of inducing hyperthyroidism. During the treatment, both WT and D3KO mice initially gained weight before they started to lose it after onset of significant thyrotoxicosis (data not shown). Indeed, WT mice were losing weight at the end of the treatment, although their weight was still higher than that measured before the initiation of treatment. Our results likely reflect the fact that when using this specific protocol, D3KO mice have more difficulty clearing the excess T3, and the onset of thyrotoxicosis and associated weight loss occur much sooner. Although food consumption is not a variable analyzed in this experiment, the initial weight gain in T3-treated animals of both genotypes as well as in the untreated controls suggest that this is not likely an important factor.
Taken together, these results define for the first time a critical role for the D3 in establishing the normal functioning of the HPT axis. Thus, the congenital absence of this enzyme results in marked abnormalities in the function of the hypothalamus, pituitary gland, and the thyroid gland. As a consequence, the D3KO animal exhibits a hypothyroid phenotype and impaired responsiveness to alterations in TH levels. At present, the molecular correlates of these abnormal physiological responses remain undefined.
These findings may have important clinical implications. They suggest that different degrees of TH exposure during development may be an important factor in determining the set-point of the HPT axis in adulthood. Indeed, perinatal thyrotoxicosis, such as occurs in the setting of poorly controlled maternal Graves’ disease, is known to result in central hypothyroidism (29, 30). Although most clinical reports suggest that this central hypothyroidism is transient, the long-term effects of perinatal thyrotoxicosis on the function and responsiveness of the thyroid axis are only now starting to be examined. Thus, consistent with our findings of significant abnormalities in the thyroid gland of the D3KO mouse, Kempers et al. (31) have recently reported that a significant proportion of children born to mothers with poorly controlled Graves’ disease manifest primary hypothyroidism in later childhood. This thyroidal dysfunction is characterized, at least in some cases, by a small thyroid gland as determined by ultrasound examination and low radioactive iodide uptake.
Our findings are also relevant to infants born to mothers with elevated serum TH levels due to resistance to TH. These infants have decreased birth weight (32) and as adults exhibit lower serum TSH concentrations relative to their serum TH levels (S. Refetoff, unpublished results). Finally, one might speculate that should genetic, medical, or environmental conditions be defined in the future whereby D3 activity is impaired, these situations may be accompanied by significant alterations in the thyroid axis and an impaired ability of the individual to adapt to alterations in thyroid function.
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Footnotes |
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Disclosure Statement: The authors have nothing to disclose.
First Published Online September 6, 2007
Abbreviations: D, Deiodinase; D3KO, D3-deficient; HPT, hypothalamic-pituitary-thyroid; MMI, methimazole; PVN, paraventricular nucleus; SSC, standard saline citrate; TH, thyroid hormones; WT, wild type.
Received May 16, 2007.
Accepted for publication August 27, 2007.
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