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Departments of Physiology and Medicine, Dartmouth Medical School, Lebanon, New Hampshire 03756-0001; and Reactor Research Laboratories, University of Missouri, Columbia, Missouri 65211
Address all correspondence and requests for reprints to: Valerie Anne Galton, Department of Physiology, Dartmouth Medical School, 1 Medical Center Drive, Borwell Building, Lebanon, New Hampshire 03756-0001. E-mail: val.galton{at}dartmouth.edu
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Abstract |
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The present study was designed to determine, in rats: 1) whether the effects of Se-deficiency are greater in the fetus and neonate than in the adult; 2) whether there are tissues other than brain and thyroid in which deiodinase activities are maintained; 3) whether the maintenance of deiodinase activity in a specific tissue is associated with a concomitant preservation of Se level in that tissue; and 4) whether TH economy and general health is maintained over several generations. The tissues studied included liver, cerebrum, thyroid, pituitary, skin, brown adipose tissue, uterus, ovary, testis, placenta, and the implantation site (uterus plus contents) at E9.
The results have revealed that, with the exception of liver, skin, and nonpregnant uterus, all of the tissues studied maintained substantial deiodinase activity (>50%) during prolonged Se-deficiency. Second, although the ability of a tissue to maintain deiodinase activity in the face of dietary Se deprivation was associated in some tissues with a concomitant local preservation of Se concentration, this was not the case for all tissues. Only when Se levels were decreased by more than 80% was deiodinase activity markedly decreased. Third, the effects of Se-deficiency were no greater in the fetus than in the adult; and fourth, at the level of Se-deficiency employed in this study, TH economy and general health were successfully maintained over six generations of Se-deficient rats. How Se levels are maintained in specific tissues, whether Se is sequestered in specific cells of a tissue or organ during dietary Se deprivation, and the precise mechanisms by which plasma T3 levels are maintained in Se-deficient animals remain unanswered. Further insights may be gained by using diets that are even lower in Se than those that were used herein and/or by conducting studies using radioactive forms of Se and thyroid hormones.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The two 5'-deiodinases are differentially expressed in tissues; D1 is found primarily in liver, kidney, and thyroid; whereas D2 is expressed in brain, pituitary, and brown adipose tissue (BAT) (1, 2). D3 is found in cerebral cortex and skin (3, 4) and is expressed at very high levels in placenta (5, 6, 7) and pregnant uterus (7), and at much lower levels in several fetal rat tissues (7, 8, 9).
All three deiodinases contain selenium (Se), which is present in the form of the amino acid selenocysteine located at their active sites (10, 11, 12, 13, 14, 15, 16). Thus, one would predict that a nutritional Se deficiency would result in significant changes in deiodinase activities and, hence, in TH economy. However, in the adult rat, the effects of nutritional Se deprivation on the thyroid axis are relatively modest and seem to be limited to a few select tissues (17, 18). The most notable effects included a marked decrease (>90%) in hepatic and renal D1 activity (19) and protein (20) and a 40–50% increase in serum T4 concentration. Serum T3 and TSH levels and thyroidal D1 and brain D3 activities were largely unchanged (18, 21, 22). Brain D2 activity was decreased in these animals, but this was attributed to the down-regulating effects of the elevated circulating T4 level (23, 24), rather than to a direct effect of Se deficiency (22, 25). These findings have led to the suggestion that brain and thyroid contain mechanisms for local conservation of Se (22, 26, 27).
The impact of Se status on various clinical parameters is currently being investigated. For example, the plasma T3/T4 ratio is low in individuals prone to Se deficiency, such as the elderly (28), patients with phenylkenouria (29), and cystic fibrosis (30), and it normalizes upon Se supplementation (31). This may reflect Se-induced alterations in D1 activity. Other studies have suggested that Se deficiency is related to adverse outcomes of pregnancy. Thus, maternal blood Se levels are low in women who experience a first trimester miscarriage, when compared with women at the same stage of pregnancy who carry to term (32). Maternal Se levels were also found to be decreased in women with preterm deliveries; and the activity in cord blood of glutathione peroxidase, another selenocysteine containing enzyme, was diminished in the premature infants (33). The authors suggested that this could be a factor in the higher rate of retinopathy and respiratory distress syndrome observed in preterm infants.
Information regarding the impact of Se deficiency on TH economy during development is limited. Because the fetus develops de novo, one would expect it to be more prone than the adult to the adverse effects of Se deficiency. However, based on the limited information available, it is uncertain whether or not this is the case. Although it has been shown that severe Se deficiency can effect fertility in both male and female rodents (34), rats can be carried through three generations on a diet low in Se (22). In some reports, however, significant abnormalities involving sparse hair, delayed growth, retarded motor skills, and ocular abnormalities have been observed in the Se-deficient offspring (35, 36). One group has reported significant decreases in glutathione peroxidase and D1 activity in liver of fetuses from Se-deficient rats, but no changes in the levels of T4, T3, rT3, or TSH in fetal serum were observed, and fetal brain D2 and placental D3 activities were unaffected (37). However, this study involved a relatively modest, short-term Se-deficiency (4 weeks) in the dams before pregnancy, and the investigators examined only selected tissues in near-term (gestation day 21) fetuses.
The present study was designed to answer several questions. First, are the effects of Se-deficiency greater in the fetus and neonate than in the adult? Second, are there tissues other than brain and thyroid in which deiodinase activities are maintained in Se-deficient rats? Third, can the maintenance of deiodinase activity in a specific tissue of Se-deficient rats be explained by a concomitant preservation of Se level in that tissue? Fourth, are TH economy and general health maintained over several generations in Se-deficient animals?
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tissue preparation
Rats were killed by decapitation and exsanguination. Blood,
cerebrum, liver, skin, BAT, and placenta were taken from E21 fetuses.
Blood, cerebrum, liver, BAT, thyroid, and pituitary were obtained from
the P12 neonates, the dams of the fetuses and neonates, and the
age-matched nonpregnant controls. Ovaries, uteri, and testes were
obtained from fourth-generation weanlings at P30; and individual
implantation sites, which consisted of uterus and its contents
(decidual tissue and embryo), were obtained at E9 from sixth-generation
pregnant rats. From preliminary studies, it was determined that the
activities of the deiodinases in muscle, heart, and adrenals were too
low to allow significant comparisons to be made.
Representative samples of tissue and serum were snap-frozen in 2-ml microfuge tubes on dry ice and then stored at -80 C until they were shipped on dry ice to the University of Missouri for analysis of their Se content. Aliquots of serum were also stored at -20 C for subsequent analysis of TH levels.
For determination of 5'D and 5D activities, tissues were homogenized in a deiodinase buffer (0.25 mM sucrose and 20 mM Tris-Hcl, pH 7.6) using a Tissumizer (Tekmar Co., Cincinnati OH). The homogenates were centrifuged at 1000 x g for 15 min, and the supernates were stored at -20 C for subsequent assay.
5D and 5'D assays in rat tissue homogenates
Tissue samples were assayed for 5D and 5'D, according to
published methods (38, 39). The reaction mixture (total vol, 50 µl)
contained between 25 and 250 µg tissue protein for the 5D assay, and
1 µg (adult liver) to 500 µg (most fetal and neonatal tissues) for
the 5'D assay. Protein concentrations for both assays were adjusted to
ensure that deiodination was less than 20%. The incubation time for
both assays was 1 h. For the 5D assays, 1 nM
[125I]T3 was used as
substrate and 50 mM dithiothreitol as cofactor; activity is
expressed as femtomoles or picomoles of 3,3'-diiodothyronine
(T2) generated per hour per milligram of protein.
For the 5'D assays, EDTA (1.2 mM) was included in the
incubation mixture, the substrate was 1.0 nM
[125I]rT3, and the
cofactor was 20 mM dithiothreitol; activity is expressed as
femtomoles or picomoles of iodide generated per hour per milligram of
protein. In determining 5'D activity, the percent of iodide generated
was multiplied by 2 because the specific activities of the labeled
products were only half that of the substrate. D1 and D2 5'D activities
were distinguished, respectively, by the inclusion of 1 mM
6-n-propyl-2-thiouracil and/or 100 nM nonradioactive
T4 in the incubation medium.
[125I]iodothyronines
([125I]rT3: specific
activity 
959 µCi/µg;
[125I]T3: 3390
µCi/µg) were obtained from Dupont de Nemours (Boston, MA) and were
purified by chromatography using Sephadex LH-20 (Sigma, St
Louis, MO) before use. Protein concentrations of all samples were
determined, according to the method of Comings and Tack, using BSA as
the standard (40). Because initial studies revealed that D1, D2, and D3
activity in P12 Se-deficient and Se-sufficient rats was not influenced
by gender, most assays in P12 rats used tissues from both sexes.
Determination of Se content of serum and tissues
Tissue samples were transferred to clean polyethylene vials
(0.25 ml) that had been previously tared. The samples were dried and
then weighed using an analytical balance (Mettler AT261, Fisher Scientific, Pittsburgh, PA), which had a sensitivity of 0.00001
g. Finally, spacers were used to fix the samples in the bottom of the
vials during all subsequent analysis steps. Samples prepared in this
way, along with Se standards and quality-control samples (NIST Standard
Reference Material 1577, Bovine Liver) were placed in shuttle capsules
and irradiated for 7 sec at a thermal neutron flux of 8E13
n/cm**2/sec using the pneumatic-tube irradiation facility at the
Missouri University Research Reactor. During the irradiation, naturally
occurring, nonradioactive Se-76 atoms capture neutrons to produce
radioactive Se-77m (half life, 17.4 sec). After the irradiation,
samples and standards were removed from the shuttle capsule and placed
in a fixed counting position approximately 5 mm from a high-purity
germanium detector (EG&G ORTEC, Oakridge, TN) coupled to a
state-of-the-art high-resolution 
-ray spectrometer (Canberra-Nuclear
Data, Meridian, CT). At precisely 15 sec, measured from the end of the
irradiation, each sample and standard was real-time counted for a
period of 25 sec to quantify the -ray emissions (161.9 keV) from the
photon decay of Se-77m. Pulse pile-up corrections were made by the
Westphal virtual-pulse method using a loss-free counting module
(Canberra-Nuclear Data). Data reduction to produce the Se concentration
for each tissue and quality control sample was carried out by standard
comparison. Se concentrations are expressed as ppm. For liver,
cerebrum, BAT, skin, pituitary, and thyroid, ppm = µg Se/g dry
tissue). For all other tissues ppm = µg Se/g wet tissue. Each
sample was analyzed at least twice by the above method, and the small
samples were analyzed three times. Results are reported as means for
the two or three determinations for each sample. The absolute
sensitivity for an Se measurement made by this method is approximately
0.1 ng, and this permitted Se levels to be quantified in tissue samples
of less than 50 mg from Se-deficient animals.
Analysis of plasma thyroid hormone concentration by RIA
Serum total T3 and
T4 concentrations were determined, in duplicate,
by species-adapted specific RIAs, using commercial kits according to
the manufacturer’s directions (Diagnostic Products, Los
Angeles, CA). A T3 resin uptake assay was also
performed using a kit from the same company.
Statistical analysis
Student’s t test was used to compare differences
between the mean values obtained in Se-deficient and Se-sufficient in
each tissue analyzed at each developmental period (41). Data are
expressed as mean ± SE. Statistical
significance was defined as P < 0.05. To test the
significance in multigroup comparisons, one-way ANOVA was used;
differences at the 5% level (P < 0.05) were assessed
by Tukey’s post hoc probability test (42).
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Results |
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Effects of a Se-deficient diet on tissue Se content and deiodinase
activity
Serum Se levels were much lower in Se-sufficient fetal and
neonatal rats than in their dams (P < 0.004), and Se
levels in these dams were lower than in the age-matched nonpregnant
rats (P < 0.004) (Fig. 1
). However, in all groups, Se-deficiency
resulted in a substantial decrease in serum Se levels, ranging from an
82% decrease in fetal serum to a greater-than-92% decrease in serum
from the adult rats.
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). In liver, the Se level was decreased
by 90% or more and D1 activity was greatly diminished (Fig. 2, A and
B); D2 and D3 were not expressed to a measurable extent in this tissue
at the stages of development studied. It was also noted that, as in
serum, Se concentration in liver was significantly lower in the fetal
and neonatal rats than in adult rats (P < 0.004). In
neonatal skin, the Se level was decreased by 85% (Fig. 2C) This tissue
expresses all three deiodinases and, with the exception of D2 in the
P12 rats (which was minimal, even in the Se-sufficient rats),
deiodinase activities were greatly decreased at both E21 and P12 (Fig. 2D). In uterus from P30 rats, the Se level was decreased by 90%, and
this was associated with a marked decrease in tissue D3 activity (Fig. 2, E and F). Although substantial 5'D activity, which proved to be
entirely attributable to expression of D2, is present in adult uterus
(Galton, unpublished observations); in the present study, this
deiodinase was only minimally expressed at P30.
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). In cerebrum from Se-deficient rats,
the decrease in the Se level was less than 45%; and, with the
exception of D1 activity in nonpregnant rats, the activities of all
three deiodinases were unchanged (Fig. 3, A and B). It was also noted
that, in contrast to serum and liver, Se levels were significantly
higher in fetal than in adult brain (P < 0.003). In
thyroid, the decrease in Se level was less than 43% in all but the P12
rats, and no decrease in deiodinase activity was observed (Fig. 3, C
and D). Similarly, the decrease in Se level in pituitary was less than
41%, and deiodinase activity was minimally affected (Fig. 3, E and F).
Under the conditions of these studies, no D3 activity was expressed in
either thyroid or pituitary, and D1 constituted all the 5'D activity in
thyroid and more than 95% of that in pituitary.
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, A and B). BAT was another tissue in
which Se levels were much higher in the fetus than in the adult. In
ovary, the Se level was decreased by 62%, but the activities of the
two deiodinases expressed (D1 and D3) were unchanged (Fig. 4, C and D).
In testis, the Se level was decreased 67%, but D1 activity was
unchanged, and D3 activity only slightly decreased (Fig. 4, E and F).
Finally, in placenta and E9 implantation site, although the Se levels
were decreased 78% and 73%, respectively, the levels of D3 activity
were not affected, and those of D2 activity were only minimally reduced
(Fig. 5 A–D).
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). Mean values for serum
T4 levels were slightly increased in the
Se-deficient rats, but this increase was not significant. The mean
value for T3 concentration was reduced in
Se-deficient fetal rats, but again this difference was not
statistically significant; and in all other groups, serum
T3 concentration was not changed in the
Se-deficient group. T3 resin uptake was unchanged
in the serum of Se-deficient rats (data not shown), indicating that the
TH binding activity of the serum was not affected by this
condition.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been suggested that the ability of a tissue to maintain levels
of deiodinase activity is a function of the extent to which it can
maintain its local Se concentration (22, 26, 27). The present findings
in liver, cerebrum, thyroid, and pituitary are consistent with that
view. Thus, in liver, both Se levels and deiodinase activity were
greatly diminished; whereas in cerebrum, thyroid, and pituitary, Se
levels were decreased less than 50%, and deiodinase levels were well
maintained. However, in many other tissues, deiodinase levels were also
well maintained, in spite of greatly diminished local Se levels. To
examine this relationship further, the percent decreases in the
activities of D1, D2, and D3 in all tissues and at all stages of
development were plotted against the corresponding percent decrease in
Se concentration (Fig. 7A). Examination
of the data in this way revealed that local Se levels can fall by
almost 80%, and a tissue is still able to maintain substantial levels
of deiodinase activity. Only when the decrease was more that 80%, such
as occurred in liver, skin, and uterus, was it associated with a marked
decrease in deiodinase activity. The decreases in deiodinase activity
were also plotted against the absolute Se concentrations achieved
during Se deprivation (Fig. 7B). These concentrations ranged from
0.01–1.1 ppm. In all tissues in which Se concentrations remained above
0.2 ppm, deiodinase activities were decreased less than 50%. However,
several tissues exhibited Se levels below 0.1 ppm. At these low levels
of Se, there seems to be no correlation with the change in deiodinase
activity. Thus, ovary, testis, E9 implantation site, and BAT exhibited
little or no decrease in deiodinase activity, whereas a marked decrease
was observed in liver, skin, and nonpregnant uterus. These observations
indicate that in Se-deprived rats, the decrease in levels of deiodinase
expression correlates more closely with the fractional decrease in Se
concentration than with the absolute Se concentration. However, many of
these tissues are heterogeneous; and in tissues such as ovary, testis,
and E9 implantation site, the possibility cannot be excluded that Se is
sequestered in the cells that express the deiodinase activity.
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). In
serum, the Se concentration in adults was more than four times that in
the fetus and neonate; and in liver; it was at least double. In
contrast, the Se concentration in fetal and neonatal cerebrum was
greater than that in adult cerebrum, and the concentration in fetal BAT
was four times that in adult BAT. It was also noted that the highest
levels of Se were found in adult liver and pituitary. The significance
of these observations remains to be determined.
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In view of the findings that plasma TH concentrations are essentially unaffected at the level of Se-deficiency attained in the present study, the lack of any distinct phenotype, including signs of altered thyroid status or reproductive capability, is not really surprising. The only problems observed were a slight retardation in growth, poor hair development in the neonatal phase, and an occasional cataract. The first two problems were temporary; adult Se-deficient rats were comparable in weight and coat thickness with age-matched Se-sufficient rats. Furthermore, cataracts were a relatively rare occurrence. The thyroid is known to play a major role in mammalian growth (43, 44, 45); and in rats, this is achieved, in part, through a direct stimulation of the GH gene expression (46). In the present study, the pituitary was a tissue in which Se levels were not greatly depressed. However, whereas levels of D1 activity were unaffected in the adult nonpregnant rat, activity was reduced by 50% in the neonatal P12 rat. Because this is the period when the growth retardation was noted, it is tempting to speculate that, as a result of the temporary decrease in pituitary D1 activity, intrapituitary T3 levels were reduced, leading to a decrease in transcription of the GH gene. However, given the known complex role of the thyroid in growth, this explanation is unlikely to be the whole answer. Furthermore, the possibility that these morphological abnormalities are the result of Se- deprivation per se, or secondary to an effect of this deficiency on a process unrelated to the thyroid-pituitary axis, cannot be excluded.
The effect of Se deficiency on hair growth might reasonably be attributed to the substantial decreases in deiodinase activities resulting from the marked decrease in Se levels in skin. Skin and hair development are known to be influenced by TH (47), and thus would be expected to be influenced by changes in intradermal T3 levels. The high level of D2 expression in skin at E21 coincides with a critical time of differentiation when there is formation of the skin permeability barrier in preparation for birth (48). T3 and glucocorticoids accelerate this barrier development by stimulation of two important enzymes, steroid sulfatase and cholesterol sulfotransferase (49, 50). The situation in skin may be compared with that in tadpoles, where D2 expression in given tissues is highest at the time of that tissue’s maximum T3-dependent differentiation (51). In addition, as previously reported by us and others (4, 8, 9), D3 activity rises markedly after birth, reaching a peak around P12, the time that hair growth becomes significant. It has been postulated that in tissues undergoing T3-dependent differentiation, the expression of both D3 and D2 serve to ensure that critical intracellular levels of T3 are maintained (2, 51). If this is so, then the marked decreases in the levels of skin D2 and D3 activities in Se- deficient fetal and neonatal rats would be expected to have significant effects on intradermal T3 levels, which would, in turn, influence T3-dependent developmental processes.
Because of the high levels of D1 activity in liver and kidney, these two tissues are generally considered to be the major source of plasma T3 (52). The present finding that plasma T3 levels were unaffected by a 95% decrease in hepatic D1 activity seems inconsistent with this view. There are several possible explanations for this apparent paradox. First, it may be that, in spite of the marked decrease in hepatic D1 activity, the remaining activity was sufficient to maintain plasma T3 levels. Second, because the D1 enzyme has both 5'D and 5D activities, it is possible that the decrease in hepatic T3 generation was countered by a comparable decrease in hepatic T3 degradation, thus leaving the amount released to the plasma unchanged. Third, a decrease in the amount of plasma T3 generated in the liver or kidney may have been made up with T3 generated in the thyroid and/or other tissues less affected by Se efficiency. Fourth, there may have been a decrease in the clearance of T3 from plasma; and fifth, there may have been a shift in the enterohepatic circulation of TH, such that either T3 secretion in the bile was reduced or T3 resorption through intestinal wall into the circulation was increased in the Se-deficient rats.
The Se-deficient rat shares an important characteristic with the C3H/Hej inbred mouse. In this mouse strain, the hepatic D1 activity is only 10% of that in the C57BL/6j (C57) strain, which exhibits a D1 phenotype more typical of this species (53, 54). In spite of the low hepatic D1 activity, the C3H/Hej mouse exhibits a serum T3 level in the normal range. However, these mice also exhibit a 2-fold increase in the serum free T4 concentration (53) and a decrease in T3 clearance (55), and the authors suggest that these are likely mechanisms through which serum T3 concentration is maintained (53).
In summary, the results obtained in this study have provided the answers to the four questions posed regarding Se-deficient rats. First, there are tissues, in addition to brain and thyroid, in which substantial deiodinase activity is maintained during prolonged Se-deficiency; in fact, with the exception of liver, skin, and uterus, all of the tissues studied fell into this category. Second, the ability of a tissue to maintain deiodinase activity in the face of dietary Se deprivation could not be explained in all tissues by a concomitant local preservation of Se concentration. Third, the effects of Se-deficiency were no greater in the fetus than in the adult; and fourth, at the level of Se-deficiency employed in this study, TH economy and general health were successfully maintained over six generations of Se-deficient rats. However, other questions, such as how Se levels are maintained in specific tissues, whether Se is sequestered in specific cells of a tissue or organ during dietary Se deprivation, and the precise mechanisms by which plasma T3 levels are maintained in Se-deficient animals, remain unanswered. Further insights may be gained by using diets that are even lower in Se than those that were used herein, and/or by studies using radioactive forms of Se and thyroid hormones.
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Acknowledgments |
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Footnotes |
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Received January 5, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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