Vol. 273, Issue 6, E1121-E1126, December 1997
Effects of marginal iodine deficiency during pregnancy: iodide
uptake by the maternal and fetal thyroid
P. M.
Versloot,
J. P. Schröder-Van Der
Elst,
D.
Van Der
Heide, and
L.
Boogerd
Department of Human and Animal Physiology, Agricultural
University, 6709 PJ Wageningen, The Netherlands
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ABSTRACT |
Iodide uptake by the thyroid is an active
process. Iodine deficiency and pregnancy are known to influence thyroid
hormone metabolism. The aim of this study was to clarify the effects of iodine deficiency and pregnancy on iodide uptake by the thyroid. Radioiodide was injected intravenously into nonpregnant and 19-day pregnant rats receiving a normal or marginally iodine-deficient diet.
The uptake of radioiodide by the thyroid was measured continuously for
4 h. The absolute iodide uptake by the maternal and fetal thyroid
glands at 24 h was calculated by means of the urinary specific
activity. Pregnancy resulted in a decrease in the absolute thyroidal
iodide uptake. Marginal iodine deficiency had no effect on the absolute
iodide uptake by the maternal thyroid. The decreased plasma inorganic
iodide was compensated by an increase in thyroidal clearance. A similar
compensation was not found for the fetus; the uptake of iodide by the
fetal thyroid decreased by 50% during marginal iodine deficiency. This
can lead to diminished thyroid hormone production, which will have a
negative effect on fetal development, especially of the brain.
thyroxine; 3,5,3'-triiodothyronine; plasma inorganic iodide; iodide kinetics
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INTRODUCTION |
IT IS KNOWN THAT THYROID FUNCTION is affected by
various physiological conditions, for instance, food deprivation (24), pregnancy (10, 11, 12), and iodine deficiency (19, 23). Iodide is an
essential element for the production of thyroid hormones. The uptake of
iodide by the thyroid gland is an active process that is regulated by
thyroid-stimulating hormone or thyrotropin (TSH) (26) and the thyroidal
blood flow (3). Alterations in the thyroidal uptake of iodide can cause
changes in the production of thyroid hormones.
Iodine deficiency affects the physical and mental development of humans
in large areas of the world (13). In rats it has been shown that during
iodine deficiency the plasma thyroxine (T4) level decreased while the
3,5,3'-triiodothyronine
(T3) level remained unchanged
(23). The weight of the thyroid and the
T3-to-T4 ratio in the thyroid of rats on a low-iodine diet increased (19, 23).
Studies of 10-day-old rats have shown that the thyroidal iodide uptake
was considerably higher in iodine-deficient rats than in controls (31).
Physiological changes in thyroid function also occur during pregnancy.
Normal pregnancy in humans is accompanied by a rise in
T4-binding globulin and total
T4 and
T3 (12). However, the free
T4 level is decreased at the end
of gestation (29). The availability of iodide for the maternal thyroid
is decreased because of increased renal clearance (1) and transport to
the feto-placental complex during the late phase of gestation (10). The
maternal thyroid is enlarged and the radioiodide uptake, expressed as a percentage of the dose, is increased during pregnancy (1, 10, 13).
In the rat normal pregnancy results in a decrease in plasma total
T4 and
T3 concentrations (4). This is
comparable to the decrease in free
T4 in the third trimester of human
pregnancy (29). The thyroidal uptake of
131I is decreased in the pregnant
rat (9, 11, 15). No changes were found in the urinary excretion of
iodide during the last days of gestation (9). Iodine eficiency
induces a further decrease in plasma
T4 in the near-term pregnant
rat (8). Also the weight of the thyroid is increased by iodine
deficiency in the pregnant rat (7).
Most studies of the iodide uptake in rats are performed by tracer
injection of a radioactive isotope of iodide
(131I,
125I, or
123I). After a certain period the
thyroid is removed and the percentage of the injected radioactivity is
calculated (9, 11, 15, 31). In our laboratory we developed a method for
measuring continuously the in vivo uptake of
125I by the thyroid. By means of
this method it is possible to study not only the amount of
radioiodide taken up by the thyroid but also the kinetics of the
thyroidal uptake of iodide. We were also able to calculate the
absolute iodide uptake by the thyroid.
The aim of this study was to clarify the effects of pregnancy and
iodine deficiency on iodide uptake by the thyroid. We used four groups
of rats: nonpregnant and near-term (day
19) pregnant rats receiving a normal iodine diet or a
marginally iodine-deficient diet. This marginally iodine-deficient
situation closely reflects the iodine status of large populations of
humans in the world. As previously described, pregnancy as well as
iodine deficiency affects plasma thyroid hormone levels. However, the
effects on the absolute iodide uptake by the thyroid are unknown. In
particular iodine-deficient, near-term pregnant rats represent an
important group. What are the effects of iodine deficiency on iodide
metabolism in the near-term pregnant rat? Are the low amounts of iodide
available taken up totally by the maternal thyroid, or is there still
iodide available for the fetuses?
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MATERIALS AND METHODS |
Animals.
Three-month-old female Wistar rats (CPB/WU, IFFA CREDO, Brussels) were
used. The rats were individually housed in metabolic cages at 22°C,
with alternating 14-h light and 10-h dark periods. The animals were fed
a semisynthetic American Institute of Nutrition (AIN) diet (2) mixed
with distilled water (60% dry weight-40% water) and potassium iodide:
55 ng [normal iodine dose (NID)] or 2.9 ng [marginal
iodine dose (MID)] per gram of feed. The marginally iodine-deficient groups received 1%
KClO4 in the drinking water during
the first 2 days of the MID 
4 wk before measurement was started.
KClO4 was given to accelerate
thyroidal depletion of total iodine stores.
After two regular estrus cycles the rats were mated. Mating was
confirmed by the presence of sperm in a vaginal lavage the following
morning, called day 0 of pregnancy.
Design of the study.
In this study four groups of animals were studied:
1) nonpregnant rats on a normal diet
(NID, C); 2) pregnant rats on a
normal diet (NID, P); 3) nonpregnant
rats on a marginally iodine-deficient diet (MID, C);
4) pregnant rats on a marginally
iodine-deficient diet (MID, P). The pregnant rats were assessed at the
end of gestation, i.e., day 19.
Fetuses were delivered on day 21. The
more frequently used day 20 was not
suitable in this experiment, because the animals were killed and bled
24 h after the injection of radioiodide.
Daily feed intake and urinary iodide excretion were determined for all
rats. The mean feed intake was 30 g, resulting in a daily iodide intake
of 1.3 µg for the NID groups and 66 ng for the MID groups.
Urinary iodide was determined as described by Sandell and Kolthoff
(22).
The experiments were approved by the University Committee on Animal
Care and Use of the Agricultural University of Wageningen.
Thyroidal iodide uptake.
The rat was anesthetized with xylazine (25 µl of 2% Rompun/100 g
body wt sc), atropine (5 µg/100 g body wt sc), and ketamine (50 µl
of 10% ketamine/100 g body wt ip). The anesthesized rat was fixed in a
bed of plaster. The body temperature was monitored via the rectum and
maintained at 38°C by a warming jacket.
The scintillation probe [type 42A NaI crystal 23 mm long × 1 mm thick, connected to mini-Assay type 6-20 (Mini Instruments, Essex, UK)] was placed as close as possible to the thyroid
region.
To measure the thyroidal iodide uptake in the rat, a cannula was
inserted into the right vena jugularis (20) and a 400-µl bolus of
saline containing 10 µCi carrier free
Na125I (Amersham, Aylesbury, UK)
was injected. The radioactivity taken up by the thyroid was measured
automatically every 30 s for 4 h and calculated as a percentage of the
injected dose. The percentage dose of iodide taken up by the thyroid
was fitted to the equation %dose = A
[1 
exp(t/
)] by nonlinear
regression analysis using the program NLFIT/FIT4EXP, which is based on
the Levenberger-Marquart method. A
represents the maximum percentage of dose taken up by the thyroid, and
is the time constant (min).
Perchlorate discharge test.
To investigate the effects of perchlorate on radioactivity in the
thyroid, three animals from each group underwent a
perchlorate-discharge test (17). Four hours after the administration of
Na125I, potassium perchlorate (10 mg/kg body wt ip) was administered. Thyroidal radioactivity was
measured for another 30 min.
Iodide kinetics in plasma.
To study the disappearance of the injected
125I, plasma samples (50-100
µl blood) were taken via the cannula in the vena jugularis 1, 3, 5, 10, 16, 25, 40, 80, 150 and 240 min after injection of the
125I. Radioactivity in the plasma
samples was expressed as percentage dose per milliliter.
The disappearance of iodide from plasma can be described by an
exponential function. The data were fitted, together with the plasma
volume at t(0), individually to sums
of n = 1-3 exponentials (6)
by
use of the program DIMSUM, whereby
Ai
coefficients are expressed in percentage dose per milliliter and
exponents 
i are expressed per
minute (16).
Absolute iodide uptake after 24 h.
After measurement the rats were placed in metabolic cages for
collection of urine.
Twenty-four hours after injection of the
125I the rats were killed by
bleeding and perfusion with saline under ether anesthesia. The maternal
thyroid, mammary gland, placentas, and fetuses were removed. The fetal
thyroid was collected by excising that part of the trachea containing
the thyroid.
All radioactivities measured (i.e., maternal and fetal thyroid, plasma,
urine, mammary gland, placentas, and fetuses minus thyroid at 24 h)
were expressed as percentages of the injected dose.
The assumption can be made that, during a steady-state situation, the
specific activity of iodine (ratio of
125I to
127I) in urine is the same as that
in the plasma from which it originated (28). The absolute iodide uptake
(AIU) by the maternal and fetal thyroids, mammary gland, placentas, and
fetuses minus thyroid, as well as the plasma inorganic iodide (PII),
can be calculated after determination of the specific activity of
iodine in urine (1)
Radioiodide
clearance from the plasma by the thyroid
(CTh) and by the kidneys
(CR) is calculated from the
increment between 120 and 240 min divided by the radioactivity in a
plasma sample collected simultaneously (1)
Statistical analysis.
All data are expressed as means ± SE. Data were analyzed using the
Statistical Package for Social Sciences (25). All data were subjected
to one-way analysis of variance, and statistical differences between
groups were determined using the least significant difference
method.
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RESULTS |
Marginal iodine deficiency had no effect on either the body weight of
the rats or the number of fetuses. No significant alterations were
found for plasma TSH. Plasma T4
and T3 did not change
significantly during marginal iodine deficiency. Pregnancy resulted in
a decrease in plasma T4 and
T3 in NID as well as MID rats
(Table 1).
Feed intake and urinary iodide excretion.
At the start of the experiments, the marginally
iodine-deficient groups received potassium perchlorate for 2 days. The
effect of this treatment on urinary iodide excretion is shown in Fig. 1. Potassium perchlorate treatment from
day 0 to day
2 resulted in an increase in iodide excretion. Within 1 wk after perchlorate treatment, urinary iodide excretion had decreased
to 0.4 µg/day; it remained constant during the rest of the
experimental period.
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Fig. 1.
Effect of KClO4 treatment on 24-h
urinary iodide excretion in marginally iodine-deficient nonpregnant
rats.
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The mean feed intake and urinary iodide excretion for the four groups
of rats are shown in Fig. 2. No effect of MID on feed intake was found. During pregnancy, feed intake and urinary iodide excretion increased.
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Fig. 2.
Effect of marginal iodine deficiency and pregnancy on daily feed intake
(A) and urinary iodide excretion
(B).
P < 0.05: # pregnant (P) vs.
control (C); * marginal iodine dose (MID) vs. normal iodine dose
(NID).
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Thyroidal 125I uptake.
Table 2 shows the data on thyroidal
125I uptake. The weight of the
thyroid increased significantly in both marginally iodine-deficient groups; pregnancy had no effect on the weight of the thyroid.
The 4-h 125I uptake by the thyroid
increased in C and P MID rats. Pregnancy induced a decrease in
125I uptake by the thyroid in both
NID and MID rats. The 4-h 125I
uptake is a direct measurement of the thyroid;
A and are the results of fitting
the data to the one-exponential function %dose = A [1 exp(t/)]. Two- and
three-exponential functions did not yield satisfactory results. The
time constant () of the 125I
uptake was unchanged in all groups. The mean fitted thyroidal 125I uptake is given in Fig.
3, where we also see that the thyroidal 125I uptake was lower in P rats
and increased in the MID groups.
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Fig. 3.
Fitted 4-h thyroidal radioiodide uptake based on mean maximal %dose
taken up by thyroid (A) and time
constant () values.
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Perchlorate discharge test.
No discharge of radioiodide from the thyroid was found for any of the
four groups. The radioactivity of the thyroid remained unchanged
(results not shown).
Iodide kinetics in plasma.
Table 3 shows the parameters of iodide
kinetics in plasma. No significant changes were found except for
A1 in pregnant
rats.
AIU after 24 h.
Table 4 shows the specific activity of
urine and the results of calculations of the AIU by the maternal
thyroid , PII, CTh, and
CR. The urinary specific activity
was unchanged during pregnancy, but marginal iodine deficiency caused
an increase in specific activity. The AIU by the thyroid was decreased
by pregnancy, whereas marginal iodine deficiency had no effect on the
AIU. PII was decreased in the MID groups, whereas pregnancy had no
effect. Unidirectional iodide CTh
was increased in the MID groups.
CR was increased by pregnancy,
whereas MID resulted in a decrease in
CR in C and near-term P rats
(Table 4).
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Table 4.
Urinary specific activity, absolute iodide uptake by thyroid at 24 h,
plasma inorganic iodide, and clearance of iodide from plasma by
thyroid and kidneys
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The AIU values at 24 h by the maternal thyroid, placentas, fetal
thyroids, remaining part of the fetuses, and mammary gland are shown in
Fig. 4. Whereas MID had no effect on the
AIU by the maternal thyroid, a pronounced decrease was found for the
fetal thyroids and the remaining part of the fetuses. The amount of iodide taken up by the mammary gland was also decreased by MID, whereas
no significant effect was found for the placentas.
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Fig. 4.
Absolute iodide uptake by maternal thyroid and feto-placental
compartment; 1) placentas;
2) fetal thyroids;
3) fetuses minus thyroids;
4) mammary gland (1 g).
* P < 0.05, NID,P vs.
MID,P.
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DISCUSSION |
The process by which the thyroid gland adapts to an insufficient iodine
supply is to increase the trapping of iodide. When iodine intake is
low, adequate secretion of thyroid hormones may still be achieved by
marked modifications of thyroid activity. The thyroid is stimulated by
an increased thyroid blood flow (3) and TSH (19, 23). The
T3-to-T4
ratio of iodothyronines secreted by the thyroid is increased during
iodine deficiency, especially because of a decrease in
T4 production (23).
Marginal iodine deficiency was induced in our rats by feeding them a
MID diet. Within 2 wk of the start of the MID diet, urinary iodide
excretion remained at the same level. So, at the moment of measurement,
4 wk after start of the MID diet, the rats were in a steady state.
The fact that only a marginal iodine-deficient state was achieved, and
not a severe iodine-deficient state, is demonstrated by the unchanged
plasma T4 and
T3 levels. Despite a slight
increase in plasma TSH, the weight of the thyroid had already increased
by 50%. The unchanged number of fetuses during pregnancy also
demonstrates that the induced iodine deficiency was not severe (8).
In this study we were able to measure thyroidal radioiodide uptake
continuously. For the kinetic analysis of radioiodide uptake in the
human thyroid, a three-compartmental model is used (3, 14, 30). In this
model, a plasma iodide pool and an inorganic and an organic thyroidal
iodide pool can be distinguished. We tried to fit our data to this
model; however, our data could only be fitted to a one-exponential
function. Therefore, we assume that, even in euthyroid rats, iodide
transport from plasma into the thyroid is unidirectional because of an
extremely avid iodine organification. This idea is confirmed by the
total absence of a perchlorate discharge in all rats, meaning that
there is no efflux of inorganic iodide from the thyroid (17).
The thyroidal uptake of radioiodide was stimulated by marginal iodine
deficiency. The kinetic analysis shows that the time constant for
thyroidal radioiodide uptake was not affected by iodine deficiency,
meaning that the time needed to achieve the maximum effect remained the
same. However, the AIU by the thyroid remained normal. This was
achieved by an increased CTh resulting from the increased
thyroid volume and thyroidal blood flow (3).
The urinary specific activity was increased, whereas the radioiodide
activity in plasma was not altered by marginal iodine deficiency. This
resulted in a PII that was significantly lower, such as is found in
humans residing in areas of iodine deficiency (5) and in 10-day-old
iodine-deficient rats (31).
Our observations emphasize the need for caution in interpretation of
results obtained by studies measuring the thyroidal radioiodide uptake
only. We have demonstrated that a decrease or increase in radioiodide
uptake does not automatically mean that the AIU has changed.
Also, during normal pregnancy, changes in iodide metabolism are found.
The urinary iodide excretion was higher for P than C rats of the NID as
well as MID groups. This can be explained by the increased feed intake
and the increase in CR. Galton
(11) also found an increased urinary iodide excretion for pregnant rats
during the last days of gestation.
At the end of gestation the percentage of radioiodide taken up by the
thyroid was significantly decreased. This has also been reported for
rats with a normal iodine intake (9, 11, 15). Because the urinary
specific activity was not altered by pregnancy, this also resulted in a
decrease in the absolute iodide uptake by the maternal thyroid at the
end of gestation in NID as well as MID rats. It seems that the thyroid
of the near-term P rat has less iodide available for the production of
thyroid hormones. However, no change in thyroidal hormone production is
found at the end of gestation (27). This would seem to imply that the use of iodide in the thyroid of the near-term P rat is more efficient or that the thyroglobulin stores are depleted.
The difference in thyroidal iodide uptake between C and near-term P
rats cannot be attributed entirely to the increase in urinary iodide
excretion. We suggest that the remaining part of the iodide is used by
the mammary glands and the feto-placental compartment. For lactating
rats it has been shown that, 4 h after injection, the mammary glands
contain as much radioiodide as the thyroid, and it was suggested that
during pregnancy radioiodide was already being transported to the
mammary glands (15). The latter was contradicted by our measurements.
One gram of the mammary gland had only taken up 6.5 ng iodide at 24 h;
this is less than 1% of the thyroidal uptake.
The placenta possesses a mechanism for actively transporting iodine
(21). Therefore, it is to be expected that a certain amount of
radioiodide is transported to the fetal compartment. Our results,
collected 24 h after injection, show that the fetal thyroid is capable
of concentrating iodide on day 20 of
pregnancy. The thyroidal region of the fetus contained as much iodide
as the rest of the fetus. However, the total amount of iodide in placentas and fetuses could not explain the decreased uptake of iodide
by the maternal thyroid. Therefore, the feto-placental compartment and
the mammary glands are not the only factors responsible for the
difference in maternal thyroidal iodide uptake.
During marginal iodine deficiency the AIU of the maternal thyroid
remained normal. However, there was already a tendency toward a shift
in thyroid hormone synthesis; T4
decreased and T3 remained normal.
In contrast to the maternal thyroid, no compensation by an increased
thyroid clearance for the decreased PII concentration was found for the
fetal thyroid. The AIU by the fetal thyroid was decreased by 50%. This
pattern can lead to lower T4
availability for the fetus. This is supported by kinetic studies of
marginally iodine-deficient, near-term pregnant rats showing that the
maternal transfer of T4 and
T3 to the fetuses is decreased
during marginal iodine deficiency (unpublished data). As long as the
increase in type II deiodinase is sufficient to maintain normal
T3 values in the fetal brain,
problems need not be expected (18). If this is not achieved, defects in
brain development will occur.
In conclusion, during pregnancy the AIU by the maternal thyroid gland
is decreased. Marginal iodine deficiency does not affect the maternal
thyroidal AIU. The low availability of iodide was compensated by
increased activity of the maternal thyroid, whereas fetal thyroidal
uptake of iodide decreased by 50%. The fetus is apparently not able to
regulate its iodide metabolism in case of marginal iodine deficiency.
Therefore, this level of marginal iodine deficiency, despite the near
euthyroid status of the mother, already has an effect on the
availability of iodide for the fetus. This can mean that fetal
T4 production is markedly
diminished at a time when it is of eminent importance for the normal
development of many organs, especially the brain.
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ACKNOWLEDGEMENTS |
We are grateful to J. S. Goense for setting up the measurements and
G. van Niftrik (Gelderse Vallei Hospital, Bennekom, The Netherlands)
for designing the measuring bed for the rats. We thank M. van Lieshout
for contributing to the experiments, T. Viets for performing the iodide
measurements, Dr. R. Bakker for developing the mathematical model, and
G. P. Bieger-Smith for correcting the text.
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FOOTNOTES |
Reagents used for the rat TSH assay were kindly provided by the Rat
Pituitary Hormone Distribution Program of the National Institute of
Diabetes and Digestive and Kidney Diseases.
Address for reprint requests: D. van der Heide, Dept. of Human and
Animal Physiology, Agricultural Univ., Haarweg 10, 6709 PJ, Wageningen,
The Netherlands.
Received 23 May 1997; accepted in final form 12 August 1997.
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AJP Endocrinol Metab 273(6):E1121-E1126
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Abstract
Introduction
