help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schröder-van der Elst, J. P.
Right arrow Articles by Obregón, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schröder-van der Elst, J. P.
Right arrow Articles by Obregón, M. J.
Endocrinology Vol. 139, No. 5 2229-2234
Copyright © 1998 by The Endocrine Society

ARTICLES

Iodothyronine Deiodinase Activities in Fetal Rat Tissues at Several Levels of Iodine Deficiency: A Role for the Skin in 3,5,3'-Triiodothyronine Economy?1

Janny P. Schröder-van der Elst2, Daan van der Heide, Gabriella Morreale de Escobar and María Jesús Obregón

Unidad de Endocrinologia Molecular (J.P.S.-v.d.E., G.M.d.E., M.J.O.), Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, 28029 Madrid, Spain; and Human and Animal Physiology (D.v.d.H.), Agricultural University, 6709 PJ Wageningen, The Netherlands

Address all correspondence and requests for reprints to: Dr. J. P. Schröder-van der Elst, Instituto de Investigaciones Biomédicas, Arturo Duperier 4, 28029 Madrid, Spain. E-mail: jvanderelst{at}biomed.iib.uam.es


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Iodothyronine deiodinases, types I, II, and III (D1, D2, and D3) activities were measured in tissues of fetal rats, at 18 and 21 days of gestation, at several levels of iodine deficiency (ID): mild ID diet (MID) and moderately severe ID, MID + 0.005% perchlorate (MID+P). D2 was present in fetal skin, increased between days 18 and 21, and also in MID and MID+P. In skin, D3 increased during ID at day 18, whereas there was a decrease at day 21. Skin T4 decreased in MID and MID+P, showing an inverse relationship with D2. Skin T3 decreased at day 18 in MID and MID+P but increased at day 21, probably because of the increased D2 and decreased D3, maintaining T3 concentrations. No effect of ID was observed on hepatic D1. D2 increased in brain and brown adipose tissue at day 21 in MID+P. No changes were found in maternal placental D2 and D3, but D2 and D3 increased in the fetal placenta at day 18 in MID+P.

A higher level of D2 is present in fetal skin than in the brain. As the activity is increased, in even mild ID (and already at 18 days) it can be concluded that skin D2 is likely to be of considerable physiological importance, at least for fetal thyroid hormone economy, by contributing to the intracellular T3 content of the skin and, possibly, to the plasma T3.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
T4 IS BIOACTIVATED into T3 by enzymatic deiodination. T3 homeostasis in tissues is maintained by the iodothyronine deiodinase isoenzymes, types I, II, and III (D1, D2, and D3). Their activity is dependent on the thyroid (hormone) and nutritional status and is regulated by glucocorticoids and growth factors (1, 2). The presence and activities of these enzymes are tissue specific. D1 is found in the liver, kidney, pituitary, and thyroid; D2 is found in the central nervous system, pituitary, brown adipose tissue (BAT), placenta, (human) thyroid, and muscle; D3 is present in the brain, skin, placenta, and several fetal tissues (1, 2, 3, 4, 5). The ontogenic appearance of D1 in the rat fetal liver and lung, of D2 in the fetal brain and BAT (6, 7, 8), and of D3 in the cerebral cortex (9) and in fetal tissues (2) are well described. Changes in tissue deiodinase activity are of great importance in those organs, which are dependent on locally produced T3 (1, 2, 3, 4, 5, 6, 7, 8).

During pregnancy, thyroid hormones of maternal origin are found in fetal rat tissues before onset of fetal thyroid function (10, 11, 12, 13), as well as in humans (14, 15), and are, at present, believed to play a role in early development (16, 17, 18) and to have a protective role when fetal thyroid function is impaired (19), although this role is sometimes contested (20). Until onset of its own thyroid function, the fetus is mainly dependent on the maternal supply of T4 (10, 11, 12, 13). During pregnancy, T4 and T3 levels in maternal plasma and tissues in the rat are decreased (21).

One of the situations in which thyroid function is impaired is iodine deficiency (ID). ID is characterized by a decrease in plasma and tissue T4 concentrations, normal or even higher than normal plasma T3, and an increased plasma TSH. The thyroid is enlarged (6, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32). There is a preferential synthesis and secretion of T3 by the thyroid (23, 24), which is also stimulated by the TSH-dependent increase in thyroid D1 activity (29, 33). This results in higher T3/T4 ratios in plasma and tissues. In this situation, less T4 from the maternal circulation is available for the fetus (6, 12, 13, 18, 27). Fetal plasma and tissue T4 and T3 levels are lowered and D2 activity is increased in fetal brain and BAT, whereas D1 activity in liver decreased (6). Most of these studies were performed with severely iodine-deficient rats, whose fetuses had lowered plasma T3 levels.

Even in adult rats that were only marginally ID, with slightly lowered plasma T4 levels, D2 activity increased in the brain (34).

Our aim was to obtain more information about changes in iodothyronine deiodinase activities in fetal rat tissues (brain, BAT, liver, placenta, and skin) at degrees of ID that are more comparable with the mild and moderate ID that affects inhabitants in large parts of the world. We considered it of interest to assess the capacity of the different iodothyronine deiodinases of the developing fetus, to respond to these situations, and their contribution to the maintenance of T3 levels.

Because it is known that there are developmental changes of D1, D2, and/or D3 activities during the last stage of gestation, two time-points were chosen, i.e. day 18 of gestation (just as the fetal thyroid starts to function) and day 21 (1 day before birth) (6, 7, 8, 9).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
The experiments were approved by the local committee on animal care. Three groups of rats (CPB/WU, Iffa Credo, Brussels, Belgium) were used (BW, 210 ± 5 g). The rats were housed at 22 C, with alternating 14-h light, 10-h dark periods. They were fed the American Institute of Nutrition (AIN) diet (35), without iodine (mild iodine diet, MID). In one group, potassium perchlorate (0.005%) was added to this diet (MID+P); and in the third group, potassium iodide (1.5 µg/day) was added to the diet (MID+I). This last group served as controls. After 3 months, rats were mated, and the day that sperm was present was taken as day zero of pregnancy. During 5 days, the rats were housed in metabolic cages. This allowed us to collect 24-h urine and to measure the iodine excretion according to Sandell and Kolthoff (36). At 18 and 21 days of pregnancy, three rats were bled and perfused under light ether anesthesia. Fetal tissues were taken and were kept frozen at -70 C until used. The skin was taken, excluding that of the head, legs, and tail. The fetal and maternal (basal) sides of the placenta were isolated by separation of the two distinct layers from each other, with blunt forceps, on ice (37).

Chemicals
T4, T3, dithiothreitol (DTT), and propylthiouracil (PTU) were from Sigma Chemical Co. (St. Louis, MO). 125I and 131I were from New England Nuclear-Dupont (Dreieich, Germany), inner-ring labeled T3 was purchased from Formula (Berlin, Germany). Anion exchange resins Dowex AG 1X2 and 50WX2 were obtained from Bio-Rad (Richmond, CA).

Determinations of plasma TSH, T3, and T4 in plasma and skin
In plasma, the concentrations of T4 and T3 were assayed by rat-specific RIA (38). Plasma TSH was measured by the specific RIA developed for the rat by the NIDDK (NIH, Bethesda, MD). Reference preparation-2 was used as a standard.

In skin, thyroid hormones were determined as previously described in detail for rat tissues (39). The fetal skin was frozen in liquid nitrogen and crushed to a fine powder while frozen. The powder was taken up quantitatively and homogenized in methanol, after which the procedure of extraction and purification used for other tissues was followed.

Determination of 5'-D1, D2, and D3 activities
For determination of D1, D2, and D3 activity the release of [125Iodide] from [125I]-labeled substrates was measured using homogenates.

Before use, the labeled substrates were purified by paper electrophoresis, to separate them from the contaminating iodide. The contribution of the mass of radioactive substrates added was taken into account for calculation of the total substrate concentrations. After the reaction, the [125I] iodide released was separated, by ion exchange chromatography, on Dowex 50W-X2 columns, as previously described (6, 7, 8, 40). The protein content was measured by the method of Lowry et al. (41).

The conditions were as set forth below.

For D1. [125I]rT3 (60.000 cpm/tube) was used in the presence of 200 nM rT3 and 2 mM DTT, after 15 min incubation at 37 C, using 20–50 µg protein/100 µl.

For D2. [125I]T4 (60,000 cpm/tube) was used in the presence of 2 nM T4, 1 µM T3, 20 mM DTT, and 1 mM PTU, after 1 h incubation at 37 C; 150–200 µg protein/100 µl was used (42). For skin, we checked with paper chromatography and found that equal molar amounts of iodide and T3 were released. Endogenous T4 from the skin contributed less than 2% to the total substrate concentration.

For D3. [125I, 3]T3 (60,000 cpm/tube) was used in the presence of 20 nM T3, 20 mM DTT, and 1 mM PTU, after 1 h incubation at 37 C; 30–50 µg protein/100 µl was used.

Statistics
Mean values ± SE are given. Statistical analysis was performed by ANOVA (43), and differences between mean values were considered statistically significant at P <= 0.05.

The program SPSS 6.1 (Real Stats, Real Easy, Chicago, IL) was used for comparison of the slopes of the linear regression.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The experimental model chosen provided three levels of iodine intake: normal iodine intake (MID+I), moderate (MID), and low iodine intake (MID+P). The daily urinary iodine excretion was: 1.62 ± 0.08 µg (MID+I); 0.42 ± 0.04 µg (MID); and 0.60 ± 0.05 µg (MID+P). The excretion of iodine in MID+P is higher than that in MID because the uptake of iodide, not only from the diet but also from thyroid hormone metabolism, is completely blocked by perchlorate, whereas in MID, part of this iodide can be reused for thyroid hormone synthesis. The maternal BW (at day 18: 296 ± 8 g; at day 21: 321 ± 6 g) and the number and weight of fetuses were not influenced by MID and MID+P (data not shown). The maternal thyroids were enlarged in MID+P (58.0 ± 5.5 mg), compared with those of controls (21.0 ± 4.2 mg) and MID (27.2 ± 2.4 mg).

Table 1Go shows the T4, T3, and TSH values in maternal and fetal plasma. In MID, maternal plasma T4 was decreased to 60% of MID+I and decreased below detection limit (<1.5 nM) in the MID+P group at 21 days of gestation. Plasma TSH increased 10x in MID+P. The plasma T3 concentrations did not change. Similar changes were observed at days 18 and 21 of gestation.


View this table:
[in this window]
[in a new window]
  		Table 1. Concentrations of T4, T3, and TSH in maternal and fetal plasma

 
In the fetal plasma, we found changes comparable with those described for the mothers: a decrease in T4 concentration in MID, with T4 being below detection limit in MID+P, together with an unchanged plasma T3; an increase in plasma TSH was only observed in MID+P.

Deiodinase activities
Liver. The developmental pattern, an increase in activity from day 18 to day 21, was present in all three groups. Hepatic D1 activity was not affected by MID and MID+P either on day 18 or on day 21 (Fig. 1Go).



View larger version (35K):
[in this window]
[in a new window]
  		Figure 1. Hepatic D1 activities in fetuses at day 18 and day 21 in MID+I, MID, and MID+P. Values are the means ± SE. n = 8 fetal livers. For this and the following figures: *, statistically significant difference at a given age, with respect to MID+I; &, statistically significant difference between MID and MID+P; #, statistically significant difference for a given group between 18 and 21 days.

 
BAT. No D2 activity could be measured at day 18, whereas it was clearly detected on day 21. The mean value of D2 activity was slightly higher at day 21 in MID, compared with MID+I, but the difference was not statistically significant. A marked increase in D2 activity was present in MID+P at day 21 (Fig. 2Go).



View larger version (29K):
[in this window]
[in a new window]
  		Figure 2. D2 activity in fetal BAT at day 21. ND, BAT of 18 days was not present. Values are the means ± SE. *, At least P < 0.05 (n = 8 fetal BAT); *, statistically significant difference, at a given age, with respect to MID+I; &, statistically significant difference between MID and MID+P.

 
Brain. An increase in D2 activity was seen during development, from day 18 to day 21. At day 18, no statistically significant increases in D2 activity were found in MID and MID+P. At day 21, D2 activity clearly was increased in MID+P (but not in MID) fetuses.

In brain, the D3 activity at day 18 decreased in MID, and further in MID+P fetuses, to 30% of MID+I values. On the contrary, at day 21, the D3 activity increased 2-fold, both in MID and MID+P (Fig. 3Go).



View larger version (31K):
[in this window]
[in a new window]
  		Figure 3. D2 activity (left panel) and D3 activity (right panel) in brain from 18- and 21-day-old fetuses. Values are the means ± SE. n = 8 fetal brains. *, #, and &, as explained in Fig. 1Go legend.

 
Fetal side of the placenta. D3 activity was lower at day 21 than at day 18 in all three groups (Fig. 4Go).



View larger version (33K):
[in this window]
[in a new window]
  		Figure 4. D2 activity (left panel) and D3 activity (right panel) in the fetal side of the placentas from 18- and 21-day-old fetuses. Values are the means ± SE. n = 8 fetal placentas. *, #, and &, as explained in Fig. 1Go legend.

 
D2 activity increased marginally (but significantly) in MID+P at day 18. This increase in D2 activity was not found at day 21. The same increase in D3 activity was observed in MID+P at day 18.

Maternal placenta. There were no changes in D2 and D3 activities in the maternal basal side of the placenta caused by either gestational age or by MID and MID+P (Fig. 5Go).



View larger version (33K):
[in this window]
[in a new window]
  		Figure 5. D2 activity (left panel) and D3 activity (right panel) in the maternal side of placentas from 18- and 21-day-old fetuses. Values are the means ± SE. n = 8 maternal placentas.

 
D2 activity in the maternal side of the placenta was found to be about 10 times higher than in the fetal side of the placenta, whereas D3 activities were comparable.

At day 18, D3 activities in the fetal and maternal placenta were similar, but they differed at day 21, when the activity in the maternal placenta was much higher than in the fetal side.

Skin. D1 activity was not present in measurable amounts in fetal skin. The changes in D2 and D3 activity in fetal skin are presented in Fig. 6Go. The developmental increase in D2 activity, from day 18 to day 21, was present in all three groups. Not only is D2 activity present in the fetal skin, but it increased in MID fetuses and further increased 3- to 4-fold in MID+P, both at day 18 and at day 21.



View larger version (31K):
[in this window]
[in a new window]
  		Figure 6. D2 activity (left panel) and D3 activity (right panel) in fetal skin from 18- and 21-day-old fetuses. Values are the means ± SE. n = 8 fetal skins. *, #, and &, as explained in Fig. 1Go legend.

 
The pattern was different for D3 activity in fetal skin. At day 18, the D3 activity increased almost 2-fold in MID and in MID+P fetuses, whereas at day 21, a sharp decrease in D3 activity was found: in MID fetuses, the activity was 50% of the MID+I value; and in MID+P fetuses, it was 30% of the MID+I value.

An inverse logarithmic relationship was found between the D2 activity and the T4 concentration in skin, both at day 18 and at day 21 (Fig. 7Go). A different sensitivity of D2 activity to changes in the concentration of T4 is observed at both gestational days. This suggests that the activity of the enzyme is suppressed by smaller amounts of T4 at day 18. T4 concentration in the fetal skin increased from day 18 to day 21, and it decreased in the MID fetuses and was more pronounced in the MID+P group (Fig. 8Go). The T3 concentration responded in an opposite manner to MID and MID+P, with a decrease at day 18 and an increase at day 21.



View larger version (30K):
[in this window]
[in a new window]
  		Figure 7. An inverse relationship was present between D2 activity and the T4 concentration in the skin. As T4 content decreased, D2 activity increased, both at day 18 (open symbols) and day 21 (filled symbols). Each correlation is obtained using the mean values obtained from fetal samples from each dam of the three experimental groups (the total number is 24 for each correlation) and the SE for the mean of the fetal values from each dam. MID+I, diamonds; MID, circles; MID+P, squares. The slope of the linear regression at day 18 is significantly different from that at day 21 (P < 0.0001, t = 9.7, df = 8). Values for the slopes are -0.419 ± 0.026 at day 18; -0.086 ± 0.018 at day 21.

 


View larger version (31K):
[in this window]
[in a new window]
  		Figure 8. In the left panel, fetal skin T3 concentrations are shown at day 18 and at day 21 in MID+I, MID, and MID+P. In the right panel, skin T4 concentrations are presented at day 18 and at day 21 in MID+I, MID, and MID+P. For both panels, values are the means ± SE. *, at least P < 0.05; n = 6–8 fetal skins. *, #, and &, as explained in Fig. 1Go legend.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The plasma T4, T3, and TSH levels of the MID+I rats are comparable with the plasma levels of rats on a commercial pellet diet and with those of rats in kinetic experiments receiving potassium iodide (10 mg/liter) in their drinking water to prevent reuse of labeled iodide by the thyroid (44).

The degree of ID in this study was not as marked as that reported in previous studies (6, 12, 13, 24, 25, 26, 27). Using the AIN diet, without adding extra iodine, we induced a marginal ID. As was seen from the urinary iodine excretion in MID, the rats received some iodine, probably from the casein in the AIN diet (23). This degree of ID can be compared with that occurring in large parts of the world, where endemic goitre exists because of the low intake of iodine, often aggravated by the interference of other nutritional or environmental factors with the iodine-uptake, organification, and thyroid hormone secretion (45).

The diet, together with 0.005% perchlorate (200 times less than the amount that is goitrogenic), resulted in the moderately severe ID, with undetectable plasma T4, high TSH, but still normal T3 levels in rat mothers and their fetuses. This degree of ID was less than reported in previous studies (6, 12, 13, 24, 25, 26, 27) using a Remington-type diet, and in which fetal plasma T3 decreased.

The normal T3 levels in ID in adult rats has long been known (12, 22, 23, 24, 25, 26, 29, 30, 31, 32). How can the normal T3 levels in the mild and moderately severe ID fetus be explained, considering that the maternal supply of T4 is so much lower than in the normal situation, and that maternal-to-fetal transfer of T3 is not sufficient to ensure normal fetal plasma T3 (19)? One explanation can be the increase in fetal thyroidal T3 secretion. In the adult rat, TSH-stimulated D1 activity in the thyroid (33); D1 activity was increased in the thyroid during ID (29). But it is not known whether this is the case in the fetal thyroid. The finding that the fetal thyroid is not stimulated to increase iodine uptake gives the impression that the fetal thyroid is not yet fully responsive to TSH (46). Another possibility is that extrathyroidal responses of the iodothyronine deiodinases contribute to this phenomenon.

Until now, D2 activity had been found in the central nervous system, pituitary gland, BAT, pineal gland, placenta, and muscle. Although Kaplan et al. (42) showed the presence of D2 in human cultured epidermal keratinocytes from the neonate and adult, no activity was found in homogenates of fresh fetal or cadaveric epidermis. But because the skin is a large part of the body mass in the fetus (15%), it thus seemed an interesting target for our study.

This is the first time that the presence of D2 activity in the fetal rat skin is reported. It seems to be higher than D2 activities in fetal brain, and moreover, it responds to degrees of ID that do not affect brain or BAT D2, and it does so already at day 18. Because D2 is of crucial importance for both local production of T3 in particular tissues and systemic thyroid hormone homeostasis, and because BAT D2 is considered responsible for a large proportion of the circulating T3 under hypothyroid conditions (47), the role of the skin in producing T3 has to be taken into account. Because of the total mass of the skin, the D2 activity might contribute, in an important way, not only to the skin T3 content but eventually also to the plasma T3, especially in situations in which the maternal supply of T4 is lowered. As can be calculated, the amount of T3 in skin is 11.6% of the total amount of T3 in the extrathyroidal fetal pool, as measured by RIA (unpublished data), much more than brain (5.8%), or even BAT (1.8%).

In addition to the availability of T4 in fetal tissues during gestation and the level of ID, D3 activity also plays an important role in fetal skin in regulating T3 levels by inactivating the biological active thyroid hormone. There is no significant difference between the T3 concentration in skin between day 18 and day 21 in MID+I, whereas there is a clear and significant increase in MID and MID+P from day 18 to day 21. Based only on D2 and D3 activity, we cannot find a cause for this discrepancy.

At day 18, D3 increases in ID, which explains the lowering of the T3 levels in the skin. But at day 21, a sharp decrease in D3 activity is found in MID and MID+P, resulting in higher than normal levels of T3 in this tissue; and so, the skin might contribute to systemic T3. Skin T4 levels decreased in accordance with the decrease in T4 in other tissues (plasma, brain, and liver) during ID (6, 12, 13, 25). The inverse relationship between T4 and D2 was found at both 18 and 21 days. This had been previously shown on day 21 in BAT (8) and brain (7) in hypo and hyperthyroidism. Interesting is the fact that in skin, the changes in D2 and D3 activity are already pronounced in MID on day 18, whereas such an effect was not found in brain, suggesting an earlier maturation of the skin.

D1 activity in liver did not change, indicating a diminished T3 production caused by the lowered availability in substrate (T4), as was described in the adult and fetal rat (6, 29). D2 activity in brain and BAT increased in MID+P, in agreement with previous findings, at day 21, under conditions of severe ID (6, 12, 13, 18, 27). Present data show that MID is not enough to elicit a D2 response in the fetal brain and BAT, even at day 21. But even MID is enough to affect D3 activity at both day 18 and day 21. The decrease in cerebral D3 activity at day 18 is as expected in situations where lower T3 levels occur. But at day 21, there is an unexpected increase in D3 activity in MID and MID+P, counteracting the increase of D2, at least in MID+P. No information is available about the response of D3 in MID and severe ID. An essential aspect can be that, at a certain time-point, one tissue will be more mature than the other. This may cause differences in behavior and regulation of activity levels of D3 in tissues such as skin and brain. Moreover, changes in growth factors might influence the developmental patterns in tissues (48). The induction of D3 activity by growth factors is stronger than that caused by thyroid status. So, a minor change in growth factor (increase in D3) at a given age can have a more important impact on D3 activity than thyroid status (decrease in D3) (49).

D2 activity increased in the the fetal side of the placenta at day 18. A developmental pattern of D2 was not observed in the placenta, in contrast to D3. The developmental decrease in D3 activity was found in the fetal side of the placenta, in accordance with McCann et al. (2). In our study, there is no clear role for D2 and D3 in the placenta, for the regulation of plasma T3 levels. The absence of an effect in maternal placenta might indicate that D2 and D3 activities in this tissue are regulated by plasma T3. This was also shown in human placenta during hypothyroidism (50).

Summary and conclusions
Mild and moderate ID caused a decrease in T4 concentrations, although the developmental increase from day 18 to day 21 was still observed. In spite of the lowered amount of substrate, the marked increased D2 and decreased D3 activities at day 21 resulted in higher than normal intracellular T3 concentrations. T3 can remain entirely in the skin itself, but there might be a net outflux of T3 into the circulation.

The presence of D2 in a tissue is considered an indication that this tissue needs local production of T3 (as is the case of brain and BAT). These results show that high D2 activity is present in fetal skin, even higher than in fetal brain. Because the activity is increased (as early as day 18) during both mild and moderately severe ID, it can be concluded that skin D2 is likely to be of considerable physiological importance, at least for fetal thyroid hormone economy, by contributing to the intracellular T3 content of the skin, for its own development and possibly by contributing to the plasma T3. The latter would be a benefit for those tissues dependent on plasma T3, but not for the brain, because this organ is mainly dependent on T4 and its own D2 for its intracellular T3 concentration.


   Acknowledgments
 
We thank Mrs. S. Duran and Mrs. M. J. Presas for measuring skin T3 and T4 content and Miss Z. A. A. Huijsmans and Miss H. M. C. van Nuenen for their work during their graduation period.


   Footnotes
 
1 This work was supported by Training and Mobility of Researchers Grant ERBFMBICT 960663 and Research Grant PB 95–0097 from Promoción General del Conocimiento. Part of the study was presented, in preliminary form, at the 24th Annual Meeting of The European Thyroid Association, Munich, August 31-September 3, 1997. Back

2 Recipient of Training and Mobility of Researchers Grant (Marie Curie) from the European Community. Back

Received October 13, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Leonard JL, Visser TJ 1986 Biochemistry and deiodination. In: Hennemann G (ed) Thyroid Hormone Metabolism. Marcel Dekker Inc., New York, pp 189–229
  2. McCann UD, Shaw EA, Kaplan MM 1984 Iodothyronine deiodination reaction types in several rat tissues: effects of age, thyroid status, and glucocorticoid treatment. Endocrinology 114:1513–1521[Abstract]
  3. Davey JC, Becker KB, Schneider MJ, St. Germain DL, Galton VA 1995 Cloning of a cDNA for the type II iodothyronine deiodinase. J Biol Chem 270:26786–26789[Abstract/Free Full Text]
  4. Croteau W, Whittemore SL, Schneider MJ, St. Germain DL 1995 Cloning and expression of a cDNA for a mammalian type III iodothyronine deiodinase. J Biol Chem 270:16569–16575[Abstract/Free Full Text]
  5. Salvatore D, Low SC, Berry MJ, Maia AL, Harney JW, Croteau W, St. Germain DL, Larsen PR 1995 Type 3 iodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme. J Clin Invest 96:2421–2430
  6. Obregón MJ, Ruiz de Oña C, Calvo R, Escobar del Rey F, Morreale de Escobar G 1991 Outer ring iodothyronine deiodinases and thyroid hormone economy: responses to iodine deficiency in the rat fetus and neonate. Endocrinology 129:2663–2673[Abstract]
  7. Ruiz de Oña C, Obregón MJ, Escobar del Rey F, Morreale de Escobar G 1988 Developmental changes in rat brain 5'-deiodinase and thyroid hormones during the fetal period: the effects of fetal hypothyroidism and maternal thyroid hormones. Pediatr Res 24:588–594[Medline]
  8. Obregón MJ, Ruiz de Oña C, Hernández A, Calvo R, Escobar del Rey F, Morreale de Escobar G 1989 Thyroid hormones and 5'-deiodinase in rat brown adipose tissue during fetal life. Am J Physiol 257:E625–E631
  9. Huang TS, Beredo A, Solomon DH, Chopra IJ 1986 The inner ring (5-) monodeiodination of thyroxine (T4) in cerebral cortex during fetal, neonatal and adult life. Metabolism 35:272–277[CrossRef][Medline]
  10. Obregón MJ, Mallol J, Pastor R, Morreale de Escobar G, Escobar del Rey F 1984 L-Thyroxine and 3,5,3'-L-Thyronine in rat embryos before onset of fetal thyroid function. Endocrinology 114:305–307[Abstract]
  11. Morreale de Escobar G, Pastor R, Obregón MJ, Escobar del Rey F 1985 Effects of maternal hypothyroidism on the weight and thyroid hormone content of rat embryonic tissues, before and after onset of fetal thyroid function. Endocrinology 117:1890–1900[Abstract]
  12. Escobar del Rey F, Pastor R, Mallol J, Morreale de Escobar G 1986 Effects of maternal iodine deficiency on the L-thyroxine and 3,5,3'-triiodo-L-thyronine contents of rat embryonic tissues before and after onset of fetal thyroid function. Endocrinology 118:1259–1265[Abstract]
  13. Morreale de Escobar G, Obregón MJ, Calvo R, Escobar del Rey F 1993 Effects of iodine deficiency on thyroid hormone metabolism and the brain in fetal rats: the role of the maternal transfer of thyroxine. Am J Clin Nutr [Suppl] 57:280S–285S
  14. Bernal J, Pekonen F 1984 Ontogenesis of the nuclear 3,5,3'-triiodothyronine receptor in the human fetal brain. Endocrinology 114:677–679[Abstract]
  15. Ferreiro B, Bernal J, Goodyer CG, Branchard CL 1988 Estimation of nuclear thyroid hormone receptor saturation in human fetal brain and lung during early gestation. J Clin Endocrinol Metab 67:853–856[Abstract]
  16. Boyages SC 1993 The damaged brain of iodine deficiency: evidence for a continuum of effect on the population at risk. In: Stanbury JB (ed) The Damaged Brain of Iodine Deficiency. Cognizant Communication Corporation, Elmsford, New York, pp 251–258
  17. Porterfield SP, Hendrich CE 1993 The role of thyroid hormones in prenatal and neonatal neurological development: current perspectives. Endocr Rev 14:94–106[CrossRef][Medline]
  18. Martínez-Galan JR, Pedraza P, Santacana M, Escobar del Rey F, Morreale de Escobar G, Ruiz Marcos A 1997 Early effects of iodine deficiency on radial glial cells of the hypocampus of the rat fetus. A model of neurological cretinism. J Clin Invest 99:2701–2709[Medline]
  19. Calvo R, Obregón MJ, Ruiz de Oña C, Escobar del Rey F, Morreale de Escobar G 1990 Congenital hypothyroidism, as studied in rats: crucial role of maternal thyroxine, but not 3,5,3'-triiodothyronine in the protection of the fetal brain. J Clin Invest 86:889–899
  20. Schwartz H, Ross ME, Oppenheimer JH 1997 Lack of effect of thyroid hormone on late fetal rat brain development. Endocrinology 138:3119–3124[Abstract/Free Full Text]
  21. Calvo R, Obregón MJ, Ruiz de Oña C, Ferreiro B, Escobar del Rey F, Morreale de Escobar G 1990 Thyroid hormone economy in pregnant rats near term: a "physiological" animal model of non-thyroidal illness? Endocrinology 127:10–16[Abstract]
  22. Abrams GM, Larsen PR 1973 Triiodothyronine and thyroxine in the serum and thyroid glands of iodine deficient rats. J Clin Invest 52:2522–2531
  23. Riesco G, Taurog A, Larsen PR 1977 Variations in the response of the thyroid gland of the rat to different low-iodine diets: correlations with iodine content of the diet. Endocrinology 99:270–280[Abstract]
  24. Santisteban P, Obregón MJ, Rodriguez-Peña A, Lamas L, Escobar del Rey F, Morreale de Escobar G 1982 Are iodine deficient rats euthyroid? Endocrinology 110:1780–1789[Abstract]
  25. Obregón MJ, Santisteban P, Rodríguez-Peña A, Pascual A, Cartagena P, Ruiz-Marcos A, Lamas L, Escobar del Rey F, Morreale de Escobar G 1984 Cerebral hypothyroidism in rats with adult-onset of iodine deficiency. Endocrinology 115:614–624[Abstract]
  26. Escobar del Rey F, Ruiz de Oña C, Bernal J, Obregón MJ, Morreale de Escobar G 1989 Generalized deficiency of 3,5,3'-triiodo-L-Thyronine (T3) in tissues from rats on a low iodine intake, despite normal circulating T3 levels. Acta Endocrinol (Copenh) 120:490–498[Medline]
  27. Morreale de Escobar G, Calvo R, Obregón MJ, Escobar del Rey F 1992 Homeostasis of brain T3 in rat fetuses and their mothers: effects of thyroid status and iodine deficiency. Acta Med Austriaca Suppl 19:110–116
  28. Meinhold H, Campos-Barros A, Walzog B, Köhler R, Müller F, Behne D 1993 Effects of selenium and iodine deficiency on type I, type II and type III iodothyronine deiodinases and circulating thyroid hormones in the rat. Exp Clin Endocrinol 101:87–93[Medline]
  29. Pazos-Moura CC, Moura EG, Dorris ML, Rehnmark S, Melendez L, Silva JE, Taurog A 1991 Effect of iodine deficiency and cold exposure on thyroxine 5'-deiodinase activity in various rat tissues. Am J Physiol 260:E175–E182
  30. Heninger RW, Albright EC 1966 Effect of iodine deficiency on iodine-containing compounds of rat tissues. Endocrinology 79:309–315[Medline]
  31. Silva E 1972 Disposal rates of thyroxine and triiodothyronine in iodine-deficient rats. Endocrinology 91:1430–1435[Medline]
  32. Fukuda H, Yasuda N, Greer MA, Kutas M, Greer SE 1975 Changes in plasma thyroxine, triiodothyronine and TSH during adaptation to iodine deficiency in the rat. Endocrinology 97:307–314[Abstract]
  33. Erikson VJ, Cavalieri RR, Rosenberg LL 1982 Thyroxine 5'-deiodinase of rat thyroid, but not of increased activity in liver, is dependent on thyrotropin. Endocrinology 111:434–440[Medline]
  34. Janssen PLTMK, Van der Heide, Visser TJ, Kaptein E, Beynen A 1994 Thyroid function and deiodinase activity with marginal iodine deficiency. Biol Trace Elem Res 40:237–246[Medline]
  35. Ad Hoc Committee on Standards for Nutritional Studies 1977 Report of the American Institute of Nutrition. J Nutr 7:1340–1348
  36. Sandell E, Kolthoff LM 1937 Microdetermination of iodine by a catalytic method. Mikrochim Acta 1:9–25
  37. Calvo RM, Obregón MJ, Escobar del Rey F, Morreale de Escobar G 1992 The rat placenta and the transfer of thyroid hormones from the mother to the fetus. Effects of maternal thyroid status. Endocrinology 131:357–367[Abstract]
  38. Van der Heide D, Van der Ende-Visser M 1980 T4, T3 and reverse T3 in the plasma of rats during the first 3 months of life. Acta Endocrinol (Copenh) 93:448–454[Medline]
  39. Morreale de Escobar G, Calvo R, Escobar del Rey F, Obregón MJ 1994 Thyroid hormones in tissues from fetal and adult rats. Endocrinology 134:2410–2415[Abstract]
  40. Obregón MJ, Calvo R, Hernández A, Escobar del Rey F, Morreale de Escobar G 1996 Regulation of uncoupling protein messenger ribonucleic acid and 5'-deiodinase activity by thyroid hormones in fetal brown adipose tissue. Endocrinology 137:4721–4729[Abstract]
  41. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ 1951 Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275[Free Full Text]
  42. Kaplan MM, Pan C, Gordon PR, Lee J, Gilchrest A 1988 Human epidermal keratinocytes in culture convert thyroxine to 3,5,3'-triiodothyronine by type II iodothyronine deiodination: a novel endocrine function of the skin. J Clin Endocrinol Metab 66:815–822[Abstract]
  43. Snedecor GW, Cochran WG 1992 Statistical Methods. Iowa State University Press, ed. 8, Ames, Iowa
  44. Versloot PM, Gerritsen J, Boogerd L, Schröder-van der Elst JP, Van der Heide D 1994 Thyroxine and 3,5,3'-triiodothyronine production, metabolism, and distribution in pregnant rat near term. Am J Physiol 267:E860–E867
  45. Gaitan E 1996 Editorial: flavonoids and the thyroid. Nutrition 12:127–129[CrossRef][Medline]
  46. Versloot PM, Schröder-van der Elst JP, Van der Heide D, Boogerd L 1997 Effects of marginal iodine deficiency during pregnancy: iodide uptake by the maternal and fetal thyroid. Am J Physiol 273:E1121–E1126
  47. Silva JE, Larsen PR 1985 Potential of brown adipose tissue type II thyroxine 5'-deiodinase as a local and systemic source of triiodothyronine in rats. J Clin Invest 76:2296–2305
  48. Fisher DA, Lakshmanan J 1990 Metabolism and effects of epidermal growth factor and related growth factors in mammals. Endocr Rev 11:418–442[Abstract]
  49. Courtin F, Liva P, Gavaret JM, Toru-Delbauffe D, Pierre M 1991 Induction of 5-deiodinase activity in astroglial cells by 12-O-tetradecanoylphorbol 13-acetate and fibroblast growth factors. J Neurochem 56:1107–1113[CrossRef][Medline]
  50. Koopdonk-Kool JM, de Vijlder JJ, Veenboer GJ, Ris-Stalpers C, Kok JH, Vulsma T, Boer K, Visser TJ 1996 Type II and type III deiodinase activity in human placenta as a function of gestational age. J Clin Endocrinol Metab 81:2154–2158[Abstract]



This article has been cited by other articles:


Home page
 Endocr. Rev.Home page
J. Kohrle, F. Jakob, B. Contempre, and J. E. Dumont
Selenium, the Thyroid, and the Endocrine System
Endocr. Rev., December 1, 2005; 26(7): 944 - 984.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
D. P. Carvalho
Modulation of Uterine Iodothyronine Deiodinases--A Critical Event for Fetal Development?
Endocrinology, October 1, 2003; 144(10): 4250 - 4252.
[Full Text] [PDF]

Home page
 Endocr. Rev.Home page
A. C. Bianco, D. Salvatore, B. Gereben, M. J. Berry, and P. R. Larsen
Biochemistry, Cellular and Molecular Biology, and Physiological Roles of the Iodothyronine Selenodeiodinases
Endocr. Rev., February 1, 2002; 23(1): 38 - 89.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. P. Schroder-van der Elst, D. van der Heide, J. Kastelijn, B. Rousset, and M. Jesus Obregon
The Expression of the Sodium/Iodide Symporter Is Up-Regulated in the Thyroid of Fetuses of Iodine-Deficient Rats
Endocrinology, September 1, 2001; 142(9): 3736 - 3741.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
R. Peeters, C. Fekete, C. Goncalves, G. Legradi, H. M. Tu, J. W. Harney, A. C. Bianco, R. M. Lechan, and P. R. Larsen
Regional physiological adaptation of the central nervous system deiodinases to iodine deficiency
Am J Physiol Endocrinol Metab, July 1, 2001; 281(1): E54 - E61.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. M. Bates, Vickie. L. Spate, J. S. Morris, D. L. St. Germain, and V. A. Galton
Effects of Selenium Deficiency on Tissue Selenium Content, Deiodinase Activity, and Thyroid Hormone Economy in the Rat during Development
Endocrinology, July 1, 2000; 141(7): 2490 - 2500.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schröder-van der Elst, J. P.
Right arrow Articles by Obregón, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schröder-van der Elst, J. P.
Right arrow Articles by Obregón, M. J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals