Escape from the Acute Wolff-Chaikoff Effect Is [630560]

Escape from the Acute Wolff-Chaikoff Effect Is
Associated with a Decrease in Thyroid Sodium/IodideSymporter Messenger Ribonucleic Acid and Protein*
PETER H. K. ENG, GUEMALLI R. CARDONA, SHIH-LIEH FANG,
MICHAEL PREVITI, SHARON ALEX, NANCY CARRASCO, WILLIAM W. CHIN, AND
LEWIS E. BRAVERMAN
Division of Genetics (P.H.K.E., G.R.C., S.-L.F., M.P., S.A., W.W.C., L.E.B.), Department of Medicine,
Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115; andDepartment of Molecular Pharmacology (N.C.), Albert Einstein College of Medicine,Bronx, New York 10461
ABSTRACT
In 1948, Wolff and Chaikoff reported that organic binding of iodide
in the thyroid was decreased when plasma iodide levels were elevated(acute Wolff-Chaikoff effect), and that adaptation or escape from theacute effect occurred in approximately 2 days, in the presence ofcontinued high plasma iodide concentrations. We later demonstratedthat the escape is attributable to a decrease in iodide transport intothe thyroid, lowering the intrathyroidal iodine content below a criticalinhibitory threshold and allowing organification of iodide to resume.We have now measured the rat thyroid sodium/iodide symporter(NIS) messenger RNA (mRNA) and protein levels, in response to bothchronic and acute iodide excess, in an attempt to determine the mech-anism responsible for the decreased iodide transport. Rats were given0.05% NaI in their drinking water for 1 and 6 days in the chronicexperiments, and a single 2000-
mg dose of NaI ip in the acute exper-
iments. Serum was collected for iodine and hormone measurements,and thyroids were frozen for subsequent measurement of NIS, TSHreceptor, thyroid peroxidase (TPO), thyroglobulin, and cyclophilinmRNAs (by Northern blotting) as well as NIS protein (by Westernblotting). Serum T
4and T3concentrations were significantly de-
creased at 1 day in the chronic experiments and returned to normalat 6 days, and were unchanged in the acute experiments. Serum TSHlevels were unchanged in both paradigms. Both NIS mRNA andprotein were decreased at 1 and 6 days after chronic iodide ingestion.NIS mRNA was decreased at 6 and 24 h after acute iodide adminis-tration, whereas NIS protein was decreased only at 24 h. TPO mRNAwas decreased at 6 days of chronic iodide ingestion and 24 h afteracute iodide administration. There were no iodide-induced changes inTSH receptor and thyroglobulin mRNAs. These data suggest thatiodide administration decreases both NIS mRNA and protein expres-sion, by a mechanism that is likely to be, at least in part, transcrip-tional. Our findings support the hypothesis that the escape from theacute Wolff-Chaikoff effect is caused by a decrease in NIS, with aresultant decreased iodide transport into the thyroid. The observeddecrease in TPO mRNA may contribute to the iodine-induced hypo-thyroidism that is common in patients with Hashimoto’s thyroiditis.(Endocrinology 140: 3404–3410, 1999)
AUTOREGULATION IN THE thyroid refers to the
regulation of iodine metabolism within the thyroid
gland, independent of TSH. It was first reported by Mortonet al. (1) in 1944, who observed that large amounts of iodide
inhibited the formation of thyroid hormones by incubatedsheep thyroid slices. Wolff and Chaikoff (2) then reportedthat organic binding of iodide within the rat thyroid wasblocked when the plasma iodide level achieved a criticalthreshold. This inhibition defines the Wolff-Chaikoff ef-fect. They next demonstrated that this inhibitory effect ofexcess iodide was transient, lasting from 26–50 h, and thatthe thyroid escaped or adapted to prolonged iodide excess,resuming near-normal hormone synthesis (3). The mech-anism responsible for the acute Wolff-Chaikoff effect re-mains elusive and has been postulated to be caused byorganic iodocompounds formed within the thyroid (4).
a-Iodohexadecanal, a major iodolipid, has been shown toinhibit nicotinamide adenine dinucleotide phosphate ox-
idase, thyroid peroxidase (TPO), and TSH-induced cAMPformation in the thyroid and thus may be a potentialmediator of the effect. The so-called escape phenomenon,however, has been less well studied. Braverman andIngbar suggested that adaptation to the acute Wolff-Chaikoff effect was caused by a decrease in iodide trans-port into the thyroid, which reduced the intrathyroidaliodide to concentrations that were insufficient to sustainthe decreased organification of iodide (5). Recently, thecomplementary DNA (cDNA) encoding the protein re-sponsible for the active transport of iodide from blood tothyroid was cloned by Dai et al. (6). This polytopic mem-
brane protein, expressed in thyroid follicular cells, istermed the sodium-coupled iodide cotransporter or sodi-um/iodide symporter (NIS). We hypothesized thatchanges in NIS expression might account for iodide au-toregulation in the thyroid. In the present study, we re-examined the mechanism responsible for the escape fromthe acute Wolff-Chaikoff effect by determining NIS mes-senger RNA (mRNA) and protein levels in rat thyroids inresponse to acute and prolonged administration of excessiodide.
Received January 19, 1999.
Address all correspondence and requests for reprints to: Peter Eng,
M.D., Division of Genetics, Department of Medicine Brigham and Wom-en’s Hospital, 75 Francis Street, Thorn 1013, Boston, Massachusetts02115. E-mail: eng@rascal.med.harvard.edu.
* This work was supported, in part, by NIH Grant DK-18919 (to
L.E.B).0013-7227/99/$03.00/0 Vol. 140, No. 8
Endocrinology Printed in U.S.A.
Copyright © 1999 by The Endocrine Society
3404Downloaded from https://academic.oup.com/endo/article-abstract/140/8/3404/2990434 by guest on 24 June 2019

Materials and Methods
Animals
Sprague Dawley male rats (200–250 g; Charles River Laboratories,
Inc., Kingston, NY) were used in all of the experiments and were main-tained on Lab Diet no. 5001, PMI International (Brentwood, MO) andwater ad libitum .
The chronic excess iodide experiment was carried out as follows: The
rats were divided into 3 groups: control and 1 and 6 days of iodideexcess. Rats were given either distilled water (control group) or 0.05%iodide, as NaI, in the drinking water for 1 or 6 days. The addition ofiodide to the drinking water was timed so that all the rats were killedon the same day. The thyroid gland from each rat was removed im-mediately, snap frozen, and stored at 270 C for measurement of specific
RNA and proteins. Blood from each rat was collected, and the serum wasfrozen for later measurement of serum iodide, TSH, T
3, and T4concen-
trations. There was a total of 48 rats, with 16 rats in each group. Threeseparate experiments were carried out using the same protocol. The firstexperiment had 8 rats in each group, and the second and third exper-iments had 4 rats in each group. The results of the 3 experiments werepooled for the purpose of statistical analysis.
The acute excess iodide experiment was carried out as follows: Rats
were divided into 5 groups: control and 1, 2, 6, and 24 h after an acuteiodide load. There were 4 rats in each group. A single ip injection of 2000
mg NaI in 0.5 ml saline was administered to the 1-, 2-, 6-, and 24-h groups
before being killed. Saline alone was injected into the control group. Ratswere killed, and their thyroid glands and blood were obtained as de-scribed above. A similar protocol was repeated with only 3 groups of rats(6 rats in each group): control and 6 and 24 h after iodide administration.The results of the 2 experiments were pooled for statistical analysis.
This study was approved by the Harvard Area Standard Committee
on Animals, and it conforms with federal and state regulations govern-ing the use of laboratory animals.
Serum iodine and hormone measurements
Serum iodine concentrations were assayed according to the modified
Sandell-Koltoff method of Benotti and Benotti (7). Serum thyroid hor-mones, T
3and T4, and TSH concentrations were measured in duplicate
by RIAs, in random order and in the same assay for each experiment.Serum TSH was measured by RIA using materials obtained from theNational Pituitary Agency, NIH (Bethesda, MD). Serum T
3and T4con-
centrations were determined by species-adapted RIAs using a singleantibody technique with polyethylene glycol precipitation (8).
Thyroid RNA analysis
Total thyroid RNA was extracted using a commercial kit (RNeasy;
QIAGEN, Inc., Chatsworth, CA). Northern analysis of the RNA wascarried out as follows. Total RNA (10
mg/lane) was subjected to elec-
trophoresis fo r3hi n1 % agarose containing formaldehyde in 1 34-mor-
pholinopropanesulfonic acid. The RNA was then transferred overnightto a nylon membrane (Nytran; Schleicher & Schuell, Inc., Keene, NH) bydiffusion blotting, and was UV cross-linked. The membrane was hy-bridized sequentially with five rat cDNA probes: NIS, TSH receptor(TSHr), TPO, thyroglobulin (Tg), and cyclophilin. Cyclophilin mRNAwas used for normalization of the levels of thyroid mRNAs. The cDNAprobes were labeled with [
a-32P]deoxycytidine 5 9-triphosphate using a
random primer protocol (Prime-It II Random Primer Labeling Kit; Strat-agene, La Jolla, CA) to a specific activity of 0.2–2 310
9cpm/ mg DNA.
Purified cDNA inserts (TSHr and TPO were provided by L. D. Kohn,National Institute of Diabetes and Digestive and Kidney Diseases, NIH(Bethesda, MD); and Tg by G. Vassart, Institut de Recherche Interdis-ciplinaire, Bruxelles, Belgium) were used as the probes. The membranewas prehybridized 1–2 h at 42 C, followed by an overnight hybridizationat 42 C with the radiolabeled probes. The membrane was washed twicewith 6 3SSPE (NaCl, NaPO
4, EDTA)/0.5% SDS at room temperature,
twice with 1 3SSPE /0.5% SDS at 37 C, and (if high stringency was
required) a further wash with 0.1 3SSPE/0.1% SDS at 60 C. The mem-
brane was exposed to a phosphorimager screen for an appropriatelength of time, and the signal intensity was analyzed by a phospho-rimaging system (Molecular Dynamics, Inc., Sunnyvale, CA).Thyroid protein analysis
Total protein from the thyroid glands was extracted as follows. Fro-
zen thyroid glands were thawed in RIPA buffer (1 3PBS, 1% Nonidet
P-40, 0.5% sodium deoxycholate, 0.1% SDS) and protease inhibitors(aprotinin, sodium orthovanadate, and phenylmethylsulfonylflouride)were added. Homogenization was performed using a mechanical device(Polytron; Kinematica, Luzern, Switzerland). The homogenate was cen-trifuged at 15,000 3g, and the supernatant (which contained the whole
cell lysate) was quantified spectrophotometrically using a modifiedLowry method (Dc Protein Assay; Bio-Rad Laboratories, Inc., Hercules,CA). Western blot analysis was carried out as follows: Twenty-fivemicrograms of protein per lane were loaded on an 8% SDS polyacryl-amide gel and subjected to electophoresis at a constant voltage (150 V).Electroblotting to a nitrocellulose membrane (Protran; Schleicher &Schuell, Inc.) was performed fo r2ha t9 0m A using a semidry elec-
troblotting system (MultiphorII Electrophoresis System; Pharmacia LKBBiotechnology, Uppsala, Switzerland). Blocking was done overnightusing TTBS/milk (TBS, 1% Tween 20 and 5% milk). The membrane wasincubated with a 1:5000 dilution of affinity-purified anti-NIS antibodyin TTBS/milk. Two 5-min and two 15-min washes in TTBS were thenperformed. The membrane was incubated with a 1:25,000 dilution of ahorseradish peroxidase conjugated antirabbit antibody (Pierce ChemicalCo., Rockford, IL) in TTBS/milk. Two 5-min and two 15-min washeswere again performed. The membrane was then incubated with anenhanced chemiluminescent substrate (Supersignal Substrate WesternBlotting, Pierce Chemical Co.) and exposed to film. Quantitation of thesignal intensity was performed by densitometry (Molecular Dynamics,Inc.).
Statistical analysis
Statistical analysis was performed using a statistical analysis program
(Instat v 2.02; GraphPad Software, Inc., San Diego, CA). Comparisonbetween groups was by ANOVA, followed by Tukey-Kramer test forintergroup comparison. Results are expressed as mean 6se.
Results
We first performed experiments to determine the effect of
chronic excess oral iodide administration on thyroid mRNAlevels, especially NIS, over a period of 6 days.
Chronic iodide ingestion
Serum iodine and hormone levels. Serum iodine levels, after 1
and 6 days of iodide administration, were markedly elevated(more than 60-fold), compared with values in the controlgroup (Table 1). There was no statistical difference in theserum iodine levels between the 1-day and 6-day groups.Serum T
3and T4concentrations were significantly decreased
in the rats treated with iodide for 1 day, compared withvalues in the control rats. Serum T
3concentrations, after 6
days of iodide administration, were similar to those in the
TABLE 1. Effect of chronic and acute iodide administration on
serum iodine
Groups nSerum iodine concentrations
(mg/dl) (mean 6SE)
Control 16 10 61.4
1 day of iodide in drinking watera16 1915 6161
6 days of iodide in drinking water 16 1688 6133
Control 10 7.3 60.3
1 h after ip iodide injectionb4 1314 6145
2 h after ip iodide injection 4 594 6108
6 h after ip iodide injection 10 394 629
24 h after ip iodide injection 10 129 617
a0.05% I (NaI) in the drinking water.
b2,000 mg I (NaI) ip.ESCAPE FROM THE ACUTE WOLFF-CHAIKOFF EFFECT 3405Downloaded from https://academic.oup.com/endo/article-abstract/140/8/3404/2990434 by guest on 24 June 2019

control rats; but T4concentrations, after 6 days of iodide
administration, were significantly higher than 1-day andcontrol rats. TSH concentrations were not significantly dif-ferent from control values at 1 or 6 days after iodide admin-istration, although values were slightly higher at 1 day (Fig.1).
mRNA expression. All mRNA results were normalized to thy-
roid cyclophilin mRNA levels. The expression of NIS mRNAwas significantly decreased, to approximately 55% of controlvalues, after 1 day of iodide administration; and it decreased
further, to approximately 40% of control values, at 6 days(Fig. 2). TPO mRNA was decreased significantly 6 days afteriodide administration but not after 1 day (Fig. 3). In contrast,TSHr mRNA and Tg mRNA were unchanged during iodideadministration (data not shown).
Protein expression. The level of NIS protein was determined
by Western blot analysis. It was markedly decreased, 1 and6 days after iodide administration, compared with values inthe control rats (Fig. 4).
The results from the chronic iodine ingestion experiments
revealed an effect of NIS mRNA and protein as early as 24 h.Thus, we performed another set of experiments to determine,
FIG. 1. Rat serum hormone levels during chronic iodide ingestion.
Results are pooled from three separate experiments, with n 516 rats
in each group. Shown are the means 6SEMof each group. A Pvalue
of,0.05 is significant.
FIG. 2. Northern blot analysis of thyroid RNAs: chronic excess iodide.
A, Autoradiograph of a representative Northern blot of thyroid RNAextracted from rats subjected to chronic excess iodide. The blot washybridized with a
32P-labeled NIS probe and exposed to film. Lanes
1 and 2 are controls, lanes 3 and 4 are from rats in the 1-day group,and lanes 5 and 6 are from rats in the 6-day group. B, Rat thyroid NISmRNA levels, during chronic iodide ingestion, as determined byNorthern blotting. Band density was measured using a Phosphorim-ager. Results are pooled from three separate experiments and arenormalized, with respect to individual thyroid cyclophilin mRNAs.They are expressed as relative units, with the control group mean 5
1 [control group (n 510), 1-day group (n 511), and 6-day group (n 5
12)]. Shown are the means 6
SEMof each group. A Pvalue of ,0.05
is significant.3406 ESCAPE FROM THE ACUTE WOLFF-CHAIKOFF EFFECTEndo ²1999
Vol 140 ²No 8Downloaded from https://academic.oup.com/endo/article-abstract/140/8/3404/2990434 by guest on 24 June 2019

more accurately, when the change occurred. We adminis-
tered a single ip injection of NaI and measured the levels ofthyroid mRNAs and NIS protein at several time points, upto 24 h.
Acute iodide administration
Serum iodine and hormone levels. Serum iodine concentrations
were markedly increased 1 h after iodide administration andprogressively decreased at 2, 4, 6, and 24 h, but they were stillgreater than 100
mg/dl at 24 h (Table 1). There were no
significant changes in serum T3,T4, or TSH concentrations at
any time point after iodide administration (data not shown).
mRNA expression. The level of NIS mRNA was unchanged at
1 and 2 h after the acute administration of 2000 mg NaI ip but
was significantly decreased a t 6 h (60% of control) and fur-
ther decreased at 24 h (40% of control) (Fig. 5). TPO mRNAwas unchanged at 1, 2, an d 6 h but was decreased at 24 h (Fig.
6). There were no statistical differences among the levels ofTSHr or Tg mRNA at 1, 2, 6, and 24 h after the acute ad-ministration of iodide (data not shown).
Protein expression. The level of NIS protein, as determined by
Western blot analysis, was unchange d 6 h after iodide ad-
ministration but was markedly decreased to 30% of controlvalues at 24 h (Fig. 7).
Discussion
The acute Wolff-Chaikoff effect and its escape occur dur-
ing the exposure of the normal thyroid to high levels ofplasma iodide. In the present experiments, high concentra-
tions of iodide in the circulation were achieved in normal ratsby the administration of 0.05% NaI in the drinking water for1 and 6 days or by a single ip injection of 2000
mg NaI. After
1 day of iodide ingestion, serum T3and T4concentrations
significantly decreased and returned to normal after 6 daysof continued iodide treatment. The decrease in the serumthyroid hormone concentrations, after 1 day, was possiblythe result of both acute inhibition of iodide organificationand subsequent thyroid hormone synthesis (the acute Wolff-Chaikoff effect) and acute inhibition of hormone release from
FIG. 3. Rat thyroid TPO mRNA levels during chronic iodide inges-
tion, as determined by Northern blotting. Band density was measuredusing a Phosphorimager. Results are pooled from three separate ex-periments and are normalized, with respect to individual thyroidcyclophilin mRNAs. They are expressed as relative units, with thecontrol group mean 51 [control group (n 510), 1-day group (n 57),
and 6-day group (n 57)]. Shown are the means 6
SEMof each group.
APvalue of ,0.05 is significant.
FIG. 4. Western blot analysis of NIS protein in thyroid tissue: chronic
excess iodide. A, Autoradiograph of Western blot of thyroid proteinextracted from rats subjected to chronic excess iodide. The blot washybridized with a primary anti NIS-antibody and a secondary horse-radish peroxidase-conjugated antibody. Protein detection was by en-hanced chemiluminesence. Lanes 1 and 2 are controls, lanes 3 and 4are from rats in the 1-day group, and lanes 5 and 6 are from rats inthe 6-day group. The NIS protein is approximately 90 kDa. B, Ratthyroid NIS protein levels, during chronic iodide ingestion, as deter-mined by Western blotting. Band density was measured using adensitometer. Results are from one experiment and are expressed asdensitometry units [control group (n 54), 1-day group (n 54), and
6-day group (n 54)]. Shown are the means 6
SEMof each group. A P
value of ,0.05 is significant.ESCAPE FROM THE ACUTE WOLFF-CHAIKOFF EFFECT 3407Downloaded from https://academic.oup.com/endo/article-abstract/140/8/3404/2990434 by guest on 24 June 2019

the thyroid (9, 10). Of note, the serum TSH concentrations
increased, but not significantly, in response to the decreasedserum T
4and T3values after 1 day of iodide administration.
It is possible that a greater rise occurred during the night,before the midmorning termination of the chronic iodideexperiment.
It had been postulated in 1963 that the adaptation to or
escape from the acute Wolff-Chaikoff effect was caused by adecrease in the active transport of iodide from the plasmainto the thyroid, thereby decreasing the high concentrationsof intrathyroidal iodide that inhibit hormone synthesis. Wehave now reinvestigated this postulate by determining thelevel of NIS mRNA and protein in the thyroids of iodide-exposed rats. The level of NIS mRNA significantly decreasedafter 1 and 6 days of iodide ingestion. The decrease in NISprotein was even more dramatic, decreasing to approxi-mately 23% of the control values at both time points. Thedecrease in NIS occurred in the absence of a significant in-crease in TSH, which would have increased NIS or reducedthe iodide induced-decrease in NIS, because TSH has beenshown to increase NIS expression (11, 12). The decrease inNIS expression, after 1 day of excess iodide exposure, sug-gested the possibility that the active transport of iodide intothe thyroid, which induces the acute Wolff-Chaikoff effect,might occur rapidly ( ,24 h) after iodide administration. To
evaluate this hypothesis, rats were killed from 1–24 h afterthe acute administration of excess iodide ip. No change inNIS mRNA occurred at 1 o r 2 h after iodide administration,
but a significant decrease was observed at 6 and 24 h. Also,no change in NIS protein was observed at 6 h, when NISmRNA was already decreased; however, a marked decreasein NIS protein was found at 24 h. These findings suggest thatthe decrease in active iodide transport into the thyroid oc-curred between 6 and 24 h after excess iodide exposure. Thus,it is likely that the excess iodide transported into the thyroid,before the decrease in NIS protein, was responsible for theacute inhibition of hormone synthesis previously described(2, 13). Uyttersprot et al. (14) recently reported that the acute
administration of a single small dose of iodide to the iodine-deficient, propylthiouracil-, and perchlorate-treated dog,with elevated serum TSH concentrations, decreased NISmRNA in the thyroid at 48 h. They did not measure NISprotein. Also, they did not determine serum iodine concen-trations. Our observations are also likely more physiological,because the rats were on a normal iodine intake, were notreceiving any antithyroid drugs, and did not have markedlyelevated serum TSH values.
The present results also suggest that the half-life of NIS
protein in the thyroid, in the presence of excess iodine, is lessthan 24 h, which is far shorter than the half-life of 4 days,observed in FRTL5 cells in vitro (15, 16). It is possible that the
degradation of NIS protein is higher in the presence of excessiodide, and further studies of the half-life of NIS protein, inthe presence and absence of excess iodide, are indicated.Because both the NIS mRNA and NIS protein are decreased,it seems likely that NIS regulation by iodine is (at least partly)
FIG. 5. Rat thyroid NIS mRNA levels, during acute iodide adminis-
tration, as determined by Northern blotting. Band density was mea-sured using a Phosphorimager. Results are pooled from two separateexperiments and are normalized, with respect to individual thyroidcyclophilin mRNAs. They are expressed as relative units, with thecontrol group mean 51 [control group (n 510), 6-h group (n 510),
and 24-h group (n 59)]. Shown are the means 6
SEMof each group.
APvalue of ,0.05 is significant.
FIG. 6. Rat thyroid TPO mRNA levels, during acute iodide admin-
istration, as determined by Northern blotting. Band density wasmeasured using a Phosphorimager. Results are pooled from two sep-arate experiments and are normalized, with respect to individualthyroid cyclophilin mRNAs. They are expressed as relative units, withthe control group mean 51 [control group (n 510), 6-h group (n 5
10), and 24-h group (n 59)]. Shown are the means 6
SEM of each
group. A Pvalue of ,0.05 is significant.3408 ESCAPE FROM THE ACUTE WOLFF-CHAIKOFF EFFECTEndo ²1999
Vol 140 ²No 8Downloaded from https://academic.oup.com/endo/article-abstract/140/8/3404/2990434 by guest on 24 June 2019

transcriptional, although a posttranscriptional mechanism
cannot be ruled out. Pulse-chase experiments are planned toexamine the translational or posttranslational effects of io-dine on NIS protein turnover.
Although excess iodide administration did not affect Tg or
TSHr mRNAs, TPO mRNA levels were decreased after 6days of chronic iodide ingestion and 1 day after the acuteadministration of a large dose of iodide. These findings aresimilar to those observed in the iodine-deficient hypothyroiddog, 1 day after the administration of an acute dose of iodine(14). The decrease in TPO mRNA, after iodine administra-tion, would tend to negate the escape phenomenon. Indeed,if the decrease in TPO mRNA occurred alone, organificationof iodine and subsequent hormone synthesis would continueto be impaired. In spite of this possible decrease in TPO, thereduction in iodide transport and subsequent decrease inthyroidal iodine content would permit iodine organificationand hormone synthesis to resume.
We have recently reported that chronic iodine adminis-
tration to the diabetes and lymphocytic thyroiditis (LT)prone BB/Wor rat increases the incidence of LT and de-creases TPO mRNA in the follicular cells in contact withinfiltrating lymphocytes (17). Although spontaneous LT oriodine-induced LT does not occur in iodine-sufficient or -de-ficient Sprague Dawley rats (18), it is possible that a decreasein TPO mRNA might be one of the mechanisms responsiblefor iodine-induced hypothyroidism, so common in Hashi-
moto’s thyroiditis (19).
In summary, we have shown that excess iodide, given to
rats, chronically or acutely decreases both thyroid NISmRNA and protein. Our findings are consistent with thehypothesis that the escape from the Wolff-Chaikoff effect iscaused by a down-regulation of the NIS, resulting in de-creased iodide transport into the thyroid. This would thenlower the intrathyroidal iodine below a critical threshold andwould allow organification to resume. The decrease in NISis likely to be, at least in part, transcriptional. In addition, wehave also found that excess iodide decreases TPO mRNA andthat this decrease may contribute to iodide-induced hypo-thyroidism commonly seen in patients with Hashimotos’sthyroiditis.
References
1.Morton ME, Chaikoff IL, Rosenfeld S 1944 Inhibiting effect of inorganic
iodide on the formation in vitro of thyroxine and diiodotyrosine by surviving
thyroid tissue. J Biol Chem 154:381–387
2.Wolff J, Chaikoff IL 1948 Plasma inorganic iodide as a homeostatic regulator
of thyroid function. J Biol Chem 174:555–564
3.Wolff J, Chaikoff IL, Goldberg RC, Meier JR 1949 The temporary nature of
the inhibitory action of excess iodide on organic iodine synthesis in the normalthyroid. Endocrinology 45:504–513
4.Dugrillon A 1996 Iodolactones and iodoaldehydes–mediators of iodine in
thyroid autoregulation. Exp Clin Endocrinol Diabetes [Suppl 4] 104:41–45
5.Braverman LE, Ingbar SH 1963 Changes in thyroidal function during adap-
tation to large doses of iodide. J Clin Invest 42:1216–1231
FIG. 7. Western blot analysis of NIS
protein in thyroid tissue: acute excessiodide. A, Autoradiograph of Westernblot of thyroid protein, extracted fromrats subjected to acute excess iodide.The blot was hybridized with a primaryanti NIS antibody and a secondaryhorseradish peroxidase-conjugated an-tibody. Protein detection was by en-hanced chemiluminesence. Lanes 1–4are controls, lanes 5–8 are from rats inthe 6-h group, and lanes 9–12 are fromrats in the 24-h group. The NIS proteinis approximately 90 kDa. B, Rat thyroidNIS protein levels, during acute iodideadministration, as determined by West-ern blot analysis. Band density wasmeasured using a densitometer. Re-sults are from 1 experiment and are ex-pressed as densitometry units [controlgroup (n 54), 6-h group (n 54), and
24-h group (n 54)]. Shown are the
means 6
SEMof each group. A Pvalue
of,0.05 is significant.ESCAPE FROM THE ACUTE WOLFF-CHAIKOFF EFFECT 3409Downloaded from https://academic.oup.com/endo/article-abstract/140/8/3404/2990434 by guest on 24 June 2019

6.Dai G, Levy O, Carrasco N 1996 Cloning and characterization of the thyroid
iodide transporter. Nature 379:458–460
7.Benotti J, Benotti N 1963 Protein bound iodine, total iodine and butanol
extractable iodine by partial automation. Clin Chem 9:408–416
8.DeVito WJ, Chanoine JP, Alex S, Fang S-L, Stone S, Huber CA, Shalhoub
V, Lian JB, Stein GS, Braverman LE 1992 Effect of in vitro administration of
recombinant acidic-fibroblast growth factor on thyroid function in the rat:induction of colloid goiter. Endocrinology 131:729–735
9.Wartofsky L, Ransil BI, Ingbar SH 1970 Inhibition by iodide of the release of
thyroxine from the thyroid glands of patients with thyrotoxicosis. J Clin Invest49:78
10.Vagenakis AG, Downs P, Braverman LE, Burger A, Ingbar SH 1973 Control
of thyroid hormone secretion in normal subjects receiving iodides. J Clin Invest52:1010–1017
11.Kogai T, Endo T, Saito T, Miyazaki A, Kawaguchi A, Onaya T 1997 Regu-
lation by thyroid-stimulating hormone of sodium/iodide symporter gene ex-pression and protein levels in FRTL-5 cells. Endocrinology 138:2227–2232
12.Saito T, Endo T, Kawaguchi A, Ikeda M, Nakazato M, Kogai T, Onaya T 1997
Increased expression of the Na
1/I-symporter in cultured human thyroid cells
exposed to thyrotropin and in Graves’ thyroid tissue. J Clin Endocrinol Metab82:3331–3336
13.Nagataki S, Ingbar SH 1964 Relation between qualitative and quantitativealterations in thyroid hormone synthesis induced by varying doses of iodide.
Endocrinology 74:731–736
14.Uyttersprot N, Pelgrims N, Carrasco N, Gervy C, Maenhaut C, Dumont JE,
Miot F 1997 Moderate doses of iodide in vivo inhibit cell proliferation and the
expression of thyroperoxidase and Na
1/I-symporter mRNAs in dog thyroid.
Mol Cell Endocrinol 131:195–203
15.Paire A, Bernier-Valentin F, Selmi-Ruby S, Rousset B 1997 Characterization
of the rat thyroid iodide transporter using anti-peptide antibodies. Relation-ship between its expression and activity. J Biol Chem 272:18245–18249
16.Levy O, Dai G, Riedel C, Ginter CS, Paul EM, Lebowitz AN, Carrasco N 1997
Characterization of the thyroid Na
1/I-symporter with an anti-COOH termi-
nus antibody. Proc Natl Acad Sci USA 94:5568–5573
17.Mori K, Mori M, Stone S, Braverman LE, DeVito WJ 1998 Increased expres-
sion of tumour necrosis factor- a(TNF a), and decreased expression of thy-
roglobulin and thyroid peroxidase mRNA in the thyroids of iodide treatedBB/Wor rats. Eur J Endocrinol 139:539–545
18.Colzani RM, Alex S, Fang SL, Stone S, Braverman LE 1999 Effects of iodine
repletion on thyroid morphology in iodine and/or selenium deficient rat termfetuses, pups, and mothers. Biochimie 81:1–7
19.Braverman LE, Ingbar SH, Vagenakis AG, Adams L, Maloof F 1971 Enhanced
susceptibility to iodine myxedema in patients with Hashimoto’s disease. J ClinEndocrinol Metab 32:515–5213410 ESCAPE FROM THE ACUTE WOLFF-CHAIKOFF EFFECTEndo ²1999
Vol 140 ²No 8Downloaded from https://academic.oup.com/endo/article-abstract/140/8/3404/2990434 by guest on 24 June 2019