Iodine is an essential micronutrient, which plays a vital role in various metabolic functions of the body. Traditionally Iodine has always been associated with the synthesis of thyroid hormone. Bernard Courtois in 1811 discovered Iodine during his invention of gunpowder (Louis) It is water soluble and is present in greater concentrations in seawater than in rocks and soil. Hence most parts of the world are iodine deficient because the soil is a poor source of iodine.The richest dietary source of iodine is seafood like fish, sea weed. Milk, eggs are also very important sources of iodine. [Br Med J] [Sources of iodine]. In the U.S., iodized table salt is the most common source of iodine in the diet. One gram of table salt (NaCl) contains 74 mcg of iodine [Abraham]. Many people are on controlled diets for various reasons such as hypertension etc. and have eliminated iodized salt from their diets, as sodium is thought to be responsible for hypertension. Sodas have been replacing water and also milk which is also one of the richest source of iodine. The recommended intake for iodine is 150 mcg per day for adults and 200 mcg per day for pregnant or lactating women. [WHO].There is no documented upper limit or toxic level for iodine.[WHO]
Iodine plays a role in regulating body temperature, metabolic rate, growth, hematopoiesis, reproduction by being an integral part of the thyroid hormone.[Whitney]. Iodine is present in the thyroid in various forms- inorganic iodine, monoiodothyronine [MIT], diiodothyronine [DIT], 3, 5, 3'- triiodothyronine [T3], and thyroxine [T4], 3, 5, 3'5'-tetraiodothyronin. The thyroid stimulating hormone [TSH] is the chief hormone that regulates the synthesis of thyroid hormones by regulating the iodine pump in the thyroid. The iodine pump is an active transport mechanism, requiring energy, which allows iodine into the colloid follicle space between the thyroid cells, where it is oxidized by hydrogen peroxide. Then it forms monoiodothyronine [MIT] and diiodothyronine [DIT] by coupling with tyrosine. Thyroxine [T4] and triiodothyronine [T3] are the thyroid hormones formed as a result of coupling reactions of MIT and DIT. The synthesized hormones along with the MIT and DIT are bound to thyroglobulin, a glycoprotein and are stored in the thyroid as colloid. Hence approximately 90% of the total iodine in the thyroid gland is present in the thyroglobulin.T4 and T3 are released from the thyroglobulin into the blood by the action of proteolytic enzymes. On reaching peripheral tissues T4 is converted to T3, which is the active thyroid hormone.[ Br Med J].About 60mcg of iodine per day is required to maintain adequate levels of thyroxine. [Abraham]
METABOLISM:
Iodine is easily absorbed through the intestines mostly in the form of iodide. The velocity of iodine absorption is straightly related to the amount of its sources. [Muslimatun.]Iodine compounds, such as iodinated fatty acids, are the most easily absorbed, along with inorganic salts, and organic iodine-containing substances such as thyroxin (T4) and diiodotyrosine (DIT) [Dunn JT] .The liver obtains iodine from the portal vein and regulates the passage of iodine into the blood circulation. This is essential to keep away from a large rise in serum iodine from a too much magnitude of iodine in foods consumed [[Dunn JT] .Any excess iodine is excreted by the kidney. The quantity of iodine excreted is directly related to the quantity of iodine eaten. So by this way one can assess the level of iodine intake [Francis C] .90% of iodine is excreted in the urine, the best way to determine adequacy in nutrition is by testing urine iodine concentration by iodine loading test. [WHO, UNICEF, ICCIDD 2001]
SODIUM IODIDE SYMPORTER:
The Sodium Iodide Symporter (NIS), a membrane glycoprotein plays an important role in the active iodide uptake in the thyroid gland and numerous extrathyroidal tissues. NIS extends through the plasma membrane, with an extracellular NH2 terminus and a cytosolic COOH terminus. [Daniel H] Different tissues exhibit different degrees of NIS glycosylation, but it has not been documented if the differences in glycosylation affect the function and stability of NIS.Many hydroxy-containing amino acid residues present in the transmembrane segment IX seem to play a vital role in NIS activity, but the factors involved in this mechanism are still to be known. Electrophysiological studies show that net influx of NaI induces 2:1 sodium iodide/iodine (NaI/I2) stoichiometry, which results in a steady state inward current. [Daniel H]
Apart from thyroid tissuesNIS is also expressed in tissues like salivary glands, stomach,
lactating breast, nasal mucosa, hair follicles,thymus and the placenta. But, TSH only stimulatesiodine uptake in thyroid tissues and not in the extrathyroidal tissues because of
the lack of TSH receptors.The expression of NIS mRNA was studied using Northern blot analysis, RNase protection assay, and reverse transcription-polymerase chain reaction (RT-PCR) and also by using radioiodine uptake method.[ Venturi S]
IODINE IN BREAST TISSUE:
It was found by immunohistochemical staining that NIS was mostly on the basolateral membrane of alveolar cells and the small ductal epithelial cells in the lactating mammary gland. This supports the concept that iodide is transported from blood to alveolar and small ductal cells, and then moved to the lumen where milk is accumulated and secreted. The methods of breast radioiodine uptake in nonlactating women and lactating women may be different. [10] Specific peroxidases present in the mammary gland has a high but temporary capacity to concentrate iodides and to form iodocompounds in alveolar and ductular cells, mostly during pregnancy and lactation, which are regarded as protective conditions against breast cancer. During pregnancy and lactation, iodine adsorption and organification are increased due to hormonal stimulation of the breast that leads to glandular differentiation.[12] It is fascinating to see that the iodine absorption takes place in the same ductal epithelium, where the majority of breast cancers occur. Lactoperoxidases are the enzymes which organify iodide in the breast.These are found to be mainly active during pregnancy and lactation.. [12] A second pathway for iodine organification has been explained which involves iodine integration into specific lipid molecules [polyunsaturated fatty acids]. These iodolipids are discovered to be the regulators of thyroid cell metabolism and proliferation, especially 6-iodo-5-hydroxy-eico- satrienoic acid (delta-iodolactone) is thought to be a potent inhibitor of thyroid cells proliferation and these iodolipids may also have a role to play in anti-proliferation mechanism of breast tissue.
Thus it can be said that iodine plays a key role in the preservation of both normal thyroid and breast physiology
ROLE OF IODIDE IN MAMMARY CELLS
Many studies have been done on the relationship between breast cancer,thyroid diseases and iodine.In an ecological study by Bogardus and Finlay,when mortality rates for breast cancer in each state in US were compared with goiter incidence there was a direct relationship between them and so,it was thought that low iodine intake or iodine deficiency may be involved in the etiology of breast cancer.[12][13] A study reported that one mechanism involved in this process could be that iodine in mammary cells acts as an antioxidant.This assumption is due to the fact that iodine directly acts on cells which embryologically originated from iodide-concentrating ectoderm and epidermis. Another hypothesis showed that low intake of iodine may lead to momentary primary hypothyroidism,which inturn stimulate changes in the hypothalamic-pituitary pool.This in turn results in increased gonadotrophic stimulation,which may be responsible for hyperestrogenic state.Hyperestrogenic state is proved to increase the risk of breast carcinoma.[13]
These data suggest a role for iodine in the pathogenesis of cancer/apoptosis. Another study recently showed that the iodine molecule itself induces apoptosis in human breast carcinoma cells involving a mitochondrial mediated pathway but this effect could not be studied in normal cells.In case of iodine deficiency these processes may be hampered, which can lead to altered apoptosis mechanism and ultimately leading to malignancies.[11]
In another study,rat breast cells were fractionated by ultracentrifugation and the content of iodine in the soluble fraction was determined by I125 uptake.It was noted that the uptakes of both iodine deficiency and perchlorate blockade were significantly lower than the uptake noted in the control group of animals and in certain altered thyroid states.[13]These results also substantiate that iodine has a role to play at the breast tissue level and that biochemical homeostasis is altered when iodine deficiency is present.Iodine seems to be a requirement for normalcy of breast tissue.In iodine deficient states, the breast parenchyma showed atypia, dysplastic and neoplastic changes in the rodents.Iodine deficient breast tissues were found to have RNA/DNA ratio changes too.[13] Total tissue iodine levels in benign tumours were significantly higher than those in breast cancers in another research study. [12]
In another study,it was seen that in iodide-deficient rats,which were atrophied,necrosed and had areas of dysplasia ,were higly sensitive to stimulation by estradiol.Estradiol then,stimulates cell division and directs the development of alveoli with huge amounts of lipid and protein droplets in large vacuoles which consequently leads to the formation of cysts within the mammary gland[13]. Another research was done where estrogen was supplemented in distrurbed iodine-thyroid metabolism rats.It resulted in marked hyperplasia and papillomatosis of mammary ducts and also periductal fibrosis,which was similar to the fibrocyctic disease in women.Hence Dietary replacement therapy of iodine may be able to improve these changes in mammary tissue. [12] Ghent et al. reported that 70% of women with Fibrocystic breast disease,when treated orally with sodium iodide showed clinical improvement in their breast disease.[1]A study reported that women with benign breast disease, when treated with iodine,caused a significant bilateral decrease in breast size, and also reduced disease symptoms. Other research has shown that a seaweed-supplemented diet (rich in iodine) caused an inhibition and delay in the development of mammary cancer in rats. [12]
When statistical correlations between dietary iodine, thyroid diseases and breast cancer were carried out,an epidemiological evidence was noted for the protective role against breast cancer of dietary fish ,which is rich in iodine. Japanese women have the highest intake of iodine ,of about 4±10 mg/daily/per person [the recommended dietary allowance is150±200 mg per day], and have the lowest rate of breast cancer mortality in the world. Japanese habitually eat a significant quantity of marine algae (seaweed), which is very rich in iodine. [12]
Hence iodine can be beneficial in treatment and prevention of breast diseases like breast cancers and cysts.Also a decrease or loss of NIS expression may indicate an early aberration of thyroid and breast carcinogenesis rather than this occurring as a consequence of cancer progression and hence Mammary NIS can become an essential breast cancer marker in the future. [12] The use of iodine supplementation in treating and preventing breast cancer is considered and investigated currently. [12]
'EXCESS' IODINE HARMFUL?
The iodine which has many beneficial effects with respect to the thyroid and also the breast,has been proved to paradoxically block the organification step in the thyroid,when it becomes excess,which in turn decreases the production of the thyroid hormone. Organification is incorporation of iodine intot he tyrosine residues of the thyroglobulin.This TSH independent autoregualtion is termed as the 'Wolff Chaikoff Effect' .So,excess iodine can also lead to paradoxical hypothyroidism in the course of time. The exact mechanism involved in Wolff Chaikoff effect has not been found ,but it has been proposed that this block might act through adenylate cyclase system, interference of iodine with thyroid peroxidase enzyme action.Since there is no defined upper limit, the exact meaning of 'excess' iodine would be arbitrary. [Bürgi H et al]
CONCLUSION
The knowledge of this iodinating ability and of the antioxidant and anti-tumor activity of iodide may be beneficial for prevention and treatment of breast . But at the same time supplemtation of iodine can also have a negative effect in the form of Wolff Chaikoff effect. The evidence of the lowest incidence of breast cancer seen in Japanese who consume highest iodine on an average,and still not experiencing the 'hypothyroidism' effect due to excess iodine remains a question to be answered.Many clinical trials have not been done so far either to prove the beneficial effects of iodine on breast cancer or to prove its detrimental effects on thyroid.Lots of research ,especially clinical trials need to be done in this area to have sufficient substantiation in either case.Clinical trials and prospective studies focusing on Japanese population could be very helpful in identify the relationship between the pros and cons of iodine supplementation .Future research on the physiology behind Wolff Chaikoff effect can help in finding a solution to overcome the effect,so that iodine can be used in the prevention and treatment of breast cancer.
Until future large scale clinical trials prove the safety of iodine supplementation, I think encouraging people to consume food substances rich in iodine would be beneficial rather than advising them to take iodine supplements.
