The term iodine comes from the French word “iode” originally proposed by J.P. Gay-Lussac, derived from the Greek “ἰοειδής” due to its characteristic violet color in its gaseous state [1]. Historically, the only biological function attributed to iodine concerned its incorporation into thyroid hormones (THs), synthesized by the thyroid gland [1]. THs, namely T₄ (3,5,3′,5′-tetraiodo-L-thyronine) and T₃ (3,5,3′-triiodo-L-thyronine), are characterized by the presence of four and three iodine atoms within the molecule, respectively, and play a prominent role in human body development and homeostasis ^[2][3][2,3]. In addition, over the last two decades, additional physiological roles of iodine have emerged ^[4][5][6][7][4,5,6,7]. Specifically, iodine is thought to represent one of the oldest terrestrial antioxidants used by living organisms due to its significant activity as a scavenger of reactive oxygen species (ROS) [5]. Moreover, iodine oxidation to hypoiodite (IO⁻) possesses strong bactericidal as well as antiviral and antifungal activity ^[6][7][8][9][6,7,8,9]. Finally, iodine has been demonstrated to exert antineoplastic effects in breast cancer, and in human melanoma- and lung cancer-derived cell lines ^{[4][10][11][12][13][14]}[4,10,11,12,13,14].

2. Iodine Metabolism

Iodine is mainly ingested as iodide (I⁻); iodate (IO₃⁻), which is generally used in salt iodization; or organically bound iodine. More than 90% of ingested iodide is absorbed in the duodenum ^[1][4][15][1,4,38]. Iodate is reduced in the gut to iodide before absorption, whereas the organically bound iodine is digested, and the released iodide is absorbed [1]. The uptake is mediated by the sodium/iodide symporter (NIS), present on the apical plasma membrane of enterocytes of the duodenum, jejunum, and ileum ^[16][17][18][39,40,41]. Moreover, other carriers expressed on the brush border of enterocytes are thought to contribute to iodide absorption in the gut, including the sodium multivitamin transporter (SMVT) and the cystic fibrosis transmembrane conductance regulator (CFTR) ^[4][19][20][4,42,43]. Once absorbed, iodide is transferred to the bloodstream through molecular mechanisms that are still to be fully clarified [4]. In addition to intestinal absorption, deiodination of T4 and T3 by deiodinases in peripheral tissues contributes to the level of iodide present in the bloodstream ^[21][44]. Circulating iodide is either taken up by the thyroid gland through the action of NIS, present in the basolateral plasma membrane of thyrocytes, or eliminated in the urine. Inside the kidney, NIS expression was first localized by means of immunohistochemistry in the basolateral membrane of distal tubular cells, suggesting their role in iodide excretion ^[22][45]. However, different results were obtained in subsequent studies in which NIS expression was observed on the apical membrane of cells belonging to proximal and cortical collecting tubes, indicating a resorption action of iodide from the urine ^[4][23][4,46]. Thus, the urinary excretion of iodine could be the result of these two opposite processes.

3. Iodine Metabolism in the Thyroid

As mentioned, the main physiological function of iodine concerns TH biosynthesis by the thyroid gland [1]. Bloodstream iodide is actively transported across the plasma membrane into the cytoplasm of thyrocytes by NIS, exploiting the concentration gradient of Na⁺ generated by the Na⁺/K⁺-ATPase transporter as a driving force ^[23][24][46,52]. Iodide is then transferred to the lumen of thyroid follicles by several transporters, including PENDRIN, ANO1, and CFTR ^{[25][26][27][28]}[53,54,55,56]. Here, at the outer surface of the apical membranes of thyrocytes, the biosynthesis of THs is initiated by thyroid peroxidase (TPO), which uses H₂O₂ produced by DUOX2 to oxidize iodide to iodine radicals and incorporates it on specific tyrosine residues within thyrocyte-secreted thyroglobulin (Tg) molecules ^[29][57]. After that, TPO couples two residues of diiodotyrosine (DIT) to form thyroxine (T₄), and one monoiodotyrosine (MIT) to one DIT to form thyroxine (T₃). Mature Tg, containing THs, is stored in the colloid of the follicular lumen. The secretion of THs relies on Tg reabsorption from the lumen by micropinocytosis, and its proteolysis by lysosomal enzymes that release THs from the Tg protein ^[29][57]. Uncoupled MIT or DIT residues are deiodinated by the iodotyrosine dehalogenase (DEHAL1), a transmembrane protein localized mainly at the apical pole of thyrocytes and involved in the intrathyroidal recycling of iodide ^[30][58]. THs are transported outside the basolateral membrane of thyrocytes, mainly by monocarboxylate transporter 8 (MCT8), from which they reach the bloodstream. The pituitary thyroid stimulating hormone (TSH), through its receptor (TSHR) present on the basolateral surfaces of thyrocytes, is the mainly regulator of TH biosynthesis, controlling the expression of the thyroid-specific genes involved in TH biosynthesis ^[4][29][4,57].

4. Consequences of Iodine Deficiency

Iodine deficiency has several detrimental effects on human growth and development ^[1][31][32][1,15,16]. About four decades ago, Basil S. Hetzel first coined the term “iodine deficiency disorders” (IDD), recognizing how the negative consequences of a poor dietary iodine intake extended far beyond simple goiter ^[33][34][35][73,74,75]. As summarized in Table 1, the health risks associated with iodine deficiency may persist throughout the lifetime.

Age	Iodine Deficiency Disorders

Fetus	Abortions, stillbirths, congenital anomalies Increased perinatal mortality
Neonate	Neonatal hypothyroidism, endemic cretinism Increased susceptibility of the thyroid gland to nuclear radiation
Child and adolescent	Goiter, hypothyroidism or hyperthyroidism Impaired mental function, delayed growth and puberty Increased susceptibility of the thyroid gland to nuclear radiation
Adult	Goiter with its complications, hypothyroidism Infertility, Impaired mental function Spontaneous hyperthyroidism in the elderly Iodine-induced hyperthyroidism Increased susceptibility of the thyroid gland to nuclear radiation

As can be seen in Table 1, hypothyroidism consequent to iodine deficiency in women causes important reproductive alterations including anovulation and reduced fertility and, when pregnancy occurs, gestational hypertension, stillbirths, and congenital anomalies, and increased perinatal mortality may be observed ^[37][76]. This may have cultural and socioeconomic consequences, compromising the life quality of parents that face the responsibility of taking care of a child with serious health problems ^[37][38][76,77]. From a physiological point of view, infertility occurring in iodine-deficient hypothyroid women could be seen as a protective mechanism implemented by the body to avoid hazards related to pregnancies carried out in iodine deficiency conditions. Recently, data indicating a direct association between iodine status and fertility have been reported by Mills and colleagues ^[39][78]. They observed that the time to pregnancy was significantly delayed in women with preconception UIC values <50 μg/L, with a fecundability odds ratio reduced by 46% over each menstrual cycle ^[39][78]. The detrimental effects of iodine deficiency on the development and maturation of the fetal brain are of particular relevance, representing a major preventable cause of mental defects ^{[1][31][32][40][41][42][43][44][45][46][47]}[1,15,16,79,80,81,82,83,84,85,86].

5. Iodine Functions against Pathogens

In the salivary glands, stomach, and intestine, iodide is thought to take part in innate immune defense [4]. In these tissues, iodide may be recycled from the bloodstream and eventually re-absorbed again by the epithelial cells of the duodenum, jejunum, and ileum [4]. In the salivary glands and in the mucin-secreting and parietal cells of the stomach, iodide uptake from the bloodstream is mediated by the NIS present on the basolateral membrane of the cells, and secreted in saliva and gastric juices by low-affinity iodide transporters on the apical plasma membranes, such as CFTR, ANO1, and PENDRIN ^{[4][8][48][49][50][51][52][53]}[4,8,89,90,91,92,93,94]. The presence of DUOX2 in the apical membrane of epithelial salivary cells, of the gastric mucosa, and of the apical surface of enterocytes, along with that of tissue-specific peroxidase (salivary peroxidase, gastric peroxidase, and lactoperoxidase (LPO) in the intestinal mucus) in these sites allow for iodide oxidation to hypoiodite (IO⁻), which is endowed with fungicidal and bactericidal activity ^{[4][6][7][8][48][49][50][51][52][53]}[4,6,7,8,89,90,91,92,93,94]. In addition, through a similar mechanism to that described above, iodide oxidation has been shown to possess a strong antiviral action against lung adenoviruses ^[4][9][4,9].

6. Iodine and Cancer

Several experimental findings have indicated that iodide may elicit antiproliferative and apoptotic effects in malignant cells [4]. Vitale and colleagues reported the ability of an excess of iodide (KI) to induce apoptosis of immortalized thyroid cells and primary cultures of human thyrocytes, but not of extrathyroidal cells ^[54][96]. The apoptotic effect of thyroid cells was p53-independent and required the presence of a functional thyroid peroxidase as its inhibition by propylthiouracil completely prevented iodide-induced apoptosis [9]. Later on, Zhang and colleagues confirmed the ability of iodide to induce apoptosis of lung cancer cells transfected with NIS and TPO, but not in those transfected only with NIS ^[55][97]. Altogether, this evidence indicates that iodide needs to be oxidized to induce apoptosis. García-Solís and colleagues analyzed the effect of molecular iodine (I₂) and iodide (KI) on the induction and promotion of mammary cancer induced by N-Methyl-N-nitrosourea in rats ^[56][98]. They found that I₂, but not iodide, had a potent antineoplastic effect on the progression of mammary cancer. This antineoplastic effect was thought to be mediated by I₂-induced expression of the peroxisome proliferator-activated receptor γ (PPARγ), which is capable of triggering the apoptosis of malignant cells ^[56][57][58][98,99,100]. The observation that iodide had no effects in this experimental system was explained by the lack or low expression of NIS and/or LPO. In a different human mammary cancer model, using dimethylbenz[a]anthracene (DMBA)-induced mammary tumors, the tumor cells were shown to express both NIS and LPO ^[59][101]. In this experimental model the co-administration of iodine and/or iodide along with medroxyprogesterone acetate (MPA) inhibited mammary cancer growth at a significantly higher level with respect to MPA alone ^[60][61][102,103]. In particular, the higher growth inhibitory effects were observed in tumor tissues with a higher iodine content, indicating that direct iodine uptake by breast tumors led to the suppression of tumor growth ^[60][102]. More recently, iodine supplementation was found to enhance the antineoplastic effect of doxorubicin in canine patients affected by mammary cancers ^[13][14][13,14]. In particular, co-treatment with doxorubicin and I₂ has been shown to improve therapeutic outcomes, diminish the invasive capacity, attenuate adverse events, and increase disease-free survival. The antiproliferative and apoptotic effects of iodine were further confirmed in thymic epithelial tumour cells and different human colon cancer cell lines ^[11][12][11,12]. Altogether, this experimental evidence clearly suggests that iodine may positively contribute to the fight against cancer.