Current Chemical , 2011, 5, 000-000 1 Evolutionary Significance of

Sebastiano Venturi*

Department of Health, Marche Region, Pennabilli (Rimini), Italy

Abstract: The significance of inorganic and organic forms of iodine in the evolution of and animals is reviewed. Iodine is one of the most electron-rich atoms in the of marine and terrestrial , and it enters cells via iodide transporters. Iodide, which acts as a primitive electron donor through peroxidase , has an ancestral function in all iodide-concentrating cells from primitive marine to more recent terrestrial vertebrates. Similarly, thy- roxine and iodothyronines show antioxidant activities through deiodinase enzymes. About 500-600 million years ago, in parallel with the evolution of the primitive brain in marine animals, thyroid cells originated from the primitive gut in ver- tebrates, migrated, and specialized in the uptake and storage of iodo-compounds in a novel follicular “thyroidal” structure, an adaptation that enabled the transition from the iodine-rich ocean to the iodine-deficient terrestrial environment.

Keywords: , evolution, iodine, iodide, thyroxine.

INTRODUCTION mechanism against oxygen species (ROS). Iodides and peroxidases were present in primitive oxygenic and pho- The iodine atom (symbol I, atomic mass 126.9, atomic tosynthetic about 3  billion years ago number 53, 53 electrons, 53 protons, and 74 neutrons) is a [2,4,5]. Several authors have suggested that the production component of "nuclear ash". In fact, it derives from a process of volatile iodine (molecular iodine; I ) and iodo-compounds of nucleosynthesis that occurred more than 10 billion years 2 by marine algae is a result of the development some 3 billion ago in a star-supernova that exploded and dispersed its dust, years ago of , oxygen production, and respira- which formed our planet Earth about 5 billion years ago. The tion, probably as an adaptation to utilize light in order to iodine atom is one of the richest in electrons of our body and reduce the amount of poisonous ROS [6-8]. The importance is essential in the diet of all living animals. Iodine is scarce of antioxidants as protective substances against chronic and in the earth's surface, because, over hundreds of millions of degenerative diseases, such as and cardiovascular years, it has been washed away by rain and glaciations and diseases has been studied for many years. However, the util- transported from the terrestrial crust to the sea, which is en- ity of well-known antioxidant as protec- riched in iodine in the form of iodide (I-) and iodates [1,2]. tion against or a cure for these diseases has not been demon- Seawater has about 60 micrograms per litre, whereas terres- strated [9,10]. A recent study tracking the eating habits of trial freshwaters (estuaries, rivers, lakes) contain 10- to 200- 478,000 Europeans suggests also that consuming high fold lower quantities. Algal phytoplankton, the basis of the amounts of fruits and has little if any preventative marine chain, acts as a biological accumulator of io- effect against cancer [11]. For this reason, we have hypothe- dides, , and also polyunsaturated fatty acids (PU- sized an “evolutionary hierarchy” for the wide range of anti- FAs) [2]. Our group has suggested that iodine and selenium oxidants, where the most ancient might be more essential played an important role in protecting fragile, polyunsatu- than the “modern” ones in protecting developing stages of rated membrane , and DNA from oxidation, animal and human organisms [2]. Deficiency of iodine, the and for this reason, these elements are important in animal primitive antioxidant, causes more damage in developing development and in human brain evolution [3]. In fact, io- embryos than deficiencies of some other “modern” antioxi- dide is a mild reducing agent, which is a chemical term for dants. Iodine-deficiency causes abortions and stillborns in an antioxidant. Its antioxidant properties can be expressed pregnant women and cretinism and neuropsychological dis- quantitatively as a potential: orders in human infants [12]. The iodine species that exist  - I ⇌ 1/2 I2 + e (electron) = - 0.54 Volt within a at a pH 7.4 are: iodide (I ), triiodide (I3), molecular iodine (I2), hypoiodous acid (HIO), hypoio- Because iodide is easily oxidized, some enzymes convert dite ion (OI-), and the iodine anion (HI O-) [13]. it into electrophilic iodinating agents, as required for the bio- 2 synthesis of numerous iodine-containing natural products. In INCREASE OF OXYGEN IN EARTH’S ATMOS- an evolutionary sense, iodides are the most ancient and pow- PHERE AND ITS BIOLOGICAL CONSEQUENCES erful antioxidant, and as such they are the oldest defence The evolution of oxygen-producing cells was probably

the most significant event in the history of life after the be- *Address correspondence to this author at the Department of Health, ginning of life itself. Oxygen is a potent oxidant whose ac- Marche Region, Pennabilli (Rimini), via Tre Genghe, 3. Italy; cumulation in the atmosphere forever changed the surface Tel: (+39) 0541 928205; E-mail: [email protected] chemistry of the Earth [14]. By the start of the Cambrian

1872-3136/11 $55.00+.00 © 2011 Bentham Science Publishers Ltd. 2 Current Chemical Biology, 2011, Vol. 5, No. 3 Sebastiano Venturi

Fig. (1). Iodine in Evolution. Over three billion years ago, blue-green algae were the first living Prokaryota to produce oxygen, halocarbons (such as CH3I) in the atmosphere, and PUFAs in membranes. About 500-600 million years ago (Mya) when the primitive brain evolved in marine animals, thyroid cells originated from the primitive gut in vertebrates, migrated, and specialized in the uptake and storage of iodo- compounds in a novel follicular “thyroidal” structure that served as a reservoir for iodine. Three to four hundred million years ago some ver- tebrates evolved into amphibians and reptiles and moved to I-deficient land. Thyroid hormones became active agents in the metamorphosis and thermogenesis of vertebrates, facilitating their adaptation to the terrestrial environment. The dry terrestrial diet firstly stimulated in am- phibians the formation of I-concentrating salivary glands, and about 200 Mya the formation of I-concentrating mammary gland in mammals (from Venturi et al. [27]).

Table. 1. Biochemical Mechanism of Iodides, the Most Ancient and Powerful Mechanism of Defence Against Poisonous

- 2 I + Peroxidase + H2O2 + 2 Tyrosine, Histidine or lipids  2 Iodo-components +H2O + 2 e- (antioxidants);

2 e- + H2O2 + 2 H+ (from aqueous cytoplasm)  2 H2O period 570 million years ago (Mya) oxygen levels had in- mutase, peroxidase, catalase, and peroxiredoxins creased enough to permit rapid evolution of large, oxygen- [15]. utilizing, multicellular organisms. At the same time, endoge- IODIDE/IODINE AND IODIDE/THYROXINE: EVO- nous protection systems need to have been developed to LUTIONARY HISTORY OF A PRIMITIVE ANTI- counteract the deleterious effects of oxygen oxidations. OXIDANT Some researchers hypothesized that the relative amounts of many trace elements of the modern animal body are Over three billion years ago, blue-green algae were the similar to the composition of the primitive sea, where the most primitive oxygenic photosynthetic organisms, ancestors first forms of life began [2,15,16]. In particular, mineral an- of multicellular eukaryotic algae. Algae that contain the tioxidants such as some reduced compounds of Rubidium, highest amount of iodine (1-3 % of dry weight) and peroxi- Vanadium, , , , , Selenium, and dase enzymes were the first living cells to produce poisonous Iodine, seem to play important roles in electron transfer and oxygen in the terrestrial atmosphere [16,17]. Therefore, algal in redox chemical reactions. Most of these substances are cells needed molecules with protective antioxidant proper- essential trace elements in the cells and occur in redox and ties, and the iodides seem to have assumed this specific role antioxidant metallo-enzymes. A few organic antioxidants [2,3]. Küpper et al. confirmed this hypothesis showing that appeared more recently, in the last 100-200 million years, in iodide scavenges ROS in algae, and that its primary biologi- fruits and flowers of angiosperm plants [2]. In fact Angio- cal role is that of an inorganic antioxidant, the first to be de- sperms (the dominant type of plants today) and most of their scribed in a living system and a role that it has kept in blood antioxidant pigments evolved during the late Jurassic period. cells of modern humans [6]. Moreover, recently Soriguer et Plants employ many organic antioxidants to defend them- al. also showed a slight anti-inflammatory and antioxidative selves against ROS produced during photosynthesis. In ani- action of iodide in humans [18]. mals, the primary antioxidant enzymes are superoxide dis- Iodine in Evolution Current Chemical Biology, 2011, Vol. 5, No. 3 3

Brown algae (seaweeds) accumulate iodine to more than probably an example of convergent evolution to a common 30,000 times its concentration in seawater [6,7]. Primitive enzymatic mechanism. marine prokaryotes seem to have an efficient, active “iodide “EVOLUTION” OF IODINE FROM NON- pump”, ancestor of the pump of multicellular eukaryotic HORMONAL TO HORMONAL FUNCTIONS algae and of mammalian iodide-transporters. This cellular “iodide-pump” uses a primitive mechanism, and it lacks Since 700-800 Mya, thyroxine has been present in fi- specificity; in fact it cannot distinguish iodide from other brous exoskeletal scleroproteins of the lowest marine inver- anions of similar atomic or molecular size such as thiocy- tebrates (sponges and corals) [22]. More recent studies found anate, cyanate, fluoride, , pertechnetate, and perchlo- that the thyroid hormones (THs) thyroxine (T4) and triiodo- rate, which may act as “pseudo-iodides” [19]. The “iodide- thyronine (T3) are also present in unicellular planktonic al- pump” and /iodine symporter (NIS) in the cells are gae (Dunaliella tertiolecta) and in echinoid larvae (sea- also paradoxically inhibited by an excessive quantity of io- urchin) [23,24]. The original sources of animal hormones dine. This inhibition seems to be an ancient defensive might have been plants/algae in many cases, and could well mechanism when, in the primitive sea, excess iodide im- have been independently derived from plants/algae in dis- paired cellular trophism and functions of I-concentrating tinct lineages. The ancestral function of THs in algae and/or organisms. This well-known “Wolff-Chaikoff effect” occurs plants could also have been as feeding deterrents with the now in animal and human thyroid with a dosage just in ex- signalling functions in animals acquired secondarily, perhaps cess of 2 mg iodide [19]. even through horizontal transfer from their hosts or other co- associated microbes that had more ancient relationships with It is hypothesized that 80% of the Earth's oxygen is pro- the host [24-26]. duced by planktonic algae, prochlorphytes, Cyanobacteria, and by free-floating unicellular microbes inhabiting the sea The iodine concentration decreases stepwise from sea- close to the surface. Thus far, only one aspect of halogen (60 μg /L) to estuary (about 5 μg /L) to source of riv- , the production of volatile halocarbons, seems to ers (less than 0.2 μg /L in some Triassic mountain regions of have attracted attention from researchers, because these northern Italy), and in parallel, saltwater fishes (herring) con- compounds and particularly their iodinated forms have a tain 500-800 μg of iodine per kg compared to freshwater significant impact on the chemistry of the atmosphere and trout with about 20 μg per kg [27]. Thus, in terrestrial I- depletion of its ozone shield. Halogen metabolism in marine deficient freshwaters, some trout and other salmonids (ana- algae involves haloperoxidase enzymes [16,17,20]. Since the dromous migratory fishes) may suffer thyroid hypertrophy or iodo-peroxidase of Laminaria seaweeds is more efficient related metabolic disorders, as do some sharks in captivity than their bromo-peroxidase in the oxidation of iodide, this [2,27,28]. Youson and Sower [29] reported that the I- former activity may be largely responsible for the uptake of concentrating ability of the endostyle of sea lamprey was a iodide from seawater. There is an increased emission of io- critical factor in the evolution of metamorphosis and that the dinated halocarbons and I2 both from beds at low tide endostyle was replaced by a follicular thyroid, since post- during daytime and from kelp plants incubated under high metamorphic animals needed to store iodine following their solar irradiation causing photo- [6,16,17]. invasion of freshwater. According to Youson´s group in The family of peroxidase enzymes includes vertebrate, , some anadromous migratory fishes (sea lamprey and sal- algal, fungal, and peroxidases. Some of monids), declining serum concentrations of T4 induce these, known as halo-peroxidases, use halide ions (iodide, metamorphosis [29,30]. After metamorphosis, when these bromide, and chloride) as natural electron donors, and have adult marine fishes die in freshwaters after reproducing, they an antioxidant function in Cyanobacteria [2,7]. Taurog [21] release their iodide, selenium, and PUFAs to the environ- hypothesized that animal and non-animal peroxidases are ment, where they are beneficial for the life and health of na-

Fig. (2). In amphibian metamorphosis, iodides and thyroxine exert a spectacular apoptotic action on the cells of gills, tail, and fins, initiating the transformation of an aquatic tadpole into a “more developed” terrestrial adult frog. 4 Current Chemical Biology, 2011, Vol. 5, No. 3 Sebastiano Venturi tive animals, bringing essential trace elements back upstream iodothyronines are important as antioxidants and inhibitors from the sea to I-deficient inland regions [2,26]. The new of : they were shown to be more effective hormonal action was made possible by the formation of nu- than E, glutathione, and ascorbic acid [27,36]. clear thyroid-hormone receptors (THRs) in the cells of ver- On the other hand, the new terrestrial diet harboured tebrates. About 500 Mya, the primitive THRs with a meta- morphosing action appeared first in marine chordates, and plant iodide-transport inhibitors such as thiocyanates, cy- anates, , and some glycosides. Many plant substances then about 250-200 Mya more recent THRs with metabolic that inhibit iodide transport seem to have activ- and thermogenic actions evolved in birds and mammals. ity. In a previous work, Venturi et al. [2,27] hypothesized THR genes are c-erbA oncogenes, which have been impli- that, contrary to amphibian metamorphosis, thyroidectomy cated as tumor suppressor genes in non-thyroidal and and hypothyroidism in mammals might be considered a sort are altered in some human gastric and mammary cancers [31,32]. The role of iodine in marine and freshwater fishes is of phylogenetic and metabolic regression to a former stage of reptilian life. In fact, many disorders that seem to afflict not yet completely understood, but it has been reported that hypothyroid humans have reptilian-like features such as a I-deficient freshwater fishes suffer higher incidences of in- dry, hairless, scaly, cold and a general slowdown of fective, parasitic, atherosclerotic, and neoplastic diseases metabolism, digestion, heart rate, nervous reflexes with le- than marine fishes. On October 7, 1999, the U.S.A. Commit- thargic cerebration, hyperuricemia, and hypothermia. tee of the House and Senate regarding "Marine Research" reported that "The Committee notes the unusually low inci- ROLE OF IODIDE IN ANIMAL CELLS AND TISSUES dence of cancer in marine sharks, skates, and rays and en- courages basic research through the study of the immune Heyland and Moroz suggested that dietary sources of system of these marine animals and the examination of bio- THs may have been ancestral, while the ability to synthesize active molecules from shark, skate, and ray cells and tissues these hormones endogenously may have evolved independ- that have the potential to inhibit disease processes in hu- ently in a variety of metazoans, resulting in a diversity of mans". In amphibians, environmental iodine is the essential signalling pathways and, possibly, of morphological struc- metamorphic factor, and it stimulates the spectacular apopto- tures involved in TH-signalling [25]. In fact, increasing evi- sis of the cells of larval gills, tail, fins, and some gastro- dence suggesting that THs also function in a variety of inver- intestinal cells, adapting and transforming the aquatic vege- tebrate species are reviewed by Heyland et al. and Eales tarian tadpole into a “more developed” terrestrial carnivorous [24,25]. These researchers propose that the oxidation of io- frog (Fig. 2). In fact, programmed cell death, with nuclear dide to iodine in some marine invertebrates is a critical step changes and removal by phagocytic macrophages, occurs in for scavenging ROS, and that the reaction of iodine with a variety of organs during amphibian metamorphosis, which tyrosine residues removes potentially poisonous iodine from is under the control of T4. Indeed, because of the massive the cells. Berking et al. [37] demonstrated the antioxidant cell death that occurs during a short period, amphibian or- action of iodide and T4 in some marine invertebrates (polyps gans serve as an ideal model system for the study of mecha- of the jellyfish Aurelia aurita). In vertebrates, isolated cells nisms underlying programmed cell death. T4 induces apop- of non-thyroidal I-concentrating tissues, such as gastric mu- tosis of larval cells and differentiation of pepsinogen- cosa, salivary and mammary glands, can produce - producing cells in the of the adult carnivorous form bound mono- and diiodotyrosine as well as some iodolipids of the frog Xenopus laevis [33]. [38]. This pathway for iodine organification involves iodine incorporation into specific lipid molecules such as PUFAs. IODINE IN TERRESTRIAL ORGANISMS Iodolipids have been shown to regulate mammalian cellular metabolism [39]. Recently, several authors reported the ef- Around 300-400 Mya when some living plants and ani- fects of different iodo-components on growth inhibition and mals began to transfer from the sea to rivers and land, environmental I-deficiency was a challenge for the evolution apoptosis in different tumoral cell lines [40,41]. In thyroid cells active iodide transport is facilitated by three transport- of terrestrial life. The terrestrial diet of freshwater fishes, ers: NIS, pendrin, and apical iodide transporter. All three plants and other animals was deficient in many marine transporters are also expressed in I-concentrating extrathy- inorganic antioxidants, including iodine and selenium [27]. roidal tissues [42,43]. Gastric “iodide-pumps” are phyloge- Terrestrial plants slowly optimized the production of novel netically more primitive than the thyroidal ones: they have endogenous organic antioxidants such as ascorbic acid, , , , and , some lower affinity for iodide and do not respond to the more re- cent thyroid stimulating hormone (thyrotropin). Hays and of which became essential “vitamins” in the diet of terrestrial Solomon found that gastro-salivary clearance and secretions animals (vitamins A, E, and in humans ) [2]. of iodides are a considerable part of the “gastro-intestinal According to Coic and Coppenet [34] and Lamand [35], cycle of iodides”, which constitutes about 23% of the iodide iodine and selenium became no longer necessary for many pool in the human body [44]. Mammals, such as cows in plants. In a different way, about 500 Mya, some chordates also began to use the novel “thyroidal” follicles as reservoir their abomasum, have an efficient iodine recycling system via the oral-salivary and gastro-intestinal tract, which con- for iodine and T4 in order to transport antioxidant iodide and serves iodine and can protect them against low dietary iodine triiodothyronine (T3) into the peripheral cells. T3, the [45]. The entero-thyroidal circulation of iodides seems to be biologically active form of T4 in vertebrates, acquired mediated principally by salivary and gastric NIS [46]. In activity in the metamorphosis and thermogenesis processes mammals, dietary iodine is rapidly adsorbed as I- from the that facilitated adaptation to terrestrial freshwaters, 131- atmosphere, gravity, temperature, and diet. Moreover T4, small intestine. The fact that radioiodine I is also detect- able in radioautographies of oral mucosa, elastic arterial reverse-T3, and other iodothyronines are important as Iodine in Evolution Current Chemical Biology, 2011, Vol. 5, No. 3 5 walls (aorta), and epidermal fur of after 14 days strongly Cordain et al. indicated that the significant changes in suggests the formation of as yet unknown structural iodo- diet that began with the introduction of agriculture and ani- compounds, probably iodolipids and iodoproteins [47]. Hu- mal husbandry approximately 10,000 years ago occurred too man salivary glands rapidly take up iodine and secrete it in recently on an evolutionary time scale for the human genome saliva [48]. According to De et al. [49], the salivary glands to adjust [70]. In conjunction with this discordance between and gastric mucosa have high activity for both iodide uptake our ancient, genetically determined biology of hunter- and for peroxidase-catalyzed synthesis of iodo-compounds. gatherer and fish-gatherer human societies and the nutritional On the other hand, the chronically high quantities of iodine- patterns of contemporary Western populations, many of the intake can cause degenerative, necrotic, and neoplastic le- so-called diseases of civilization have emerged. These sions in thyroid gland, and also in stomach and salivary authors suggested that I-deficiency was probably one of sev- glands [50]. Our group studied the toxic effect of excess io- eral dietary variations introduced during the Neolithic and dide in stomach, and Joanta et al. described the daily intake Industrial Periods which have altered crucial nutritional of up to 200 mg iodine per person exert high oxidative stress characteristics of the ancestral human diet. Thus, the evolu- in I-concentrating tissues [51]. Indeed, Contempre et al. [52], tionary collision of our ancient genome with the nutritional Yang et al. [53], and Chen et al. [54] found that an appropri- qualities of recently introduced may underlie many of ate dose of the antioxidant selenium is a beneficial interven- the chronic diseases of Western civilization [71]. In 1883, tion in cases of damage to the thyroid and immune system Kocher observed that , thought to be caused induced by excess of iodide. by ROS, frequently appeared following thyroidectomies, suggesting that hypothyroidism is causally associated with Cunnane suggested that “iodine is the primary brain- atherosclerosis [72]. Between 1930 and 1960, selective in human brain evolution” [55]. Dobson iodide was used empirically in patients with arteriosclerosis suggested that Neanderthal man suffered I-deficiency disor- and cardiovascular diseases by European physicians [73]. ders caused by their inland environment or by a genetic dif- Turner´s group reported efficacy of iodine and desiccated ference of his thyroid compared to that of modern Homo thyroid in prevention of atherosclerosis in [74]. The Sapiens [56]. I-deficient humans like endemic cretins suffer antioxidant action of dietary iodides has also been described physical, neurological, mental, immune, reproductive, and in brain cells of rats as well as in therapy of some human skeletal diseases. Ongoing proximity to riverine, lacustrine, chronic diseases of the cardiovascular, articular, and ocular and maritime diets is crucial for optimal brain development systems [2,75,76]. In addition, iodine also plays an important and function [57-59]. role in antitumor defence of the . Antineoplastic Obendorf et al. [60] and Oxnard et al. [61] hypothesized and apoptotic effects have been observed in both in vivo and that Homo floresiensis, a pygmy-sized, microcephalic in vitro conditions when the cells capable of iodine-uptake hominin who lived from 95,000 to 13,000 years ago on the become cancerous [50,77,78]. In the mammary gland I2, but Indonesian island of Flores, were myxoedematous endemic not iodide, supplementation alleviates human mastalgia and cretins. Their congenital hypothyroidism led to severe dwarf- exerts potent antineoplastic and apoptotic effects on cancer- ism, mental retardation, and reduction of brain size. Indeed ous cells [79-84]. In thyroid gland, I- has an apoptotic effect iodine has favored animal development and evolution of the that is mediated by arachidonic acid or eicosapentaenoic acid nervous system for a better adaptation to the terrestrial envi- derivatives such as 6-iodo-5-hydroxy-8,11,14-eicosatrienoic ronment [2,27,55]. Ullberg and Ewaldsson [62] found high acid (also called 6-iodolactone; 6-IL) or alpha- concentrations of radioiodine in skeletal and articular sys- iodohexadecanal, respectively [84-86]. The formation of tems, indicating the likely anatomical basis of I-deficient these iodolipids requires, in addition to iodide uptake by skeletal and articular deformities and dwarfism. Our group NIS, its oxidation by thyroperoxidase. The oxidized iodine studied cases of cretinism which afflicted about 0.3 % of the intermediate has not been identified, but one of the candi- population of I-deficient Montefeltro (in the central dates is I2 [87]. Aceves et al. have shown that mammary 125 Apennines of Italy) in the 1980’s. In these cretins, our group glands of virgin rats and MNU-induced tumors take up I2 reported a high prevalence of microcephaly, hip dysplasia, by mechanisms independent of NIS or pendrin and that in 125 immune deficiencies, gonarthrosis, and oral and dental pa- the human tumoral cell line MCF-7, I2 is taken up by a thologies. Furthermore, a few years after implementation of facilitated-diffusion system and covalently bound to lipids I-prophylaxis, goiter, immune deficiency, hip dysplasia, and similar to 6-IL in both the presence and absence of peroxi- dental caries in children had disappeared or was greatly de- dase inhibitors, indicating that the oxidized iodine form I2 is creased [48,63-65]. Price, in his famous world investigation, organified in the absence of peroxidases [88]. Moreover, mentioned that fish and seafood contain essential trace ele- data of several groups showed that cancerous and normal ments such as iodine which are very important for the pre- cells exhibit differential I2 sensitivity, and on basis of these vention of health problems, physical degeneration, and tooth data, two hypotheses have been proposed to explain the I2 decay in many coastal populations [66]. Hardgrove [67] effects: a direct action, where the oxidized iodine dissipates stated that in his community (Fond du Lac, Wis. USA), the mitochondrial membrane potential, thereby triggering “since the beginning of administration of iodine to prevent mitochondrion-mediated apoptosis, or an indirect effect goitre, iodine seems to increase resistance to caries, retarding through iodolipid formation [82,84,88,89]. These effects are the process and reducing its incidence”. Bartelstone´s group discussed in detail in the following chapters. [68,69] showed in cats and humans high direct and indirect The US Food and Board and the Institute of penetration of radioiodine in intact dental enamel, dentin, Medicine recommended daily allowance of iodine ranges and pulp and in periodontal tissues. from 150 μg /day for adult humans to 290 μg /day for lactat- 6 Current Chemical Biology, 2011, Vol. 5, No. 3 Sebastiano Venturi ing mothers [90]. However, the thyroid gland needs no more ACKNOWLEGEMENTS: than 70 μg /day to synthesize the requisite daily amounts of The author would like to thank Dr. Carmen Aceves, T4 and T3. These higher recommended daily allowance lev- Centro de Neurobiología, UNAM, Campus Juriquilla, els of iodine seem to be necessary for optimal function of a México and Dr. Michel E. Bégin, Sherbrooke Geriatrics In- number of body systems, including all non-thyroidal I- concentrating organs [2,3]. Based on phylogenesis and em- stitute University, Canada and all reviewers for their help and assistance regarding the editing of this work. bryogenesis, our group [50] hypothesized in previous reports about the importance of non-hormonal iodine and of iodine REFERENCES per se, considering three mechanisms for its action, which [1] Truesdale VW, Luther GW III, Canosa-Mas C. Molecular iodine are all present in the cells of modern vertebrates: reduction in seawater: an improved rate equation considering or- 1. An ancient and direct action on endodermal fore-gut and ganic compounds. Mar Chem 1995; 48:143-50. [2] Venturi S, Venturi M. Evolution of dietary antioxidant defences. stomach and on ectodermal epidermis, where inorganic European Epi-Marker 2007; 11: 1-12 . Available from iodides act as antioxidants. http://www.icb-asbl.com/en/pdf/epimarker/epimarker_3_07. [3] Venturi S, Bégin ME. Thyroid Hormone, Iodine and Human Brain 2. A recent and direct antioxidant/ apoptotic action on nor- Evolution. In: Cunnane S, Stewart K, Eds. Human Brain Evolution, mal and neoplastic cells of different tissues that take up The Influence of Freshwater and Marine Food Resources. Wiley- iodine like thyroid, mammary glands, salivary glands, Blackwell, NJ, 2010, 105-19. ovary, and the nervous, arterial, and skeletal systems. [4] Obinger C, Regelsberger C, Strasser C, Burne,r U, Peschek CA. Purification and characterization of a homodimeric catalase- 3. A more recent indirect action of the thyroid via its iodi- peroxidase from the cyanobacterium Anacystis nidulans. Biochem Biophys Res Comm 1997; 235: 545-52. nated hormones on all vertebrate cells, where they act in [5] Bernroitner M, Zamocky M, Furtmüller PG, Peschek GA, Obinger very small quantities and utilize T3-receptors. Indeed C. Occurrence, phylogeny, structure, and function of catalases and thyroid hormones contain less than 1/30th of total body peroxidases in cyanobacteria. J Exp Bot 2009; 60: 423-40. iodine. [6] Küpper FC, Carpenter LJ, McFiggans GB, et al. Iodide accumula- tion provides kelp with an inorganic antioxidant impacting atmos- In Conclusion pheric chemistry. Proc Natl Acad Sci USA 2008; 105: 6954-8. [7] Pedersén M, Collén J, Abrahamson J, Ekdahl A. Production of Research on the evolutionary significance of iodine has halocarbons from seaweeds: an oxidative stress reaction? Sci. Mar. stimulated our need for knowledge beyond its role in thyroid 1996; 60: 257-63. hormones. The actions of iodine seem much more complex, [8] Packer L. Health Benefits of Natural Antioxidants from Herbs: Molecular Mechanisms of Action. Lecture in the XIV Biennial and we hope to have enlightened a few of these: its role as Meeting of the Society for Free Radical Research Internat. Oct. 18- antioxidant and apoptosis-inductor and its possible anti- 22, 2008. Beijing, China. tumoral and anti-atherosclerotic activities. We should point http://www.monduzzi.com/proceedings/moreinfo/20081018.htm out that extrathyroidal actions of iodide might be an impor- [9] Bjelakovic G, Gluud LL, Nikolova D, Bjelakovic M, Nagorni A, Gluud C. Meta-analysis: antioxidant supplements for diseases tant new area for investigation. Studies of molecular evolu- - The Cochrane Hepato-Biliary Group. Aliment Pharmacol Ther tion of this trace element provide the basis for further studies 2010; 32: 356-67 about many pathologies. [10] Tsubono Y, Otani T, Kobayashi M, Yamamoto S, Sobue T, Tsu- gane S. JPHC Study Group. No association between fruit or vege- table consumption and the risk of in Japan. Br J ABBREViATIONS Cancer 2005; 92: 1782-4. (I-) = Iodide [11] Boffetta P, Couto E, Wichmann J, et al. Fruit and vegetable intake and overall cancer risk in the European Prospective Investigation (ROS) = Radical oxygen species into Cancer and Nutrition (EPIC). J Natl Cancer Inst 2010; 102: 529-37 (PUFAs) = Polyunsaturated fatty acids [12] Dunn JT, Delange F. Damaged reproduction: the most important consequence of . J Clin Endocrinol Metab 2001; (I2) = Molecular iodine 8: 2360-3. [13] Gottardi W. Iodine and iodine compounds. In: Block SS. Disinfec- (I3) = Triiodide tion, Sterilization, and Preservation. Lippincott Williams & Wil- kins, Philadelphia, 1991; 152-66. (HIO) = Hypoiodous acid [14] Canfield DE. The early history of atmospheric oxygen: Hommage - to Robert M. Garrels. Ann Rev Earth Planet Sci 2005; 33: 1-36. (OI ) = Hypoiodite ion [15] Benzie IF. Evolution of dietary antioxidants. Comp Biochem - Physiol A Mol Integr Physiol 2003; 136: 113-26. (HI2O ) = Iodine anion [16] Colin C, Leblanc C, Wagner E, et al. The brown algal kelp Lami- naria digitata features distinct bromoperoxidase and iodoperoxidase (Mya) = Million years ago activities. J Biol Chem 2003; 278: 23545-52. (THs) = Thyroid hormones [17] Carpenter LJ, Sturges WT, Liss PS, et al. Short-lived alkyl iodides and bromides at Mace Head: links to macroalgal emission and (THRs) = Thyroid-hormone receptors halogen oxide formation. J Geophys Res 1999; 104: 1679-89. [18] Soriguer F, Gutiérrez-Repiso C, Rubio-Martin E, et al. Iodine (T4) = Thyroxine intakes of 100-300 μg/d do not modify thyroid function and have modest anti-inflammatory effects. Br J Nutr. 2011; 25: 1-8. (T3) = Triiodothyronine [19] Wolff J. Transport of iodide and other anions in the thyroid gland. Physiol Rev 1964; 44: 45-90. (6-IL) = 6-iodo-5-hydroxy-8,11,14-eicosatrienoic [20] Zamocky M, Furtmüller PG, Obinger C. Evolution of structure and Acid or 6-iodolactone function of Class I peroxidases. Arch Biochem Biophys 2010, 500: 45-57. Iodine in Evolution Current Chemical Biology, 2011, Vol. 5, No. 3 7

[21] Taurog, A. Molecular evolution of thyroid peroxidase. Biochimie apical membrane of thyrocytes. J Clin Endocrinol. Metab 2002; 87: 1999; 81: 557-62. 3500-03. [22] Roche J. Biochimie comparée des scléroprotéines iodées des Ant- [44] Hays MT, Solomom DH. Influence of the gastrointestinal iodide hozoaires et des Spongiaires. Experientia 1952; 8: 45-56. cycle on the early distribution of radioactive Iodide in man. J Clin [23] Chino Y, Saito M, Yamasu K, Suyemitsu T, Ishihara K. Formation Invest. 1965; 44: 117-27. of the adult rudiment of sea-urchins is influenced by thyroid hor- [45] Miller JK, Swanson .W, Spalding GE. Iodine absorption, excretion, mones. Dev Biol 1994; 161: 1-11. recycling, and tissue distribution in the dairy cow. J Dairy Sci. [24] Heyland A, Price DA, Bodnarova-Buganova, M, Moroz LL. Thy- 1975; 58: 1578-93. roid hormone metabolism and peroxidase function in two non- [46] Josefsson M, Ekblad E. Sodium Iodide Symporter (NIS) in Gastric chordate animals. J Exp Zoolog B Mol Dev Evol 2006; 306: 551- Mucosa: Gastric Iodide Secretion. In: Preedy VR, Burrow GN, 66. Watson R, Eds. Comprehensive Handbook of Iodine: Nutritional, [25] Heyland A, Moroz LL. Cross-kingdom hormonal signaling: an Biochemical, Pathological and Therapeutic Aspects. Elsevier Inc. insight from thyroid hormone functions in marine larvae. J Exp Oxford, 2009; 215-20 Biol 2006; 208: 4355-61. [47] Pellerin, P. La technique d’autoradiographie anatomique à la tem- [26] Eales JG. Iodine metabolism and thyroid-related functions in or- pérature de l’azote liquide. Path. Biol 1961; 9: 233–52. ganisms lacking thyroid follicles: are thyroid hormones also vita- [48] Venturi S, Venturi M. Iodine in evolution of salivary glands and in mins? Proc Soc Exp Biol Med 1997; 214: 302-17. oral health. Nutr Health 2009; 20: 119-34. [27] Venturi S, Donati FM, Venturi A, Venturi M. Environmental io- [49] De SK, Ganguly CK, Chakraborty TK, Bose AK, Banerjee RK. dine deficiency: A challenge to the evolution of terrestrial life? Endocrine control of extrathyroidal peroxidases and iodide metabo- Thyroid 2000; 10: 727-9. lism. Acta Endocrinol. 1985; 110: 383-7. [28] Venturi S, Venturi M. Iodide, thyroid and stomach carcinogenesis: [50] Venturi, S.; Donati. F.M.; Venturi, A.; Venturi, M.; Grossi, L.; Evolutionary story of a primitive antioxidant? Eur J Endocrinol Guidi, A. Role of iodine in evolution and carcinogenesis of thyroid, 1999; 140: 371-2. breast and stomach. Adv. Clin. Path. 2000, 4:11-7. [29] Youson JH, Sower SA. Theory on the evolutionary history of lam- [51] Joanta AE, Filip A, Clichici S, Andrei S, Daicoviciu D. Iodide prey metamorphosis: role of reproductive and thyroid axes. Comp excess exerts oxidative stress in some target tissues of the thyroid Biochem Physiol B Biochem Mol Biol 2001; 129: 337-45. hormones. Acta Physiol Hung 2006; 93: 347-59. [30] Manzon RG, Youson JH. The effects of exogenous thyroxine (T4) [52] Contempre B, Denef JF, Dumont JE, Many MC. Selenium defi- or triiodothyronine (T3), in the presence and absence of potassium ciency aggravates the necrotizing effects of a high iodide dose in perchlorate, on the incidence of metamorphosis and on serum T4 iodine deficient rats. Endocrinolology 1993; 132: 1866-8. and T3 concentrations in larval sea lampreys (Petromyzon marinus [53] Yang XF, Hou XH, Xu J, et al. Effect of selenium supplementation L.). Gen Comp Endocrinol 1997; 106211-20. on activity and mRNA expression of type 1 deiodinase in mice [31] Wang CS, Lin KH, Hsu YC. Alterations of thyroid hormone recep- with excessive iodine intake. Biomed Environ Sci. 2006; 19: 302-8. tor alpha gene: frequency and association with Nm23 protein ex- [54] Chen X, Liu L, Yao P, Hao L, Sun X. Effect of excessive iodine on pression and metastasis in gastric cancer. Cancer Lett 2002; 175: immune function of lymphocytes and intervention with selenium. J 121-7. Huazhong Univ. Sci Technolog. Med. Sci. 2007, 27(4):422-5. [32] Li Z, Meng ZH, Chandrasekaran R, et al. Biallelic inactivation of [55] Cunnane S. Brain-Selective . In: Cunnane S, Stewart K, the thyroid hormone receptor beta1 gene in early stage breast can- Eds. Human Brain Evolution, The Influence of Freshwater and Ma- cer. Cancer Res 2002; 62: 1939-43. rine Food Resources, Wiley-Blackwell , NJ, 2010: 33-61. [33] Ikuzawa M, Kobayashi K, Yasumasu S, Iuchi I. Expression of [56] Dobson JE The iodine factor in health and evolution. The Geo- CCAAT/enhancer binding protein delta is closely associated with graphical Review 1998; 88: 1-28. degeneration of surface mucous cells of larval stomach during the [57] Cabello G, Vilaxa A, Spotorno AE, et al. Evolutionary adaptation metamorphosis of Xenopus laevis. Comp Biochem Physiol Bio- of a mammalian species to an environment severely depleted of io- chem Mol Biol 2005; 140: 505-11. dide. Pflugers Arch 2003; 446: 42-5. [34] Coic Y, Coppenet M. Les oligo-éléments en agriculture et élevage. [58] Broadhurst CL, Wang Y, Crawford MA, Cunnane SC, Parkington INRA Publications 1990, Versailles, FR. JE, Schmidt WF. Brain-specific lipids from marine, lacustrine, or [35] Lamand M. Les oligo-éléments dans la Biosphère. In: Chappuis P, terrestrial food resources: potential impact on early African Homo Ed. Les oligo-éléments en médicine et biologie. Lavoisier, Paris, sapiens. Comp Biochem Physiol B Biochem Mol Biol 2002; 131: 1991. 653-73. [36] Oziol L, Faure P, Vergely C, et al. In vitro free radical scavenging [59] Crawford ME. Long-chain polyunsaturated fatty acids in human capacity of thyroid hormones and structural analogues. J Endocri- brain evolution. In: Cunnane S, Stewart K. Eds. Human Brain Evo- nol 2001; 170: 197-206. lution, The Influence of Freshwater and Marine Food Resources, [37] Berking S, Czech N, Gerharz M, Herrmann K, et al. A newly dis- Wiley-Blackwell, NJ, 2010: 13-28. covered oxidant defence system and its involvement in the devel- [60] Obendorf PJ, Oxnard CE, Kefford BJ. Are the small human-like opment of Aurelia aurita (Scyphozoa, Cnidaria): reactive oxygen fossils found on Flores human endemic cretins? Proc Biol Sci species and elemental iodine control medusa formation. Int J Dev 2008; 275: 1287-96. Biol 2005; 49: 969-76. [61] Oxnard C, Obendorf PJ, Kefford BJ. Post-cranial skeletons of [38] Banerjee RK, Bose AK, Chakraborty TK, De SK, Datta AG. Per- hypothyroid cretins show a similar anatomical mosaic as Homo flo- oxidase-catalysed iodotyrosine formation in dispersed cells of resiensis. PLoS One 2010; 5: 3018. mouse extrathyroidal tissues. J Endocrinol 1985; 106: 159-65. [62] Ullberg S, Ewaldsson B. Distribution of radio-iodine studied by [39] Pisarev MA, Gartner R. Autoregulatory actions of iodine. In: Uti- whole-body autoradiography. Acta Radiol Ther Physics Biol; 1964; ger R Werner & Ingbar's The Thryroid: A fundamental and clinical 2, 24–32. text. Philadelphia: Lippincott Williams & Wilkins; 2000; 85-90. [63] Venturi S. Studio delle tireopatie nell'Alta Valmarecchia e loro [40] Dugrillon A. Iodolactones and iodoaldehydes mediators of iodine profilassi. Ed. Botticelli, Regione Marche. Novafeltria (PU), 1978. in thyroid autoregulation. Exp Clin Endocrinol Diabet 1996; 104: [64] Donati L, Antonelli A, Venturi S, Baschieri L. Clinical picture of 41-5. endemic cretinism in central Apennines (Montefeltro). Thyroid [41] Aceves C, Anguiano B, Delgado G. Is iodine a gatekeeper of the 1992; 2: 283-9. integrity of the mammary gland? J Mammary Gland Biol Neopl [65] Venturi S, Venturi M. Iodine, thymus, and immunity. Nutrition. 2005; 10: 189-96. 2009; 25: 977-979. [42] Dohan O, De la Vieja A, Paroder V, Riedel C, Artani M, Reed M, [66] Price WA. Nutrition and Physical Degeneration: A comparison of Ginter CS, Carrasco N. The sodium/iodide Symporter (NIS): char- primitive and modern diets and their effects. 6th edition, Price- acterization, regulation, and medical significance. Endocr Rev 2003 Pottenger Nutrition Foundation. 1939; 1: 48-77. http://gutenberg.net.au/ebooks02/0200251h.html [43] Rodriguez AM, Perron B, Lacroix l, et al. Identification and char- [67] Hardgrove TA, Dental Caries. In: Lynch, Kettering, Gies, Eds. acterization of a putative human iodide transporter located at the American Dental Association (ADA booklet). 1939. 8 Current Chemical Biology, 2011, Vol. 5, No. 3 Sebastiano Venturi

[68] Bartelstone HJ. In vivo Study of the Uptake of Radioactive Iodine [81] Ghent WR, Eskin BA, Low DA, Hill LP. Iodine replacement in by Human Teeth (II). J Dent Res 1950; 29: 684-6. fibrocystic disease of the breast. Cancer J Surg 1993; 36: 453-60. [69] Bartelstone H J. Radioiodine penetration through intact enamel [82] Kessler JH. The effect of supraphysiological levels of iodine on with uptake by bloodstream and thyroid gland. J Dent Res 1951; 5: patients with cyclic mastaglia. The Breast J 2004; 10: 328-36 728-33. [83] Shrivastava A, Tiwari M, Sinha RA, et al. Molecular iodine in- [70] Cordain L, Eaton SB, Sebastian A, et al. Origins and evolution of duces caspase-independent apoptosis in human various human car- the Western diet: health implications for the 21st century. Am J cinoma cell lines. No interfering with EGF-signaling, but evidence Clin Nutr 2005; 81: 341-54. for apoptosis. Exp Clin Endocrinol Diab 2009; 118: 410-19 [71] Yun AJ, Lee PY, Bazar KA, Daniel SM, Doux JD. The incorpora- [84] Arroyo-Helguera O, Rojas E, Delgado G, Aceves C. Signalling tion of iodine in thyroid hormone may stem from its role as a pre- pathways involved in the antiproliferative effect of molecular io- historic signal of ecologic opportunity: an evolutionary perspective dine in normal and tumoral breast cells: evidence that 6- and implications for modern diseases. Med Hypotheses 2005; 65: iodolactone mediates apoptotic effects. Endocr Relat Cancer 2008; 804-10. 15: 1003-11. [72] Kocher T. Uber Kropf exstirpation und ihre Folgen. Arch Klin Chir [85] Thomasz L, Oglio R, Dagrosa MA, Krawiec L, Pisarev MA, Juve- 1883; 29: 254-337. nal GJ. 6 Iodo-delta-lactone reproduces many but not all the effects [73] Cann SA. Hypothesis: dietary iodine intake in the etiology of car- of iodide. Mol Cell Endocrinol. 2010; 323: 161-6 diovascular disease. J Am Coll Nutr 2006; 25: 1-11. [86] Gärtner R, Rank P, Ander B. The role of iodine and delta- [74] Turner KB. Studies on the prevention of cholesterol atherosclerosis iodolactone in growth and apoptosis of malignant thyroid epithelial in rabbits. The effects of whole thyroid and of potassium iodide. J cells and breast cancer cells. Hormones 2010; 9: 60-6. Exp Med 1933; 58: 115-25. [87] Smyth PP. The thyroid, iodine and breast cancer. Breast Cancer [75] Katamine S, Hoshino N, Totsuka K, Suzuki M. Effects of the long- Res 2003; 5: 235-238. term feeding of high-iodine eggs on and thyroid [88] Aceves C, García-Solís P, Arroyo-Helguera O, Vega-Riveroll L, function in rats. J Nutr Sci Vitaminol 1985; 31: 339-45. Delgado G, Anguiano B. Antineoplastic effect of iodine in mam- [76] Rieger G, Klieber M, Schimetta W, et al. The effect of iodide ion- mary cancer. Participation of 6-iodolactone (6-IL) and peroxisome tophoresis on the antioxidative capacity of the tear fluid. Graefes breast carcinoma cells involving the mitochondria-mediated path- Arch Clin Exp Ophthalmol 2010; 248: 1639-46. way. J Biol Chem. 2006; 281: 19762-71. [77] Eskin BA. Iodine and mammary cancer. Adv Exp Med Biol 1977; [89] Rosner H, Torremante P, Moller W, Gärtner R. Antiprolifera- 91: 293-304. tive/cytotoxic activity of molecular iodine and iodolactones in pro- [78] Venturi, S. Is there a role for iodine in breast diseases? The Breast liferator-activated receptors (PPAR). Molecular Cancer 2009; 8: 2001; 10: 379-82. 33-6. [79] Cann SA Van Netten, JP, Van Netten C. Hypothesis: iodine, sele- [90] Food and Nutrition Board. Institute of Medicine. Dietary Reference nium and the development of breast cancer. Cancer Caus Ctrol Intakes for , , Arsenic, Boron, , 2000; 11: 121-7. Copper, Iodine, Iron, , Molybdenum, Nickel, Silicon, [80] Funahashi H, Imai T, Mase T, et al. Seaweed prevents breast can- Vanadium, and Zinc. National Academy Press, Washington DC, cer? Jpn. J Cancer Res 2001; 92: 483-7. 2001: 258-89.

Received: 00 00, 2011 Revised: 00 00, 2011 Accepted: 00 00, 2011