Cretinism

Biofortification of staple food crops with micronutrients by either breeding for higher uptake efficiency or fertilization can be an effective strategy to address widespread dietary deficiency in human populations. Selenium and iodine deficiencies affect a large proportion of the population in countries targeted for biofortification of staple crops with Zn, Fe, and vitamin A, and inclusion of Se and I would be likely to enhance the success of these programs. Interactions between Se and I in the thyroid gland are well established. Moreover, Se appears to have a normalizing effect on certain nutrients in the body. For example, it increases the concentration of Zn and Fe at key sites such as erythrocytes when these elements are deficient, and reduces potentially harmful high Fe concentration in the liver during infection. An important mechanism in Se/Zn interaction is selenoenzyme regulation of Zn delivery from metallothionein to Zn enzymes. More research is needed to determine whether sufficient genetic variability exists within staple crops to enable selection for Se and I uptake efficiency. In addition, bioavailability trials with animals and humans are needed, using varying dietary concentrations of Se, I, Zn, Fe, and vitamin A to elucidate important interactions in order to optimize delivery in biofortification programs.

Key words: biofortification, crops, selenium, iodine, zinc, iron, vitamin A

© 2004 International Life Sciences Institute

doi: 10.1301/nr.2004.jun.247-252

Introduction

Micronutrient deficiency is widespread. More than 2 billion people consume diets that are less diverse than 30 years ago, leading to deficiencies in micronutrients, especially iron (Fe), zinc (Zn), iodine (I), selenium (Se), and vitamin A. These deficiencies increase the risk of severe disease in approximately 40% of the world's population.1 Se, Fe, Zn, and vitamins A, B, and C have immunomodulating functions and thus influence the susceptibility of a host to infectious diseases and their courses and outcomes.2,3

Diets dominated by cereals tend to lack micronutrients. Dietary diversity is desirable but may not be achievable in many countries until the population declines. In the meantime, a major effort is required to improve the micronutrient content of cereals and other staple foods to maximize impact on the lowest economic strata in societies. Programs that include fortification, education, and supplementation have been successful in countering micronutrient deficiencies in certain cases and will continue to play a role. However, they tend to be expensive, require ongoing inputs, and often fail to reach all individuals at risk. Furthermore, such programs themselves are at risk of economic, political, and logistical challenges.4,5

A strategy that exploits genetic variability to breed staple crops with enhanced ability to fortify themselves with micronutrients (genetic biofortification) offers a sustainable, cost-effective alternative, which is more likely to reach those most in need; such a strategy has the added advantages of requiring no change in current consumer behavior to be effective and being able to be transported to many countries. Substantial variations in Zn, Fe, manganese (Mn), and copper (Cu) density in wheat varieties grown together have been demonstrated. Exploiting the genetic variability in crop plants for micronutrient density may be an effective method to improve the nutrition of entire human populations.1

Fertilization (by addition to soil, seed, or leaves) to improve micronutrient concentration in crops (agronomic biofortification) can be an effective alternative6 for micronutrients, including Se and I, that are relatively mobile in plants and for which substantial genetic variation in uptake efficiency in staple crops has not yet been demonstrated.7-10 Wheat grain Se concentration, for example, can be increased inexpensively more than 100-fold on a Se-deficient soil by soil amendment.10,11

Crops biofortified with Fe, Zn, and pro-vitamin A carotenoids are proposed for Southeast Asia and Africa in the HarvestPlus program.12 We argue that inclusion of Se and I in this program is likely to be beneficial for several reasons. First, deficiencies of Se and I affect at least 20% of the world's population13,14 with a higher prevalence in those countries targeted by the biofortification program. Because of beneficial interactions (to be discussed below), the benefits of Fe, Zn, and vitamin A fortification are unlikely to be maximized in many countries without the inclusion of Se and I. In addition, fortification or supplementation with one or two nutrients in the presence of deficiencies of others may even intensify existing morbidity.15

Moreover, low dietary micronutrient intakes are not confined to developing nations. The food systems of developed countries also often fail to provide optimum nutrition. For example, New Zealand's low Se supply affects high-risk groups like the aged,16 and a recent Australian study found that 76% of schoolchildren surveyed in Melbourne had below-normal I status, with 27% suffering moderate-to-severe deficiency.17

In this paper, we discuss briefly the importance of Se and I to human health; examine Se and I interactions, with a focus on thyroid hormone metabolism; document evidence of interactions between Se and I and between Zn, Fe, and vitamin A, particularly in terms of enhancing nutritional bioavailability; and suggest research priorities to address knowledge gaps in this area.

Selenium in Human Health

Selenium is an essential micronutrient for humans and animals; it is an integral component of at least three systems required for normal cell metabolism.18 It has been suggested that approximately 100 selenoproteins may exist in mammalian systems.19 As a key component of the iodothyronine deiodinase enzymes, Se has an important role in the thyroid, and hence also in hepatic enzyme expression and neutrophil function.20 The glutathione peroxidases have an antioxidant role in reducing damaging hydrogen peroxide and lipid or phospholipid hydroperoxides that are produced in eicosanoid synthesis by the lipoxygenase and cyclo-oxygenase pathways.21 Another group of selenoenzymes, the thioredoxin reductases, are involved in the reduction of nucleotides in DNA synthesis, the regeneration of antioxidant systems, and the maintenance of cellular redox state.22

It is well established that dietary Se is important for a healthy immune response. The effects of Se deficiency can include reduced T-cell counts and impaired neutrophil, macrophage, and polymorphonuclear leukocyte activity.23-25 Se supplementation of even Se-replete individuals is immunostimulatory, and enhances natural-killer-cell activity, lymphocyte activity, and proliferation of activated T-cells.25

Mounting evidence suggests that chronic marginal Se intake increases susceptibility to viral infection and viral disease sequelae, cancer, cardiovascular diseases, thyroid dysfunction, and various inflammatory conditions.11,26 Selenium's anti-viral activity is of particular interest, given the high global prevalence of severe viral infections, including HIV/AIDS, influenza, hepatitis B, and hepatitis C. In a Se-deficient host, the benign coxsackie virus becomes cardiomyopathic, influenza viruses cause more serious lung pathology,27 and HIV infection progresses more rapidly to AIDS.28 It has been suggested that Se deficiency, due to widespread low soil levels, is the main reason for the much faster spread of AIDS in Sub-Saharan Africa than in North America.29

Available Se concentration in soil is highly variable, and low-Se soils are common in New Zealand, Denmark, Eastern Europe, United Kingdom, central Siberia, and a belt from north-east to south-central China. Large areas of Africa and Southeast Asia are also likely to be Se-deficient, but more mapping is required. It is estimated that approximately one billion people are Se-deficient.13

A practical strategy to alleviate Se deficiency is agronomic biofortification of food crops with sodium selenate, which is highly mobile in plants and in many soil types. Moreover, a high proportion of applied Se is incorporated into the sulfur amino acid, methionine, in cereal grain. Selenomethionine is a desirable, highly bioavailable Se form for humans.11

Iodine in Human Health

Iodine is an essential micronutrient involved in growth, development, and metabolic regulation, through its role as a component of thyroid hormones. Severe I deficiency is associated with goiter and retardation of growth and maturation in most organ systems. Intellectual retardation, hearing impairment, lassitude, and cretinism are common; indeed, I deficiency is the world's most prevalent cause of brain damage. Pregnant women and infants are at particular risk of I deficiency diseases (IDD).30,31

In areas of high rainfall and ancient soils I has usually been leached to low levels. Mountainous regions of Asia (including much of China) and the food production flood plains of Nepal, India, Bangladesh, Myanmar, Papua New Guinea, the Philippines, and parts of Indonesia are regions where I deficiency is endemic.32 It is estimated that more than 1.5 billion people are at risk of IDD.30

Developed countries are also affected by I deficiency. A German study found that 20% of pregnant women surveyed in Berlin were suffering from I deficiency,33 and recent surveys in Australia have provided evidence of I deficiency. A study in Sydney found 20% of pregnant women attending an obstetric clinic, and 34% of people attending a diabetes clinic, had moderate-to-severe I deficiency.34 A Melbourne survey of school-children (n = 577, years 5-12 at two private schools) found that 76% of children had below-normal I status. Girls had a mean urinary I concentration of 64 µg/L, and boys had a mean urinary I concentration of 82 µg/L (>100 normal; 50-99 mild deficiency;

Iodine supplementation, usually through iodized salt, has been effective at relieving IDD, but requires sustained inputs and, in many cases, has not succeeded in the long term. In Ethiopia, for example, iodized salt is not reaching the neediest people because it is more expensive than ordinary salt, there is a lack of knowledge of I deficiency among government officials, and distribution has been disrupted by war.35

An iodized salt program was also unsuccessful in Xingjian province, China, for cultural and infrastructural reasons. But when potassium iodate was added to irrigation water (10 kg in a single treatment), the I content of all irrigated foods and foodstuffs increased, which substantially increased the I status of livestock and people for at least 2 years. Infant mortality declined by 50% and IDD were largely eliminated.9 This program is a successful example of agronomic biofortification by fertigation.

Selenium-Iodine Interaction

Selenium and I interactions in the body mostly concern thyroid hormones. Both Se and I are required for thyroid hormone synthesis, activation, and metabolism, and the thyroid gland has the highest Se and I concentrations of all organs.36 The Se-dependent iodothyronine deiodinase enzymes catalyze the production of active thyroid hormone, tri-iodothyronine (T3) from thyroxine (T4) and also control reversion of T3 to di-iodothyronine (T2). There are three types of iodothyronine deiodinases that function in specific tissues such as liver and brain to maintain plasma and organ thyroid hormone homeostasis.20

Goiter is not necessarily due to I deficiency alone, as shown by nodular goiter, which is relatively common in I-replete populations.37 Selenium can inhibit goitrogenesis when I status is marginal or deficient. Children with goiter in south-eastern Poland had lower blood Se and glutathione peroxidase activity, but were similar to controls in T4 and TSH levels.38 In Turkey, I-deficient goitrous children had lower blood Se levels and higher DNA base lesions than non-goitrous controls.39 In a French survey, investigators observed a protective effeet of Se against goiter and thyroid tissue damage in women.40

In addition, free radical damage and fibrosis caused by Se deficiency, together with I deficiency (which can be exacerbated by consumption of goitrogenic thiocyanates from cassava), are involved in the pathogenesis of myxoedematous cretinism.15,41,42 In the rarer case of I excess, the antioxidative Se-dependent glutathione peroxidases protect the thyroid gland from oxidative damage due to excessive iodide exposure.43

Severe deficiency of both I and Se occurs in parts of central Africa15 and Asia, in a region extending from north-eastern China and adjoining areas of Siberia and Korea to south-western China, including Tibet. In this part of Asia, Kaschin-Beck disease, an osteoarthropathy involving enlarged joints, shortened fingers and toes, and even dwarfism, is prevalent. Selenium, I, and vitamin E deficiencies appear to be predisposing factors.44-46

Caution is recommended for Se supplementation in areas of concurrent I and Se deficiency. Several studies have shown that normalization of I intake is necessary before initiation of Se supplementation in order to avoid exacerbation of hypothyroidism by stimulation of thyroxine metabolism.15,43,47

Selenium Interactions with Zinc and Iron

Evidence is accumulating for important interactions of Se with Zn and Fe. Animal studies have shown that Zn can increase Se concentration in various organs, including brain, spleen, kidney, liver, lung, and heart,48 and Se can increase Zn concentration in liver, small intestine, blood, kidney, spleen, brain, and lung.48,49 Conversely, Se deficiency was found to increase Zn concentration in heart and kidney in a rat model.50

Se/Zn interaction involves a link between cellular Zn and redox state. Se compounds regulate Zn delivery from metallothionein to Zn enzymes. The metallothionein/thionein couple safeguards Zn and controls the concentration of available Zn in the cell.51 Moreover, Se, Zn, and Cu are linked in cytosolic defense against reactive oxygen and nitrogen species. Copper, Zn-superoxide dismutase catalyzes the conversion of superoxide to oxygen and hydrogen peroxide, which is then reduced to water and oxygen by glutathione peroxidase,52 the gene expression of which can be up-regulated by Zn.53

An intriguing role for Se in regulating or normalizing the levels of other mineral nutrients at key sites in the body has been suggested by several studies. A clinical trial in Serbia included participants who were moderately deficient at baseline in Se, Zn, Fe, and Cu, while Mn status was higher than normal. Those who consumed Se-enriched wheat during the trial had increased concentrations of Zn, Fe, and Cu in erythrocytes, while Mn concentration declined in both plasma and erythrocytes.54 Furthermore, interaction between Se and Fe was apparent in a trial with Schistosoma-infected mice, in which supplemented Se lowered abnormally high liver Fe concentration.55 In addition, in rat models, Se deficiency increased Fe concentration in the kidney, heart, and liver.50 and Fe deficiency decreased Se concentrations and glutathione peroxidase activity in erythrocytes and liver.56 Lower serum Se levels were observed in children with Fe deficiency anemia, but Se was normalized after Fe supplementation.57 Further studies are needed to determine to what extent Se affects the absorption, distribution, and retention of Zn, Fe, Cu, and Mn. Deeper understanding of beneficial interactions between these nutrients could lead to their exploitation to improve the efficiency and effectiveness of supplementation, fortification, and biofortification programs.

Iodine Interactions with Iron, Zinc, and Vitamin A

Evidence also exists for I interactions with Zn, Fe, and vitamin A. I, Se, Zn, and Fe are essential for normal thyroid hormone metabolism. Iron deficiency inhibits thyroid hormone synthesis by reducing the activity of heme-dependent thyroid peroxidase, while Fe-deficiency anemia reduces, and Fe supplementation enhances, the effectiveness of I supplementation.43

Several studies have suggested that Zn is necessary for normal thyroid function. A study in Turkey found that concurrent deficiencies of Zn and I were associated with endemic goiter in males, and Zn deficiency may contribute to hypothyroidism and goitre.58 In people with hypothyroidism in China, erythrocyte Zn was correlated with T3/T4 ratio and TSH;59 in a rat model, serum T3 was lower in Zn-deficient animals, and Zn deficiency appeared to induce apoptosis in thyroid cells.60 Zinc is involved in the binding of T2 to its nuclear receptor.61 Moreover, Zn and Se tend to be lower in thyroid cancer cells than in normal thyroid cells.62

As noted above, the pathogenesis of goiter is generally multifactorial. On the Croatian island of Krk, goiter prevalence of 30% was found in a sample of 1975 schoolchildren. It was associated with low plasma levels of vitamins A and E and low I intake.63 Vitamin A may stimulate the sodium/iodide symporter (NIS). For example, decreased uptake of iodide by the thyroid, due to impaired expression and/or function of the NIS, is a problem with radioiodide therapy of advanced thyroid cancer; however, retinoids (vitamin A derivatives) stimulate NIS mRNA expression and iodide uptake in human thyroid cancer cells.64

Conclusion

Selenium and I deficiencies affect a large proportion of the population in countries targeted for biofortification of staple crops with Zn, Fe, and vitamin A. Mounting evidence of important beneficial interactions between all of these micronutrients suggests that the inclusion of Se and I in HarvestPlus would be likely to enhance the program's effectiveness.

Interactions between Se and I in the thyroid gland are well established. Few studies have been conducted on interactions among Se, I, Zn, Fe, and vitamin A, especially those that have an impact on the bioavailability of Fe and Zn in cereals, such as the selenoenzymes that regulate Zn delivery from metallothionein to Zn enzymes. In addition, Se appears to have a normalizing effect on certain other nutrients at important sites in the body.

There is an urgent need for investigation into the extent of variability within staple crops for uptake and grain loading efficiency of both Se and I. Further bioavailability studies are also needed, using varying dietary concentrations of Se, I, Zn, Fe, and vitamin A in animal and human trials in order to elucidate important interactions, and to optimize delivery of these nutrients to alleviate malnutrition. It is critical that in these studies, subjects are at least mildly deficient in combinations of these nutrients.

Attention to the role of agronomy in enhancing the concentrations of Se, I, and Zn can deliver more of these nutrients faster to populations and allow breeders to concentrate on Fe and carotenoids, where fertilizers are ineffective.

Acknowledgment

The authors gratefully acknowledge the advice and assistance provided by Professor Ross Welch, Cornell University, USA, and Margaret Cargill, University of Adelaide, Australia.

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Graham H. Lyons, B.Agric.Sci., M.P.H., James C.R. Stangoulis, B.Agric.Sci., Ph.D., and Robin D. Graham, Ph.D., D.Agric.Sci.

Mr. Lyons and Drs. Stangoulis and Graham are with the School of Agriculture and Wine, University of Adelaide, Waite Campus, Urrbrae, South Australia 5064, Australia.

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