Zinc and Immunocompetence

The discovery that zinc deficiency is known to decrease immunity and to produce thymic involution and loss of T-cell function in animal studies,^36-38 provided basis for further interest of the action of zinc on immunity.^4,16,39,40 It is now known, that zinc acts as a mitogen for human lymphocytes in both animals and humans.^41-46 It has been also established that zinc stimulation of lymphocytes in vitro can be used to assess patients’ proliferative capacity in various clinical settings.⁴⁷ This process of lymphocyte transformation initated by zinc, appears to require binding of a Zn-transferring complex, acting both pharmacologically and physiologically on the lymphoid system.¹⁶ Research has also found, when peripheral blood mononuclear cells were studied in vitro, that zinc deficiency leads to decreased percentages of T-lymphocytes, increased percentages of T-suppressor cells, and to deficient responses to mitogens.^48,49 Other experimental studies on human volunteers have found zinc deficiency leading to a depressed NK-cells activity, with a similar decline in cytoxic function.^50,51 Conversely, zinc has been found to activate NK cells in vitro.⁵² Although virtually all the data on zinc interaction with immune system have focused on T-cells, findings indicate that B-cells can also be affected, as zinc has been shown to act synergistically with B-cell mitogens, thus producing a greatly enhanced response.^46,53 Since the immune system develops during gestation, maternal zinc deprivation has been studied in mice. The results showed that the offspring born to zinc deficient dams had a greatly reduced immunocompetence, the lymphoid organs being particularly affected.⁵⁴ The following study by the same authors found that this diminished immunocompetence can persist as long as for three generations of normally fed offspring.⁵⁵ Further studies showed that if the offspring were only moderately deprived of zinc, during the latter two-thirds of pergnancy, even this can lead to long-lasting, aberrant patterns of serum IgG and IgA levels, despite a complete nutritional rehabilitation beginning at birth.⁵⁶ The authors concluded that an optimal dietary zinc is essential during both pregnancy and lactation to ensure the development of an intact immune system in the offspring. Furthermore, that lack of adequate dietary zinc during these critical periods in the fetal development, can lead to a marked long-term immunodeficiency, that may persist for generations to come.⁵⁶

Zinc and Brain

Numerous studies have shown that zinc is one of the most prevalent trace elements found in the brain, where it is primarily retained in the hippocampus .^28-31,57 In fact, levels of zinc in the hippocampal area are greater than those of any other element, including calcium or iron.^58,59 Much of the zinc in the hippocampal area is associated with the axons of the mossy fibres projecting from the granule cells in the fascia dentata to the apical dendrites of the pyramidal cells.^{2831,57,60-62} By virtue of its limbic connections, the hippocampus is able to influence many brain activities, thus zinc depletion in mossy fibres may to contribute to a wide variety of cerebral physiopathologies.²⁹ The hippocampus is not the only region in the brain with a high zinc content: the neocortex,⁵⁸ amyglada,⁶³ gray matter, substania nigra, lentiform nucleus, caudate and thalamus all contain zinc.⁶⁴

Zinc and Neural Function

Zinc has an essential role in axonal transport and neuronal microtubule and tubulin synthesis and assembly.^65-68 Using animal experiments, axonal transport has been found to occur for opiate receptors in the vagus nerve, and for muscarinic cholinergic receptors in vagus sciatic and splenic nerves.³⁰ However, similar axonal flow is probably common to all other receptors.⁶⁹ Zinc ions are essential in the brain tubulin phosphorylation and in the induction of tubulin to form transport sheets, as well in increasing the number of neurofilaments.⁷⁰ Furthermore, as zinc is the most important trace metal in subcellular DNA and RNA fractions, this will also explain its vital role in the neuronal maturition and profileration.³⁰

Zinc and Brain Development

Research on rodents has allowed in depth examination on the above subject. It has been found that if pregnant rats are deprived of zinc early in pregnancy, it leads either to fetal reabsorption, abortion, or surviving fetuses displaying a variety of severe malformations, with the brain being one of the tissues affected.³¹ On the other hand, if the maternal zinc deficiency is limited to the latter one-third of pregnancy, abortion or teratology may not occur, instead zinc deficiency at that stage of the gestation is able to impair seriously the fetal growth, brain size and total brain cell count, as well as to increase cytoplasmic nuclear ratio, implying an impaired cell devision during the critical period of macroneuronal proliferation.^30,31,57,71 Postnatal zinc deficiency has also been found to retard brain growth and maturiation. For example, when zinc deficiency was induced from birth to weaning, by zinc deprivation of nursing dams, pups were found to suffer impaired incorporation of thymidine into brain DNA, depressed incorporation of sulphur into the TCA precipitate, and a decreased rate of brain protein synthesis.⁷² A deficiency of dietary zinc during the suckling period also resulted in the pups having smaller forebrains, reduced cell numbers, decreased total amount of brain DNA, a smaller hippocampus as well as a marked retention of the external granula layer of the cerebellum, compared to pups receiving adequate zinc.^30,57,72-73 Zinc is also necessary for many homeostatic processes in the brain, some of which indicate neurotransmitter function. For example, the activities of 2’-3’ cyclic nucleotide - 3 -phosphohydrolase and L-glutamic acid dehydrogenase are decreased in the hippocampus and cerebellum of zinc deficient suckling rats.³¹ The former enzyme is involved with myelination, while the latter dehydrogenates glutamic acid.³¹ Furthermore, when animals were severely deprived of zinc, levels of brain catecholamines increased i.e. elevation of noradrenaline occurred consistently, dopamine irregularly and serotonin relatively, when compared to controls.^30,74

Zinc in Reproduction

Male Reproduction

Zinc is vital for spermatogenesis and for the development of primary and secondary sexual characteristics.¹¹ Low zinc intake by young males of several species, including humans, interferes with normal sexual development.^3,4,33,34,85 In the young rat severe zinc deficiency has a marked effect on testicular weight ^108-110. Testicular lesions in young zinc deficient rats were similar to those experimental rats with cryptoridchism; severe atrophy of seminiferous tubules, sperm with malformed tails, and lesions of the axoneme.¹¹¹ In mildly zinc deficient rats, in which testicular weight was not reduced, epididymal sperm numbered only 35% of that from zinc adequate rats, motility was reduced, and sperm had various defects.¹¹² Sixty-day-old mice were sterile after three weeks of low zinc intake.¹¹³ Experimental zinc deficiency in humans leads reversibly to reduced sperm count combined with reduced serum testosterone.¹¹⁴ Zinc deficiency in humans has also been linked with oligospermia.¹¹⁵

Zinc Responsive Syndromes

Zinc Status in Anorexia Nervosa

Whole Blood Blood Serum Blood Plasm Urine Scalp Hair

12 2.50 1.75 0.60 300

ll

l lll ll ll l l

l lll

ll + + lll ll l

lll l

l ll l

Figure 1. Zinc content of body fluids and tissues for control (•) and anorexic (+) individuals: (---) mean.

Toxic Elements and Zinc

Assessment of Zinc Status

It has been establised that outward signs of zinc deficiency are primarily cutaneous striae and/or white-speckled fingernails, often also including poor skin and hair tone.^12,57 In clinical settings zinc deficiency is usually assessed using any of the following; plasma, serum, leucocyte, muscle, urine, hair, sweat or taste.¹⁴⁸ However, it has now been established that both plasma and serum zinc concentrations are subject to acute variations, being highest in the morning and falling after a meal. Stress alone can cause a rapid fall in plasma zinc values, as can certain steroid drugs, such as oral contraceptives.^148,221 Furthermore, all manner of infections tend to reduce both plasma and serum zinc levels in a way that is not necessarily related to primary nutritional zinc status. Only repeated low plasma zinc tests can provide grounds for suspecting zinc deficiency.¹⁴⁸ Muscle and leucocyte zinc are probably the most reliable analytical methods for the assessment of primary nutritional zinc status.¹⁴⁸ Hair zinc analysis represents a permanent deposition of zinc status, as the metal is firmly bound in the hair protein structure. However, caution is urged in the interpretation, as animal studies show that reduced dietary zinc leads at first to low hair zinc levels, but when zinc depletion continues, values seem to return to the normal range, presumably because the reduced hair growth resulting from impaired protein synthesis leads to a compensating increased concentrations of zinc and other elements in such hair when it grows.¹⁴⁸ Sweat zinc is presently regarded one of the most sensitive indexes of zinc status.¹¹ The “Taste-Test” for zinc deficiency is based on the evidence that the sense of taste is indeed among the first senses to be adversely affected in zinc deficiency.^4,12,143-147 The test is based on four clearly distinguished categories of taste response on test solution of 0.1% zinc sulphate heptahydrate diluted in distilled water.^{4,12,148,149,221} Recently the taste-test scores have been found to correlate closely with sweat zinc levels.¹³²

Discussion and Results

As seen from the above, the recommended dietary allowance for zinc is 15mg daily. However, according to recent statistics, the typical daily diet provides only about 9.7mg of zinc. The reasons why modern diets are so deficient in zinc are manifold. One reason lies in modern agricultural practices as farmers can grow large crops and lush greenery by using masses of NPK fertilizers containing only nitrogen, potassium and phosphorus, thus progressively inhibiting the availability and the uptake of other essential micronutrients, such as zinc and maganese etc. from the soil.^12,222-226 In a survey by the UK Agriculture Research Council, zinc concentrations for cattle were found to be more than 50% deficient from all the herbage sampled.²²⁷ Similar results were recorded from the US.²²⁸ Such findings could hardly fail to reflect the diminished zinc concentration in human diets. In addition, food processing is designed to remove anything from the food that encourages the growth of bacteria, fungi etc.²²⁹ Therefore, for example, 80% of zinc is removed from wheat flour during the milling process to ensure longer shelf life.²³⁰ Furthermore, besides phytic acid, which is found naturally in foodstuffs, many other polyphosphates, such as hexametaphosphate, acid pyrophosphate and tripolyphosphate are added to foods during processing, causing an additional defect in zinc absorption.²³¹ The food additive tartrazine is now also found to act directly as a zinc-chelating agent.^118,232 Therefore, looking at the above, under present nutritional policy, it is not at all suprising that zinc deficiency is more a norm than a rarity. This is particularly worrying because zinc requirements for infants, children and teenagers are relatively high in relation to body size because of their increased requirements for physical growth and development. The fact which is even more disturbing, is the obvious zinc deficiencies frequently encountered in pregnant women. Because of the mildness, or a comparative lack of symptomatology, maternal zinc deficiency is unlikely even to be suspected, until it is too late, and the infant is already born with irreversible damage, including a low birth weight, brain dysfunction, malformations and/or with a sub-optimal immuno-competence. It is also noteworthy to remember that these adverse effects of maternal zinc deprivation seem to remain, despite a complete nutritional rehabilitation. There also has been recently a considerable debate whether a routine iron supplementation given during pregnancy is at all wise in the absence of iron deficiency anaemia, as iron supplementation tends to exacerbate zinc deficiency by competing for its binding sites that facilitate its intestinal absorption.^{79,85,182,233-234} Considering that maternal zinc deficiency is already relatively common, an additional iron supplementation will further reduce the already diminishing zinc stores. In addition, it has also been demonstrated, that experimentally induced zinc deficiency in man results in impaired absorption of folic acid.^79,235 Folic acid deficiency in turn is now recognised as the major cause of spina bifida.²³⁶ Besides optimal zinc being absolutely vital for female reproduction, it is likewise vital for male reproduction, as a sub-optimal zinc intake has been directly linked with malformed sperm, reduced sperm count and oligospermia. In addition, zinc deficiency also leads to an impairment of vitamin A metabolism,^4,237 as well as to an inhibition of prostaglandin synthesis from essential fatty acids, either by blocking linoleic acid desaturation to gamma linolenic acid, or by inhibiting the mobilization of dihomogammalinolenic acid from the tissue membrane stores.²³⁸ Though a trace metal like zinc is, in weight terms, only a miniscule part of the human metabolism, its presence is absolutely vital in all the major metabolic pathways. This being the case, on the basis of current evidence, the treatment with zinc supplementation should become a norm in all cases of anorexia, bulimia, immuno-deficiency, alcoholism and mental depression, as well as in cases of both male and female infertility. Furthermore, all would-be mothers should be made aware of the vital importance of an optimal zinc status before and during pregnancy to prevent their off-spring to be born with congenital malformations, prematurely and/or with a low birthweight and a small head circumference, the latter leading to a greater risk of brain damage and to a subsequent mental backwardess. Because of this, all would-be mothers must be made immediately aware of the vital importance of dietary zinc in preventing birth defects, just as they have been made recently aware about importance of dietary folic acid in preventing spina bifida. This is of particular importance, as according the latest UK statistics, one child of every ten is now born with low birth weight. Furthermore, six babies of every 100 live births are now born either with ‘minor’ or ‘major’ physical malformations. In addition, it has been also estimated that one in every four babies is now born with some degree of learning disability and/or mental deficiency.²³⁹ These statistics are absolutely appalling! After all, our children are supposed to be our future, so what is happening to our future? If we can help our future just by adding few milligrams of zinc supplementation to our diet, it certainly should be worth it.

Acknowledgements

This study was supported by a grant from Foresight, The Association for the Promotion of Preconceptual Care. A special recognition is given to Professor Bryce-Smith and Mrs Belinda Barnes who both have fought tirelessly to draw attention to the dangers of zinc deficiency in reproduction. Furthermore, I would like to thank Professor Bryce-Smith for his kind help and guidance whilst I have been working on this research paper.

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