Research and Reference

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Nutrition plays a profound and increasingly recognised role in preventing chronic disease and cancer,
with specific nutrients and the cellular responses they control emerging as mediators of key
physiological events. Zinc is unique in its functional diversity, displaying structural, signaling, catalytic, and
regulatory functions 1 . Zinc is an essential cofactor for the activity of many enzymes—it is known to form part of more
than 300 metalloenzymes, which cannot function in its absence. For example, zinc is essential for the function of
DNA polymerase, thymidine kinase and DNA dependent RNA polymerase, whose involvement in nucleic acid
synthesis could explain for instance the effects of zinc on lymphoid-cell proliferation 2 . Today, even in developed
countries, dietary intake patterns for zinc are still suboptimal. It was found in the USA that 50% of men and women
age 50 and older are consuming less than the RDA, while a mere 18% of pregnant women worldwide have a zinc
intake that meets the USA RDA 1 . Zinc deficiency is characterised by impaired immune function, loss of appetite, and
growth retardation. More severe cases cause diarrhoea, hair loss, eye and skin lesions, delayed sexual maturation,
impotence and hypogonadism in males, as well as weight loss, taste and smell abnormalities, delayed healing of
wounds, and mental lethargy 3 . Recent research linked cancer to disrupted zinc status, where zinc intake is inversely associated with colon cancer risk, for example. Zinc status plays a role in cancer initiation, progression, termination, and prevention. Apart from zinc deficiency being related to DNA damage, the interaction between zinc concentration, zinc transporter expression, and immune function is interwoven with cellular signaling pathways, providing multiple mechanisms for the role of zinc in cancer 1 . Selenium exerts its biological effects through its incorporation into selenoproteins, such as the glutathione peroxidase enzymes, as the amino acid selenocysteine. Selenium’s biological functions include regulation of thyroid hormone metabolism, intra- and extra-cellular antioxidation, redox regulation, and sperm maturation/protection.
There is also mounting evidence suggesting a protective role for dietary selenium in various types of cancer 4, 5 .
Immunity and the immune system are a very complex collection of processes that act together to protect organisms
against attacks by pathogens and malignancy. Many immune functions involve inflammatory and oxidation
mechanisms that when uncontrolled, may be implicated in the pathogenesis of conditions such as coronary heart
disease, cancer, immunity and rheumatoid arthritis 6 . Therefore, apart from selenium’s antioxidant properties, it
reveals far more complex roles with respect to cancer, atherosclerosis and neurodegenerative diseases. One of the
protective properties of selenium appears to be its involvement in cellular zinc homeostasis 5 . There, therefore, exist
an important synergistic effect between zinc and selenium.
 

Immune modulation
Zinc has a major impact on the immune system affecting both non-specific and acquired immunity. Lymphopenia
and lymphoid organ atrophy have been linked to zinc deficiency, probably due to increased production of
glucocorticoids. Zinc deficient mice, challenged with sub-acute levels of infectious agents, resulted in death due to an
impaired defence system 2 . In zinc-deficient mice a decline in in vivo-generated cytotoxic T killer activity to allogenic
tumour cells has been observed. When mice were maintained on a zinc deficient diet for as little as 2 weeks, they
developed severe impairment of their ability to generate a cytotoxic response when challenged with tumour cells 2 .
The production and biological activity of various cytokines are affected by zinc deficiency. Patients on total
parenteral nutrition become zinc-deficient, presenting with immune defects, such as lymphopenia, decreased ratio
of helper and suppressor T lymphocytes, and decreased NK cell activity. Defective natural killer function, and anergic
delayed type hypersensitivity responses have been observed in patients with sickle cell anaemia, who present with
only a modest depletion of serum zinc. Various research studies indicated that even mild zinc deficiency in humans
may be accompanied by an imbalance in Th1 and Th2 cell functions, resulting in an unregulated resistance to
infection 2 . All these effects can be reversed with zinc supplementation.
Selenium is utilised by nearly all tissues and cell types, including those involved in innate and adaptive immune
responses. Selenium deficiency has been shown to result in less robust immune responses to viruses, tumours, and
allergens compared with selenium-adequate controls 4, 5 , and has been linked to increased viral pathogenicity in
humans 5 .

Antioxidant
Oxidative stress occurs in all respiring cells and involves elevated levels of reactive oxygen species (ROS), such as
superoxide, hydrogen peroxide, and hydroxyl free radicals. ROS at high levels are considered noxious, cytotoxic by-
products, capable of damaging lipids, proteins, and nucleic acids. However, when properly regulated, ROS in
phagocytes play critical roles in microbiocidal activity, intracellular signaling for proper activation and differentiation
and for cell-to-cell communication. In the form of selenoproteins, selenium plays an essential regulatory role in
phagocytes by maintaining a proper balance between the positive and negative effects of ROS. Selenium-containing
enzymes may contribute to the modulation of inflammation and immune responses most likely by shifting redox
away from oxidative stress in immune and local tissue cells 4 . Selenium can, therefore, act as an antioxidant in the
extracellular space, the cell cytosol, in association with cell membranes and specifically in the gastrointestinal tract,
all with the potential to influence immune processes. Additionally, thioredoxin reductases that contain selenium,
may also act as antioxidants 6 . It was found that zinc reduces the duration, severity, and risk of diarrheal disease via improved regeneration of intestinal epithelium, improved absorption of water and electrolytes and increased levels of brush border enzymes 3 .

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Skin health and anti-aging
Decreased NK cell activity and responses to cutaneous sensitisation have been observed in mice deficient in zinc. In
humans the genetic disorder of Zn malabsorption, acrodermatitis, is characterised by mucocutaneous lesions,
diarrhoea, failure to thrive, and frequent severe yeast, viral and bacterial infections. It was found that affected
subjects have anergy, thymic atrophy, a reduced lymphocyte proliferative response to mitogens, a selective decrease
in T4 + helper cells, and deficient thymic hormone activity. All of these symptoms may be corrected with Zn
supplementation 2 . Zinc also contributes to membrane stabilisation, acting at the cytoskeletal level. Zinc deficiency
can lead to delayed wound healing. Zinc plays a role in keratinocyte migration during wound repair and zinc-
dependent metalloproteinases that augment auto debridement. Zinc also confers resistance to epithelial apoptosis
through cytoprotection by the antioxidant activity of the cysteine-rich metallothionines 3 .
Fertility, reproductive health and hormonal balance
Gestational zinc deficiency in mice has short- and long-term deleterious effects on their offspring. Murine studies
have shown that several immune defects seen at birth persist into adulthood, even when the mice are fed a diet
containing normal amounts of zinc after weaning. Intra-uterine growth retardation was observed in humans, linked
to maternal zinc deficiency, which induced persistent cellular immune deficiency. Even a modest zinc deficiency
occurring during gestation may induce long-term deleterious consequences for the immune system 2 .
Several studies proposed the important role that zinc plays in male fertility. The actions of zinc in
spermatozoa are involvement in sperm motility, capacitation and acrosomal exocytosis, three functions
that are crucial for successful fertilisation 7 . Zinc is also a critical component in a number of processes in
female fertility that regulate germ cell growth, fertility and pregnancy 8, 9 . Zinc deficiency during pregnancy has
been related with a number of anomalies, such as spontaneous abortion, extended pregnancy or prematurity,
pregnancy-related toxaemia, birth defects, and retarded growth. Delivery is also adversely affected by deficiency.
These effects can be explained by the multiple action of zinc on the metabolism of androgen hormones, oestrogen
and progesterone, together with the prostaglandins. Nuclear receptors for steroids are all zinc finger proteins 9 .
Conversely, oestrogen regulate cellular zinc concentrations 1 . Zinc is also essential for growth and thyroid
hormone secretion and metabolism 10, 11 . 

References
1. Grattan BJ, Freake HC. Zinc and Cancer: Implications for LIV-1 in Breast Cancer. Nutrients.
2012;4(7):648-675. doi:10.3390/nu4070648
2. Dardenne M. Zinc and immune function. Eur J Clin Nutr. 2002;56(S3):S20-S23.
doi:10.1038/sj.ejcn.1601479
3. Hassan A, Sada KK, Ketheeswaran S, Dubey AK, Bhat MS. Role of Zinc in Mucosal Health and
Disease: A Review of Physiological, Biochemical, and Molecular Processes. Cureus. May 2020;12(5)e8197.
doi:10.7759/cureus.8197
4. Hoffmann PR. Mechanisms by which selenium influences immune responses. Arch Immunol Ther
Exp (Warsz). Sep-Oct 2007;55(5):289-297. doi:10.1007/s00005-007-0036-4
5. Blessing H, Kraus S, Heindl P, Bal W, Hartwig A. Interaction
of selenium compounds with zinc finger proteins involved in DNA repair. Eur J Biochem. Aug 2004;271(15):3190-3199. doi:10.1111/j.1432-1033.2004.04251.x
6. Arthur JR, McKenzie RC, Beckett GJ. Selenium in the immune system. J Nutr. May
2003;133(5):1457S-1459S.
7. Allouche-Fitoussi D, Breitbart H. The Role of Zinc in Male Fertility. Int J Mol Sci. Oct
2020;21(20)7796. doi:10.3390/ijms21207796
8. Garner TB, Hester JM, Carothers A, Diaz FJ. Role of zinc in female reproduction. Biol Reprod. May
2021;104(5):976-994. doi:10.1093/biolre/ioab023
9. Favier AE. The role of zinc in reproduction. Biol Trace Elem Res. 1992;32(1-3):363-382.
doi:10.1007/bf02784623
10. Miletta MC, Schoni MH, Kernland K, Mullis PE, Petkovic V. The Role of Zinc Dynamics in Growth
Hormone Secretion. Horm Res Paediatr. 2013;80(6):381-389. doi:10.1159/000355408
11. Nishiyama S, Futagoishisuginohara Y, Matsukura M, et al. Zinc supplementation alters thyroid-
hormone metabolism in disabled patients with zinc-deficiency. J Am Coll Nutr. Feb 1994;13(1):62-67.