Title: The case for increasing dietary selenium intake in the
Key words: selenium, selenoproteins, sperm, preganancy, peroxidases, free radicals, hydrogen peroxide, lipid, phospholipids, DNA, CHD, coronary heart disease, cancer, aging, ageing, oxidative damage, low density lipoproteins, LDL, selenoenzymes, prostaglandins, antioxidant, immune response, supplementation, cardiomyopathy, Keshan disease, HIV, thyroid, testosterone, sperm, miscarriage, infertility, infertile, memory, cognitive, mood, depression, animal husbandry, Finland,
Date: Oct 2006
Author: Morgan, G
The case for increasing dietary selenium intake in the UK
There is now substantial evidence linking the essentiality of selenium as a micronutrient with important redox and other enzyme systems within the body. Of the 18 selenoproteins so far identified in mammals such as humans, all are known to have enzymatic functions, with the sole exception of a polymerised form of the glutathione peroxidase-4 enzyme which acts as an important structural component in midpiece sperm. The total number of selenoproteins may be as high as 50 (Sunde 2001). This paper will review the role played by such selenoenzymes and the possible health consequences posed by selenium levels which have now been declining in the UK for the last 25 years.
The antioxidant activity of selenium
The selenium-dependent glutathione peroxidases (GPX-1 Ė 4) and the three thioredoxin reductases, along with the non-selenium-dependent enzymes superoxide dismutase and catalase, form the bodyís major defence against attack from oxidising radical oxygen species such as hydrogen peroxide and lipid and phospholipid peroxide. Such free radicals are highly reactive, damaging cell membranes, proteins and DNA and have been linked to coronary heart disease, cancer and possibly aging. GPX-1 is the major form of selenium in the body accounting for >50% of total body selenium.
The role of selenium in coronary heart disease (CHD)
Oxidative damage to vascular endothelium and to low density lipoproteins in association with an increased clotting tendency is thought to underlie the pathology of CHD. Selenoprotein P has been shown to protect the endothelium against oxidative damage (Burk 1997) and GPX (GPX-4 in particular) is able to destroy hydroperoxides which otherwise would lead to a vasoconstrictive and a proaggregatory state due to facilitation of thromboxane and inhibition of prostacyclin production (Spallholz 1990). Disruption of normal prostaglandin biosynthesis has led workers to consider atherogenesis as a proinflammatory disorder and selenium as protective against CHD (Neve 1996.) Since Salonenís work (1982) showed a doubling of CHD morbidity in Finnish subjects with serum selenium levels below 45 mcg/l only the recent large EURAMIC study (Kardinaal 1997) has been able to demonstrate a clear correlation between CHD and selenium levels and that in Germany where the levels were found to be particularly low. Large prospective supplementation trials are called for to determine the role of selenium in such exposed populations.
The anti-inflammatory effect of selenium
Reduction of hydrogen peroxide intermediates by selenoenzymes has been shown to lead to the production of anti-inflammatory prostaglandins via the prostacyclin and cyclo-oxygenase pathways (Spallholz 1990). The effect of giving selenium in inflammatory disorders characterised by an acute phase reaction and low serum selenium levels has been investigated in limited trials for rheumatoid arthritis (Knekt 2000, Peretz 1992), pancreatitis (McCloy 1998, Kuklinsky 1996) and asthma (Shaheen 1999, Shaw 1994, Hasselmark 1993) with beneficial results.
The anti-cancer effect of selenium
Through its antioxidant activity, selenium is known to reduce damage to the genome by free radicals. The selenoprotein selenophosphate synthetase-2 may also have a role in cancer protection (Gladyshev 1998). Upregulation of the immune response through cytokine mediation is known to occur. One study (Kiremidjian-Schumacher 1994), for example, showed a doubling of cytotoxic-lymphocyte-mediated tumour cytotoxicity and natural killer cell activity in the supplemented group.
Epidemiological evidence has shown an inverse relationship between soil and serum selenium levels across countries and the incidence of cancer (Schamberger 1976, Schrauzer 1977, Clark 1991). Certain cancers appear to have a closer association with selenium levels and others less so, e.g. breast cancer (Clark 1996). The results of large prospective studies in the US and Europe (the SELECT and PRECISE trials respectively) are awaited to definitively determine the protective effect of selenium supplementation in cancer. So far, in more limited studies, beneficial results have been found for lung, hepatocellular, colon and prostate cancers (Knekt 1998, Yu 1999, Yoshizawa 1998, Clark 1996). Reductions of cancer rates of up to 63% with prostatic cancer have been reported (Clark 1996).
The anti-viral effects of selenium
Important studies by Beck (1995) have shown that Coxsackie virus when
introduced into selenium deficient mice mutates to a form that precipitates a
cardiomyopathy. As antibodies to the Coxsackie virus are found in patients with
Keshan disease this is suggestive of an aetiological role of low selenium
levels in this disease. Some researchers have suggested that similar mutations
may have occurred to the HIV virus in
The effects selenium on the thyroid
Three selenium-dependent deiodinases are necessary for the conversion of T4 to the bioactive T3 form. Compromised T3:T4 ratios have been found in selenium deficient populations and have been improved with supplementation (Olivieri 1995). The combination of selenium and iodine deficiency is known to exacerbate clinically evident hypothyroidism (Vanderpas 1990).
The effect of selenium on reproduction
Selenium is required for testosterone biosynthesis and also ensures the structural integrity of the sperm midpiece through the action of a GPX-4 polymer. Structural abnormalities here lead to poor sperm motility which impairs fertility (Wu 1973). A study by Scott (1998) has shown increased sperm motility and fertility in supplemented groups of infertile men. Low serum selenium levels have been found in women with first-trimester or recurrent miscarriages (Barrington 1996,1997). Prospective trials are indicated to determine if this is a cause-effect relationship.
Selenium and the central nervous system
Cognitive ability and memory are impaired in Alzheimer's disease and are associated with low selenium concentrations in the brain (Hawkes 1996). Selenium levels have been shown to correlate with mood and two supplementation trials (Finley 1998, Benton 1991) have shown decreases in depression, anxiety and aggressive behaviour, an effect greatest in those who were most selenium deficient. Selenium is essential for normal neurotransmitter production and may operate through these pathways.
The case for selenium supplementation
The use of selenium supplementation in animal husbandry has been widespread since the 1950ís. The consequences of selenium deficiency varies from species to species so it is difficult to extrapolate from the animal model to humans. It is significant though that, cross-species, the effects of selenium display themselves at similar threshold levels of serum selenium (Sunde 1997). Epidemiological studies in humans have confirmed a close association between selenium intake and a range of disorders ranging from the severe and specific pathology of Keshan disease to those conditions described above in more marginally affected populations.
There is some dispute as to the precise definition of optimum nutrition
with respect to selenium. Repletion of the selenoenzyme GPX-3 has been used as
a biomarker to determine RDAs and, using this, recent reappraisal of needs have
ranged between 40 mcm/day (WHO 1996) to 100 mcm/day (Neve 2000). The US RDA has
now been revised to 55 mcm/day (National Academies 2000) but using the same
data Rayman arrived at a figure of 73 mcg/day (Rayman 2000). All of these
figures are still higher than the present day
With serum selenium levels in the UK falling towards the very low levels
associated with Keshan disease (12 mcg/day), it would seem advisable in the
light of the above evidence, as has been suggested elsewhere (Rayman 1997), to
take measures to improve the situation. CHD and cancer remain the two major
threats to public health and there is now evidence from controlled and
prospective trials to indicate that, at these very low levels of repletion,
selenium deficiency poses an increasingly serious danger. Further prospective
studies are indicated in these areas in particular but, in view of this
evidence, the lessons learned from animal husbandry and the experience of
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