Eleven men were fed foods naturally high or low in selenium for 120 d. Selenium intake was stabilized at 47 microg/d for 21 d, then changed to either 13 or 297 microg/d for 99 d, leading to significantly different blood selenium and glutathione peroxidase concentrations. Serum immunoglobulins, complement components, and primary antibody responses to influenza vaccine were unchanged. Antibody titers against diphtheria vaccine were 2.5-fold greater after reinoculation in the high selenium group. White blood cell counts decreased in the high-selenium group and increased in the low-selenium group, resulting primarily from changes in granulocytes. Apparent increases in cytotoxic T-lymphocytes and activated T-cells in the high-selenium group only approached statistical significance. Lymphocyte counts increased on d 45 in the high-selenium group. In vitro proliferation of peripheral lymphocytes in autologous serum in response to pokeweed mitogen was stimulated in the high-selenium group by d 45 and remained elevated throughout the study, whereas proliferation in the low selenium group did not increase until d 100. This study indicates that the immune-enhancing properties of selenium in humans are the result, at least in part, of improved activation and proliferation of B-lymphocytes and perhaps enhanced T-cell function.

The unique chemistry of oxygen has been both a resource and threat for life on Earth for at least the last 2.4 billion years. Reduction of oxygen to water allows extraction of more metabolic energy from organic fuels than is possible through anaerobic glycolysis. On the other hand, partially reduced oxygen can react indiscriminately with biomolecules to cause genetic damage, disease, and even death. Organisms in all three superkingdoms of life have developed elaborate mechanisms to protect against such oxidative damage and to exploit reactive oxygen species as sensors and signals in myriad processes. The sulfur amino acids, cysteine and methionine, are the main targets of reactive oxygen species in proteins. Oxidative modifications to cysteine and methionine can have profound effects on a protein's activity, structure, stability, and subcellular localization. Non-reversible oxidative modifications (oxidative damage) may contribute to molecular, cellular, and organismal aging and serve as signals for repair, removal, or programmed cell death. Reversible oxidation events can function as transient signals of physiological status, extracellular environment, nutrient availability, metabolic state, cell cycle phase, immune function, or sensory stimuli. Because of its chemical similarity to sulfur and stronger nucleophilicity and acidity, selenium is an extremely efficient catalyst of reactions between sulfur and oxygen. Most of the biological activity of selenium is due to selenoproteins containing selenocysteine, the 21st genetically encoded protein amino acid. The most abundant selenoproteins in mammals are the glutathione peroxidases (five to six genes) that reduce hydrogen peroxide and lipid hydroperoxides at the expense of glutathione and serve to limit the strength and duration of reactive oxygen signals. Thioredoxin reductases (three genes) use nicotinamide adenine dinucleotide phosphate to reduce oxidized thioredoxin and its homologs, which regulate a plethora of redox signaling events. Methionine sulfoxide reductase B1 reduces methionine sulfoxide back to methionine using thioredoxin as a

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Previous metabolic studies of selenium used pure selenium compounds with pharmacologic activities unrelated to selenium nutrition. Healthy men were fed foods naturally high or low in selenium while confined to a metabolic research unit. Selenium intake was 47 microg/d (595 nmol/d) for 21 d while energy intakes and body weights were stabilized and selenium excretion and intake came into metabolic balance. On d 22, selenium intake was changed to either 14 microg/d (177 nmol/d, low selenium) or 297 microg/d (3.8 micromol, high selenium) for the remaining 99 d. The absorption, distribution and excretion of selenium in food were similar to selenomethionine, and distinctly different from sodium selenite. Daily urinary selenium excretion and selenium concentrations in plasma and RBC showed the largest responses to selenium intake relative to interindividual variation. Urinary selenium and plasma selenium responded most rapidly to changes in selenium intake, whereas RBC reflected longer-term selenium intake. Given the difficulty of 24-h urine collections outside a metabolic research unit, RBC and plasma selenium seem to be the most useful indicators of selenium intake. During the intervention period, the high selenium group retained 15 mg (190 micromol) of selenium, with approximately 5 mg (63 micromol) going into skeletal muscle. The low selenium group lost only 0.9 mg (11 micromol) of whole-body selenium but lost 3.3 mg (42 micromol) from muscle, indicating that selenium was redistributed from muscle to tissues that have a higher metabolic priority for selenium such as testes. Fecal excretion decreased by half, representing an important but previously underappreciated adaptation to selenium restriction.

Most studies of selenium and thyroid hormone have used sodium selenite in rats. However, rats regulate thyroid hormone differently, and selenite, which has unique pharmacologic activities, does not occur in foods. We hypothesized that selenium in food would have different effects in humans. Healthy men were fed foods naturally high or low in selenium for 120 d while confined to a metabolic research unit. Selenium intake for all subjects was 47 microg/d (595 nmol/d) for the first 21 d, and then changed to either 14 (n = 6) or 297 (n = 5) microg/d (177 nmol/d or 3.8 micromol/d) for the remaining 99 d, causing significant changes in blood selenium and glutathione peroxidase. Serum 3,3',5-triiodothyronine (T3) decreased in the high selenium group, increased in the low selenium group, and was significantly different between groups from d 45 onward. A compensatory increase of thyrotropin occurred in the high selenium group as T3 decreased. The changes in T3 were opposite in direction to those reported in rats, but were consistent with other metabolic changes. By d 64, the high selenium group started to gain weight, whereas the low selenium group began to lose weight, and the weight changes were significantly different between groups from d 92 onward. Decreases of serum T3 and compensatory increases in thyrotropin suggest that a subclinical hypothyroid response was induced in the high selenium group, leading to body weight increases. Increases of serum T3 and serum triacylglycerol accompanied by losses of body fat suggest that a subclinical hyperthyroid response was induced in the low selenium group, leading to body weight decreases.

The fact that platelets, PMN leukocytes, and MN leukocytes concentrate ascorbic acid suggests that vitamin C has an important role in their physiological functions. The question still remains as to which one of the cells best reflects vitamin C status. The ascorbic acid content of PMNs and platelets correlates positively with plasma concentration and supplementation with vitamin C, as shown in Evans et al. They also found that MN leukocytes, in contrast, do not show any such relationship; however, MN leukocytes maintain the highest levels of ascorbic acid and play a very important function in immunocompetence. We have found that with a limited number of subjects, ascorbic acid content of MN and PMN leukocytes correlates positively with plasma ascorbic acid, but there was no correlation between platelets and plasma ascorbic acid (unpublished results). Therefore, further work is necessary to evaluate these three blood components for the best cellular marker of vitamin C status. We have developed a reversed-phase HPLC method for ascorbic acid that can be used in conjunction with our cellular differential centrifugation technique for the determination of ascorbic acid in relatively pure blood cell fractions. The chromatographic method is simple, sensitive, and automated. It clearly resolves ascorbic acid, which is the major form of the vitamin found in vivo and is not prone to interference by sugars, carbohydrates, or nucleotides.

Selenium (Se) is essential for sperm function and male fertility, but high Se intake has been associated with impaired semen quality. We reported previously a decrease in sperm motility in men fed high-Se foods, but we could not rule out the influence of other environmental and dietary factors. We now report on a randomized, controlled study on the potential adverse effects of Se supplementation on semen quality in 42 free-living men administered Se (300 mg/d) as high-Se yeast for 48 weeks. Semen analysis was performed 4 times before treatment began, then twice each week during treatment at 6, 12, 24, 36, and 48 weeks, and then after treatment at 72 and 96 weeks. Blood samples were collected 3 times before treatment and at each subsequent visit. Se concentration increased 61% in blood plasma and 49% in seminal plasma. However, Se supplementation had no effect on sperm Se, serum androgen concentrations, or sperm count, motility, progressive velocity, or morphology. We observed progressive decreases in serum luteinizing hormone, semen volume, and sperm Se in both the high-Se and placebo groups. Moreover, sperm straight-line velocity and percent normal morphology increased in Se-treated and placebo-treated participants. The lack of an increase in sperm Se suggests that testicular Se stores were unaffected, even though the participants' dietary Se intake was tripled and their total body Se approximately doubled by supplementation. These results are consistent with animal studies showing the Se status of testes to be unresponsive to dietary Se intake.