Whole-body Selenium Research Articles

Mercury and selenium in fish of Fountain Creek, Colorado (USA): possible sources and implications.

Fountain Creek in Colorado USA is a major tributary that confluences with the Arkansas River at Pueblo, Colorado, the result being the tributary’s influence on Arkansas River water quality affecting down-stream users. In a previous study, we found that bryophytes (aquatic plants) accumulated selenium in Fountain Creek watershed and this finding prompted us to investigate the extent of the metalloid in the whole-body tissues of fish. One hundred 11 fish (six species) were collected and analyzed for Se by inductively-coupled plasma emission mass spectrometry. Analysis of all analytical data also showed mercury in all of the fish whole bodies and selected tissues. There was a general increase in selenium but a decrease in mercury in fish with downstream travel-distance. The highest whole-body selenium was in Pueblo, Colorado (3393 µg/kg, dry weight; 906 µg/kg, wet weight); the highest mercury in fish was in the Monument Creek tributary north of Colorado Springs, Colorado (71 µg/kg, dry weight; 19 µg/kg, wet weight). In four tissues of 11 female fish captured, selenium was highest in the livers at eight sites but highest in the ovaries at three sites. Mercury was highest in the epaxial muscle at all sites. Selenium availability could be due to the watershed lithology and land uses; however, mercury could be carried by atmospheric deposition from coal-fired power plants and historic mining activities. Selenium in fish tissues and water samples were compared to U.S. national water quality criteria.

Regulation of Selenium Metabolism and Transport.

Selenium is regulated in the body to maintain vital selenoproteins and to avoid toxicity. When selenium is limiting, cells utilize it to synthesize the selenoproteins most important to them, creating a selenoprotein hierarchy in the cell. The liver is the central organ for selenium regulation and produces excretory selenium forms to regulate whole-body selenium. It responds to selenium deficiency by curtailing excretion and secreting selenoprotein P (Sepp1) into the plasma at the expense of its intracellular selenoproteins. Plasma Sepp1 is distributed to tissues in relation to their expression of the Sepp1 receptor apolipoprotein E receptor-2, creating a tissue selenium hierarchy. N-terminal Sepp1 forms are taken up in the renal proximal tubule by another receptor, megalin. Thus, the regulated whole-body pool of selenium is shifted to needy cells and then to vital selenoproteins in them to supply selenium where it is needed, creating a whole-body selenoprotein hierarchy.

Selenoprotein P is the major selenium transport protein in mouse milk.

Selenium is transferred from the mouse dam to its neonate via milk. Milk contains selenium in selenoprotein form as selenoprotein P (Sepp1) and glutathione peroxidase-3 (Gpx3) as well as in non-specific protein form as selenomethionine. Selenium is also present in milk in uncharacterized small-molecule form. We eliminated selenomethionine from the mice in these experiments by feeding a diet that contained sodium selenite as the source of selenium. Selenium-replete dams with deletion of Sepp1 or Gpx3 were studied to assess the effects of these genes on selenium transfer to the neonate. Sepp1 knockout caused a drop in milk selenium to 27% of the value in wild-type milk and a drop in selenium acquisition by the neonates to 35%. In addition to decreasing milk selenium by eliminating Sepp1, deletion of Sepp1 causes a decline in whole-body selenium, which likely also contributes to the decreased transfer of selenium to the neonate. Deletion of Gpx3 did not decrease milk selenium content or neonate selenium acquisition by measurable amounts. Thus, when the dam is fed selenium-adequate diet (0.25 mg selenium/kg diet), milk Sepp1 transfers a large amount of selenium to neonates but the transfer of selenium by Gpx3 is below detection by our methods.

Maternal‐fetal transfer of selenium in the mouse

Selenoprotein P (Sepp1) is taken up by receptor-mediated endocytosis for its selenium. The other extracellular selenoprotein, glutathione peroxidase-3 (Gpx3), has not been shown to transport selenium. Mice with genetic alterations of Sepp1, the Sepp1 receptors apolipoprotein E receptor-2 (apoER2) and megalin, and Gpx3 were used to investigate maternal-fetal selenium transfer. Immunocytochemistry (ICC) showed receptor-independent uptake of Sepp1 and Gpx3 in the same vesicles of d-13 visceral yolk sac cells, suggesting uptake by pinocytosis. ICC also showed apoER2-mediated uptake of maternal Sepp1 in the d-18 placenta. Thus, two selenoprotein-dependent maternal-fetal selenium transfer mechanisms were identified. Selenium was quantified in d-18 fetuses with the mechanisms disrupted. Maternal Sepp1 deletion, which lowers maternal whole-body selenium, decreased fetal selenium under selenium-adequate conditions but deletion of fetal apoER2 did not. Fetal apoER2 deletion did decrease fetal selenium, by 51%, under selenium-deficient conditions, verifying function of the placental Sepp1-apoER2 mechanism. Maternal Gpx3 deletion decreased fetal selenium, by 13%, but only under selenium-deficient conditions. These findings indicate that the selenoprotein uptake mechanisms ensure selenium transfer to the fetus under selenium-deficient conditions. The failure of their disruptions (apoER2 deletion, Gpx3 deletion) to affect fetal selenium under selenium-adequate conditions indicates the existence of an additional maternal-fetal selenium transfer mechanism.

Production of Selenoprotein P (Sepp1) by Hepatocytes Is Central to Selenium Homeostasis

Sepp1 transports selenium, but its complete role in selenium homeostasis is not known. Deletion of Sepp1 in hepatocytes increases liver selenium at the expense of other tissues and decreases whole-body selenium by increasing excretion. Sepp1 production by hepatocytes retains selenium in the organism and distributes it from the liver to peripheral tissues. Sepp1 is central to selenium homeostasis. Sepp1 is a widely expressed extracellular protein that in humans and mice contains 10 selenocysteine residues in its primary structure. Extra-hepatic tissues take up plasma Sepp1 for its selenium via apolipoprotein E receptor-2 (apoER2)-mediated endocytosis. The role of Sepp1 in the transport of selenium from liver, a rich source of the element, to peripheral tissues was studied using mice with selective deletion of Sepp1 in hepatocytes (Sepp1(c/c)/alb-cre(+/-) mice). Deletion of Sepp1 in hepatocytes lowered plasma Sepp1 concentration to 10% of that in Sepp1(c/c) mice (controls) and increased urinary selenium excretion, decreasing whole-body and tissue selenium concentrations. Under selenium-deficient conditions, Sepp1(c/c)/alb-cre(+/-) mice accumulated selenium in the liver at the expense of extra-hepatic tissues, severely worsening clinical manifestations of dietary selenium deficiency. These findings are consistent with there being competition for metabolically available hepatocyte selenium between the synthesis of selenoproteins and the synthesis of selenium excretory metabolites. In addition, selenium deficiency down-regulated the mRNA of the most abundant hepatic selenoprotein, glutathione peroxidase-1 (Gpx1), to 15% of the selenium-replete value, while reducing Sepp1 mRNA, the most abundant hepatic selenoprotein mRNA, only to 61%. This strongly suggests that Sepp1 synthesis is favored in the liver over Gpx1 synthesis when selenium supply is limited, directing hepatocyte selenium to peripheral tissues in selenium deficiency. We conclude that production of Sepp1 by hepatocytes is central to selenium homeostasis in the organism because it promotes retention of selenium in the body and effects selenium distribution from the liver to extra-hepatic tissues, especially under selenium-deficient conditions.

Fecal Selenium Excretion Is Regulated by Dietary Selenium Intake

Whole-body selenium is regulated by excretion of the element. Reports of studies carried out using isotopic tracers have led to the conclusion that urinary selenium excretion is regulated by selenium intake but that fecal excretion is not. Because of the limitations of tracer studies, we measured urinary and fecal selenium excretion by mice with selenium intakes in the form of sodium selenite ranging from deficient to almost toxic. Tissue and whole-body selenium concentrations increased sharply between deficient and adequate selenium intakes, reflecting tissue accumulation of selenium in the form of selenoproteins. Once the requirement for selenium had been satisfied, a 31-fold further increase in intake resulted in less than doubling of tissue and whole-body selenium, demonstrating the effectiveness of selenium excretion by the mouse. Urinary selenium excretion increased with increases in dietary selenium intake. Fecal selenium excretion, which was 20 to 30 % of the selenium excreted in the physiological range, responded to moderately high selenium intake but did not increase further when selenium intake was increased to even higher levels. Thus, fecal selenium excretion contributes to regulation of whole-body selenium at physiological selenium intakes. The pattern of its response to the full spectrum of selenium intakes was different from the urinary excretion response, suggesting that the mechanisms of fecal and urinary routes of excretion are different.

Selenium nutrition of hybrid striped bass (Morone chrysops × M. saxatilis) bioavailability, toxicity and interaction with vitamin E

Two concurrent 12-week feeding trials were conducted to evaluate the bioavailability of inorganic sodium selenite and organic seleno-DL-methionine and to investigate the potential interaction between selenium and vitamin E in juvenile hybrid striped bass. In experiment 1, purified diets utilizing casein, gelatin and an amino acid premix as protein sources with a basal selenium concentration of 0.11 mg Se kg⁻¹ were supplemented with either Na₂SeO₃ to provide selenium concentrations of 1.19, 2.00, 5.17 and 21.23 mg Se kg⁻¹ or with seleno-DL-methionine to provide 0.90, 1.26 and 2.55 mg Se kg⁻¹ and fed to juvenile hybrid striped bass in aquaria. A second experiment evaluated potential interactions by feeding these purified diets with or without supplemental vitamin E or sodium selenite, singularly or in combination. No overt selenium deficiency signs were exhibited by fish in either of the experiments; however, signs of selenium toxicity including retarded weight gain (WG), reduced feed intake and feed efficiency ratio (FER) as well as increased mortality, were observed in fish fed the diet containing more than 20 mg Se kg⁻¹. Whole-body selenium and whole-body selenium retention were linearly influenced by sodium selenite and selenomethionine. However, there was no significant effect of dietary selenium, vitamin E or their interaction on WG, FER and survival. Slope-ratio analysis showed that bioavailability of seleno-DL-methionine as a selenium source for juvenile hybrid striped bass was significantly (P < 0.01) higher (3.3-fold) than sodium selenite.

Deletion of Apolipoprotein E Receptor-2 in Mice Lowers Brain Selenium and Causes Severe Neurological Dysfunction and Death When a Low-Selenium Diet Is Fed

Selenoprotein P (Sepp1) is a plasma and extracellular protein that is rich in selenium. Deletion of Sepp1 results in sharp decreases of selenium levels in the brain and testis with dysfunction of those organs. Deletion of Sepp1 also causes increased urinary selenium excretion, leading to moderate depletion of whole-body selenium. The lipoprotein receptor apolipoprotein E receptor-2 (apoER2) binds Sepp1 and facilitates its uptake by Sertoli cells, thus providing selenium for spermatogenesis. Experiments were performed to assess the effect of apoER2 on the concentration and function of selenium in the brain and on whole-body selenium. ApoER2-/- and apoER2+/+ male mice were fed a semipurified diet with selenite added as the source of selenium. ApoER2-/- mice had depressed brain and testis selenium, but normal levels in liver, kidney, muscle, and the whole body. Feeding a selenium-deficient diet to apoER2-/- mice led to neurological dysfunction and death, with some of the characteristics exhibited by Sepp1-/- mice fed the same diet. Thus, although it does not affect whole-body selenium, apoER2 is necessary for maintenance of brain selenium and for prevention of neurological dysfunction and death under conditions of selenium deficiency, suggesting an interaction of apoER2 with Sepp1 in the brain.

Deletion of selenoprotein P upregulates urinary selenium excretion and depresses whole-body selenium content

Deletion of the mouse selenoprotein P gene (Sepp1) lowers selenium concentrations in many tissues. We examined selenium homeostasis in Sepp1 − /− and Sepp1 +/+ mice to assess the mechanism of this. The liver produces and exports selenoprotein P, which transports selenium to peripheral tissues, and urinary selenium metabolites, which regulate whole-body selenium. At intakes of selenium near the nutritional requirement, Sepp1 − /− mice had whole-body selenium concentrations 72 to 75% of Sepp1 +/+ mice. Genotype did not affect dietary intake of selenium. Sepp1 − /− mice excreted in their urine approximately 1.5 times more selenium in relation to their whole-body selenium than did Sepp1 +/+ mice. In addition, Sepp1 − /− mice gavaged with 75SeO 3 2− excreted 1.7 to 2.4 times as much of the 75Se in the urine as did Sepp1 +/+ mice. These findings demonstrate that deletion of selenoprotein P raises urinary excretion of selenium. When urinary small-molecule 75Se was injected intravenously into mice, over 90% of the 75Se appeared in the urine within 24 h, regardless of selenium status. This shows that urinary selenium is dedicated to excretion and not to utilization by tissues. Our results indicate that deletion of selenoprotein P leads to increased urinary selenium excretion. We propose that the absence of selenoprotein P synthesis in the liver makes more selenium available for urinary metabolite synthesis, increasing loss of selenium from the organism and causing the decrease in whole-body selenium and some of the decreases observed in tissues of Sepp1 − /− mice.

SELENOPROTEIN P: An Extracellular Protein with Unique Physical Characteristics and a Role in Selenium Homeostasis

Selenoprotein P is an abundant extracellular glycoprotein that is rich in selenocysteine. It has two domains with respect to selenium content. The N-terminal domain of the rat protein contains one selenocysteine residue in a UxxC redox motif. This domain also has a pH-sensitive heparin-binding site and two histidine-rich amino acid stretches. The smaller C-terminal domain contains nine selenocysteine and ten cysteine residues. Four isoforms of selenoprotein P are present in rat plasma. They share the same N terminus and amino acid sequence. One isoform is full length and the three others terminate at the positions of the second, third, and seventh selenocysteine residues. Selenoprotein P turns over rapidly in rat plasma with the consequence that approximately 25% of the amount of whole-body selenium passes through it each day. Evidence supports functions of the protein in selenium homeostasis and oxidant defense. Selenoprotein P knockout mice have very low selenium concentrations in the brain, the testis, and the fetus, with severe pathophysiological consequences in each tissue. In addition, those mice waste moderate amounts of selenium in the urine. Selenoprotein P binds to endothelial cells in the rat, and plasma levels of the protein correlate with prevention of diquat-induced lipid peroxidation and hepatic endothelial cell injury. The mechanisms of these apparent functions remain speculative and much work on the mechanism of selenoprotein P function lies ahead. Measurement of selenoprotein P in human plasma has shown that it is depressed by selenium deficiency and by cirrhosis. Selenium supplementation of selenium-deficient human subjects showed that glutathione peroxidase activity was optimized before selenoprotein P concentration was optimized, indicating that plasma selenoprotein P is the better index of human selenium nutritional status.

Absorption, Distribution and Excretion of Selenium from Beef and Rice in Healthy North American Men

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.

Effects of dietary selenite or selenomethionine on tissue selenium levels of Atlantic salmon ( Salmo salar)

A feeding experiment was carried out to compare the effects of supplementing a fish meal based diet with selenium as selenite or selenomethionine on Atlantic salmon. Five duplicate groups of Atlantic salmon parr (mean weight 4.5 g) were given a basal diet either unsupplemented or supplemented with 1 and 2 mg Se/kg as selenite or selenomethionine respectively, for 8 weeks. Weight gains were similar in all groups. Selenium concentrations in the liver were highest in the groups given selenite whereas muscle and whole-body selenium concentrations were highest in the groups given selenomethionine. Only a minor increase in muscle selenium concentration was observed by supplementing selenite. There were no significant differences in activity of the selenium-containing enzyme, glutathione peroxidase, between the dietary groups, indicating a sufficient selenium status in all groups.

Dietary Toxicity of Selenium-Contaminated Red Shiners to Striped Bass

Abstract Red shiners Notropis lutrensis (weight, about 1 g each) from the selenium-affected areas of Belews Lake, North Carolina, a cooling reservoir for an electric power plant, were fed to striped bass Morone saxatilis (about 250 g each) in a laboratory experiment. Consumption of red shiners (whole-body selenium concentration, 9.6 μg Se/g wet weight) by striped bass was followed by modified behavior, little increase in weight, a reduced condition factor (105·weight/length3), an elevated selenium concentration in muscle (3.8 ug Se/g wet weight), histological damage to the liver and trunk kidney, and the death of all fish within 78 d. Striped bass fed a comparable, uncontaminated diet of golden shiners Notemigonus crysoleucas (about 1 g each) gained weight, increased their condition factor, had muscle selenium concentrations averaging 1.1 μg Se/g wet weight, and exhibited no histological abnormalities or reduced survival during the 80-d experiment. Toxicity and death induced by selenium-contaminated prey ...

Subcellular distribution of selenium-containing proteins in the rat

The subcellular distribution of selenium in rat tissues was studied by measuring 75Se in animals provided for 5 months with [ 75Se]selenite as the main dietary source of selenium. Equilibration of the animals to a constant specific activity allowed the measurement of 75Se to be used as a specific elemental assay for selenium. Of the whole-body selenium, 51% was in the soluble fractions and 48% was bound to the particulate fractions as follows: 21 % in plasma membranes, 11% in microsomes, and 16% in mitochondria. Glutathione peroxidase was primarily a soluble enzyme, but part of the activity was associated with plasma membrane in liver, mitochondria in liver and kidney, and microsomes in testes. Selenium in glutathione peroxidase accounted for about one-third of the particulate-associated selenium. These results indicate that other selenium-containing proteins besides glutathione peroxidase are present in membranes.