Dietary selenium, glutathione peroxidase activity, and toxicity of 2,3,7,8-tetrachloro-dibenzo-p-dioxin

TCDD has been shown to inhibit selenium-dependent glutathione peroxidase activity. The role of selenium in TCDD toxicity is not known. We have therefore examined the effect of TCDD administration on hepatic glutathione peroxidase, aryl hydrocarbon hydroxylase, glutathione reductase, and glutathione S-transferase activities, glutathione content, and lipid peroxidation in rats fed 0, 0.10, and 2.0 ppm dietary selenium. TCDD treatment significantly inhibited selenium-dependent glutathione peroxidase in animals on diets containing 0.10 and 2.0 ppm selenium. The selenium-dependent glutathione peroxidase activities in rats on 0.10 and 2.0 ppm dietary selenium were 8.3-and 4.7-fold greater than in animals fed a diet containing 0 ppm selenium. TCDD administration enhanced hepatic microsomal lipid peroxidation by factors of 4.0, 4.9, and 9.8 in animals fed diets containing 0, 0.10, and 2.0 ppm selenium, respectively. The administration of a lethal dose of TCDD to rats fed diets containing 0, 0.10, and 2.0 ppm selenium resulted in 0, 46, and 7% survival, respectively, after 66 d. Aryl hydrocarbon hydroxylase, glutathione S-transferase, and glutathione reductase activities were induced by TCDD. The results indicate that optimum dietary selenium provides partial protection from the toxic effects of TCDD.     

Hepatic glutathione metabolism and lipid peroxidation in response to excess dietary selenomethionine and selenite in mallard ducklings

Studies were conducted with mallard (Anas platyrhynchos) ducklings to determine the effects of excess dietary selenium (Se) on hepatic glutathione concentration and associated enzymes, and lipid peroxidation. Day-old ducklings were fed 0.1, 10, 20, or 40 ppm Se as seleno-DL-methionine or sodium selenite for 6 wk. Selenium from selenomethionine accumulated in a dose-dependent manner in the liver, resulting in a decrease in the concentration of hepatic-reduced glutathione (GSH) and total hepatic thiols (SH). These effects were accompanied by a dose-dependent increase in the ratio of oxidized glutathione (GSSG) to GSH, and an increase in malondialdehyde concentration as evidence of lipid peroxidation. Hepatic and plasma GSH peroxidase activity was initially elevated at 10 ppm Se as selenomethionine, whereas GSSG reductase activity was elevated at higher dietary concentrations of Se. Selenium from sodium selenite accumulated in the liver to an apparent maximum at 10 ppm in the diet, resulting in an increase in hepatic GSH and GSSG accompanied by a small decrease in total hepatic SH. Sodium selenite resulted in an increase in hepatic GSSG reductase activity at 10 ppm and in plasma GSSG reductase activity at 40 ppm. A small increase in lipid peroxidation occurred at 40 ppm. These findings indicate that excess dietary Se as selenomethionine has a more pronounced effect on hepatic glutathione metabolism and lipid peroxidation in ducklings than does selenite, which may be related to the pattern of accumulation. Effects of Se as selenite appear to be less pronounced in ducklings than reported in laboratory rodents. The effects of selenomethionine, which occurs in vegetation, are of particular interest with respect to the health of wild aquatic birds in seleniferous locations.     

Effect of dietary selenium on the metabolism of aflatoxin B1 in turkeys

To investigate the biochemical mechanism of the previously reported protective effect of dietary selenium against aflatoxin toxicity, the hepatic metabolism of aflatoxin B1 in turkey poults was examined at various dietary selenium concentrations. Diets were supplemented with 0.2, 2.0 or 4.0 ppm selenium (as sodium selenite) and 500 ng aflatoxin B1/g diet in an 18-day trial. Free and conjugated aflatoxin and metabolites were quantified using high-performance liquid chromatography. The proportion of liver aflatoxins in conjugated forms increased and the ratio of free aflatoxin B1/M1 decreased with increasing dietary selenium concentrations. These in vivo results provide evidence of selenium-induced enhancement of aflatoxin detoxification processes. In a similar experiment using 2.0 ppm selenium and 750 ng aflatoxin B1/g diet, the concentration of hepatic reduced glutathione, cytochrome P-450 and the activity of enzymes involved in the metabolism of aflatoxin B1 and glutathione were determined. Although the selenium supplement increased glutathione peroxidase activity, dietary selenium had no effect on reduced glutathione or cytochrome P-450 concentrations or on the activities of glutathione transferase E, glucuronyl transferase and cytochrome c reductase. These data indicate that the protective action of selenium is not mediated by an increase in glutathione availability for aflatoxin conjugation or by effects on the activities of these enzymes as measured in vitro.     

Role of selenium toxicity and oxidative stress in aquatic birds

Adverse effects of selenium (Se) in wild aquatic birds have been documented as a consequence of pollution of the aquatic environment by subsurface agricultural drainwater and other sources. These effects include mortality, impaired reproduction with teratogenesis, reduced growth, histopathological lesions and alterations in hepatic glutathione metabolism. A review is provided, relating adverse biological effects of Se in aquatic birds to altered glutathione metabolism and oxidative stress. Laboratory studies, mainly with an organic form of Se, selenomethionine, have revealed oxidative stress in different stages of the mallard (Anas platyrhynchos) life cycle. As dietary and tissue concentrations of Se increase, increases in plasma and hepatic GSH peroxidase activities occur, followed by dose-dependent increases in the ratio of hepatic oxidized to reduced glutathione (GSSG:GSH) and ultimately hepatic lipid peroxidation measured as an increase in thiobarbituric acid reactive substances (TBARS). One or more of these oxidative effects were associated with teratogenesis (4.6 ppm wet weight Se in eggs), reduced growth in ducklings (15 ppm Se in liver), diminished immune function (5 ppm Se in liver) and histopathological lesions (29 ppm Se in liver) in adults. Manifestations of Se-related effects on glutathione metabolism were also apparent in field studies in seven species of aquatic birds. Reduced growth and possibly immune function but increased liver:body weight and hepatic GSSG:GSH ratios were apparent in american avocet (Recurvirostra americana) hatchlings from eggs containing 9 ppm Se. In black-necked stilts (Himantopus mexicanus), which contained somewhat lower Se concentrations, a decrease in hepatic GSH was apparent with few other effects. In adult American coots (Fulica americana), signs of Se toxicosis included emaciation, abnormal feather loss and histopathological lesions. Mean liver concentrations of 28 ppm Se (ww) in the coots were associated with elevated hepatic GSH peroxidase, depletion of hepatic protein bound thiols and total thiols, but a small increase in GSH. Diving ducks in the San Francisco Bay area exhibited a positive correlation between hepatic Se concentration and GSH peroxidase activity (r=0.63, P<0.05), but a negative correlation between hepatic Se and GSH concentration (r=-0.740, P<0.05). In willets (Catoptrophorus semipalmatus) from the San Diego area, positive correlations occurred between hepatic Se concentration and GSSG (r=0.70, P<0.001), GSSG:GSH ratio, and TBARS. In emperor geese (Chen canagica) from western Alaska, blood levels of up to 9.4 ppm occurred and were associated with increased plasma GSH peroxidase activity (r=0.62, P<0.001), but with decreased plasma GSSG reductase activity. When evaluating Se toxicity, interactive nutritional factors, including other elements and dietary protein, should also be taken into consideration. Further studies are needed to examine the relationship between different forms of environmentally occurring selenium, arsenic and mercury on reproduction, hepatotoxicity and immune function of aquatic birds. Further selenium nutritional interaction studies may also help to illucidate the mechanism of selenium induced teratogenesis, by optimizing GSH and other antioxidant defense mechanisms in a manner that would stabilize or raise the cell's threshold for susceptibility to toxic attack from excess selenium. It is concluded that Se-related manifestations of oxidative stress may serve as useful bioindicators of Se exposure and toxicity in wild aquatic birds.     

Selenium and drug metabolism--I. Multiple modulations of mouse liver enzymes

Male albino mice were raised on diets containing less than 10 ppb selenium (Se-) or supplemented with 0.5 ppm selenium (Se+) for 6 months. In the (Se-) group total liver selenium was less than 10% of the control, liver selenium-dependent glutathione peroxidase (GSH-Px) less than 2%. The specific activities of catalase and superoxide dismutase showed essentially no differences between the dietary groups. Several phase I-related specific enzyme activities were measured in liver microsomes. No significant differences between the two animal groups were found for cytochrome P-450 and b 5 content, NADH-cytochrome b 5 reductase, as well as for aniline hydroxylation and aminopyrine dealkylation rates. In (Se-) microsomes, NADPH-cytochrome P-450 reductase activity was about half that found in (Se+) microsomes. An increase in microsomes from (Se-) mice was found for 7-ethoxycoumarine deethylation rate (460%), cytochrome P-450 hydroperoxidase activity (170%), and heme oxygenase (276%). The N-oxidation rate of the flavin-containing monooxygenase decreased by 35%, the N-demethylation rate by 50% in (Se-) animals. Stopped-flow measurements of the reduction rates of microsomal pigments did not support evidence for limitations in microsomal electron supply during selenium deficiency. Among the phase II reactions examined, sulfotransferase activity towards 4-nitrophenol was 47% of the controls in Se-deficient liver cytosols while UDP-glucuronyl transferase activity towards this substrate increased to 215%. Glutathione-S-transferase activity was much higher in (Se-) livers than in (Se+): 310% with 1,2-dichloro-4-nitrobenzene, 255% with 1-chloro-2,4-dinitrobenzene and 120% with ethacrynic acid as substrate. The data indicate that in addition to GSH-Px many other enzyme activities in mouse liver are affected by prolonged dietary selenium deficiency. These effects might be useful in assessing the severity of selenium deficiency. A microsomal selenium-dependent metabolic modulator is discussed as a possible mechanism.     

Synthetic seleno-organic compound with glutathione peroxidase-like activity in the chick

The glutathione peroxidase activity catalyzed by the seleno-organic anti-inflammatory drug Ebselen (registered under the trademark of the Natterman Corp. Cologne, FRG) [PZ51, 2-phenyl-1,2-benzisoselenazol-3(2H)on], as measured by NADPH oxidation, was inhibited in vitro by the selenium-dependent glutathione peroxidase (SeGSHpx) inhibitors aurothioglucose and D-(-)penicillamine HCl. Vitamin E- and selenium-deficient chicks were given 0, 80 or 320 ppm PZ51 in diets devoid of vitamin E and supplemented with low levels of sodium selenite (0.04 ppm selenium added to the basal diet containing ca. 0.015 ppm selenium) when a small number of chicks (ca. 13%) had exudative diathesis (ED). By 24 hr, the high PZ51 dose (320 ppm) delayed the onset of ED compared to untreated controls. Similarly, vitamin E-deficient chicks fed diets containing 0, 80, 160, 320, 640 or 1280 ppm PZ51 and supplemented with 0.04 ppm selenium showed ED in inverse proportion to log PZ51 dose. Plasma and liver post-mitochondrial supernatant samples from these chicks also exhibited log-linear relationships between dietary PZ51 level and selenium content or SeGSHpx-like activity. The amount of SeGSHpx-like activity for chicks given PZ51 above that determined for untreated chicks was extractable into ethanol, indicating that those PZ51-associated increases were not due to protein-bound selenium or SeGSHpx. This suggests that selenium from PZ51 was not available to support synthesis of SeGSHpx. Dietary PZ51 (1280 ppm) or selenium (0.1 ppm) alone or in combination decreased the acute lethalities of nitrofurantoin or paraquat in vitamin E-adequate chicks. The results indicate that SeGSHpx-like activity in selenium-deficient chicks is increased by oral administration of PZ51, which appears to mimic the true enzyme by affording protection against clinical signs of selenium deficiency (i.e. ED) and pro-oxidant drug lethality.     

Excessive dietary selenium decreases the vitamin A storage and the enzymatic antioxidant defence in the liver of rats

This study investigated the influence of selenium intake, over 8 weeks, on vitamin A level and on enzymatic antioxidant defence in the liver of young rats. Deficient animals were fed a well-balanced diet but without selenite addition; the Se content of this diet which originated from natural Se content of ingredients was 0.05 mg/kg. Controls were fed the same diet with 0.40 mg/kg added Se. The two other groups received high levels of Se, 2.05 or 4.05 mg/kg. Excessive Se intake decreased the concentrations of retinol and retinyl palmitate in the liver. The linear regression analysis indicated a significant (P < 0.001) dose-dependent vitamin A decline. As expected, Se deficit lowered glutathione peroxidase activity. The highest Se excess decreased the enzymatic antioxidation: Zn,Cu Superoxide dismutase, catalase, glutathione peroxidase activities. Data showed that high dietary Se can sometimes enhance carcinogenesis and our results suggest that it is best to be cautious in administrating Se to humans with the aim of preventing diseases.     

Effects of cadmium treatment on selenium-dependent and selenium independent glutathione peroxidase activities and lipid peroxidation in the kidney and liver of rats maintained on various levels of dietary selenium

Rats fed a basal, low-selenium diet, or this diet supplemented with 0.1 ppm and 1.0 ppm selenium and treated with cadmium, showed significant reductions in the activity of the selenoenzyme glutathione peroxidase in kidney and liver. Cadmium treatment resulted in a significant increase in the activity of selenium-independent glutathione peroxidase activity in the liver of selenium-supplemented rats. Selenium-independent glutathion peroxidase activity was significantly reduced in the kidney of rats fed the basal low-selenium diet. There was no significant increase in lipid peroxidation in any of the groups studied. Cadmium concentrations in the kidney and liver of these animals ranged from about 250 to 700 g Cd/g tissue, dry weight.Supported by NIEHS Center Grant ES-00159 and a Grant from the Selenium-Tellurium Development Association     

Subchronic hepatotoxicity of selenomethionine ingestion in mallard ducks

Two-year-old male mallards (Anas platyrhynchos) received a control diet (0.2 ppm Se) or diets containing 1, 2, 4, 8, 16, or 32 ppm Se as selenomethionine for 14 wk. Se accumulated readily in the liver in a dose-dependent manner, reaching a mean concentration of 29 ppm (wet weight) in the 32 ppm group. Dietary Se of 2 ppm or greater increased plasma glutathione peroxidase activity. Mortality (10%) and histopathological effects, including bile duct hyperplasia and hemosiderin pigmentation of the liver and spleen, occurred in the 32 ppm group. These histopathological effects were accompanied by lower hemoglobin concentrations (16 and 32 ppm groups) and hematocrit (32 ppm group), and elevated plasma alkaline phosphatase activity (32 ppm group) indicative of cholestatic liver injury. Other manifestations of hepatotoxicity included significant linear dose responses for hepatic oxidized glutathione (GSSG) concentrations and ratio of GSSG to reduced glutathione (GSH). Means for both of these responses differed from controls in groups receiving 8-32 ppm Se. Mean hepatic GSH and malondialdehyde (a measure of lipid peroxidation) concentrations were significantly elevated in the 16 and 32 ppm groups. Subchronic effects of selenomethionine, which occurs in vegetation, are of particular interest with respect to the health of wild aquatic birds in seleniferous locations.     

Dietary iron and 2,3,7,8-tetrachlorodibenzo-p-dioxin induced alterations in hepatic lipid peroxidation, glutathione content and body weight

The effects of various levels of dietary iron on hepatic lipid peroxidation (malondialdehyde [MDA] content), reduced glutathione (GSH) and GSH peroxidase (GSH-PX) activity as well as liver and body weights of female rats following TCDD administration were examined. Rats were fed diets containing deficient (6 ppm), normal (35 ppm) and supplemented (120 ppm) iron for 17, 24 and 31 days. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, 40 micrograms/kg/day P.O.) in corn oil or the vehicle was given on days 9, 8 and 7 prior to sacrifice. TCDD treatment produced a 3-fold increase in hepatic MDA content in animals on normal iron diet. TCDD administration failed to increased MDA content in iron deficient animals. In the iron supplemented groups, TCDD resulted in 2.5 fold increases in lipid peroxidation. Dietary iron had no effect on hepatic GSH-PX activity. Animals on the iron deficient diet had 12-21% decreases in hepatic GSH content. TCDD administration resulted in 15-22% decreases in GSH content in animals on the control and iron supplemented diets. TCDD treatment resulted in significant decreases in body weights of animals on all 3 diets. TCDD induced lipid peroxidation appears to be iron dependent. However, the loss in body weight due to TCDD toxicity may not be dependent on lipid peroxidation.     

Cigarette smoke exposure alters [14C]arachidonic acid metabolism in aortas and platelets of rats fed various levels of selenium and vitamin E

Rats were placed on a basal diet supplemented with 0, 0.03, or 3 ppm selenium and 0 or 20 ppm vitamin E for 41-43 wk. Selenium deficiency decreased hepatic glutathione peroxidase activity and lowered both aortic prostacyclin (PGI2) and platelet thromboxane (TXA2) production compared to selenium- and vitamin E-supplemented animals. Vitamin E deficiency increased hepatic lipid peroxidation and decreased aortic PGI2 synthesis. Rats exposed daily for 31-32 wk to fresh smoke from a UK 2R1 reference cigarette had carboxyhemoglobin levels of 0.75 +/- 0.12 and 4.73 +/- 0.12% in sham- and smoke-exposed groups, respectively. Animals chronically exposed to cigarette smoke displayed a nearly twofold increase in pulmonary arylhydrocarbon hydroxylase activity. Smoke exposure produced a 26-33% decrease in aortic PGI2 synthesis compared to shams in the Se3E20, Se0.03E20, and Se3E0 groups. Smoking also increased platelet thromboxane 91% and 98% in the Se3E20 and Se3E0 groups compared to shams. It is concluded that cigarette-smoke exposure and selenium or vitamin E deficiency alter aortic PGI2 and platelet TXA2 production.     

Effects of cadmium and dietary selenium on cytoplasmic and mitochondrial antioxidant defense systems in the heart of rats fed high dietary copper

Rats were fed a high copper diet (50 ppm copper) supplemented with 0, 0.1 and 0.5 ppm selenium and treated with either 50 ppm cadmium admixed with their feed or given 5 mg cadmium via osmotic minipumps. Only rats fed the low-selenium basal diet and treated with cadmium via the osmotic minipumps showed a significant rise in thiobarbiturate-reactive substances. This was associated with marked reductions in the activity of the selenoenzyme, glutathione peroxidase in heart cytosol and mitochondria. Cytosolic superoxide dismutase was unaffected and catalase activity was increased as a result of cadmium treatment. Dietary cadmium also resulted in marked reductions in the activities of cytosolic glutathione peroxidase, superoxide dismutase, and catalase. These biochemical lesions were not accompanied by decreases in the corresponding mitochondrial enzymes and no increase in thiobarbiturate-reactive substances was observed. Heart metal levels indicate the formation of cadmium-selenium complexes in rats treated with cadmium via the osmotic minipumps. Dietary cadmium does not appear to interact with selenium in a similar fashion. Heart copper levels were increased by dietary cadmium treatment. Thus, heart mitochondria appear to be the site of the primary biochemical lesion for cadmium and involve increased lipid peroxidation only when mitochondrial antioxidant defense enzymes are compromised.     

Selenium and drug metabolism--II. Independence of glutathione peroxidase and reversibility of hepatic enzyme modulations in deficient mice

Male mice were fed a diet containing less than 0.01 ppm selenium (Se-) for 6 months. A control group received the same diet containing 0.5 ppm selenium (Se+). In the livers of the Se- animals a drastic decrease in glutathione peroxidase (GSH-Px) activity was observed. It reached undetectable levels after 17 days of the Se- diet. At that time, GSH-transferase activity began to increase significantly, followed by changes in many other enzyme activities. After the 60th day, these enzyme modulations had reached a plateau with the following percentage changes compared to controls: GSH-transferases: 320% (1,2-dichloro-4-nitrobenzene), 218% (1-chloro-2,4-dinitrobenzene); glutathione reductase: 160%; ethoxycoumarin deethylase: 330%; cytochrome P-450-hydroperoxidase: 230%; heme oxygenase: 240%; UDP-glucuronyltransferase: 200%; GSH-thioltransferase: 64%; sulphotransferase: 62%; NADPH-cytochrome-P-450-reductase: 65%; flavin-containing mono-oxygenase: 57%. No significant changes were observed for GSH-transferase activity assayed with ethacrynic acid or for microsomal H2O2 formation and aniline hydroxylase activity. In single-pulse repletion experiments by injection of 250 micrograms selenium/kg body wt, different individual time constants for the recovery process of the enzymatic perturbations were observed. The half-times for the recovery ranged from 5.7 hr for the microsomal NADPH-cytochrome-P-450 reductase to over 29 hr for GSH-Px up to 44 hr for part of the GSH-transferase activity. 250 micrograms selenium/kg body wt were needed to restore 50% of GSH-Px activity in the long-term Se- mice compared to Se+ controls. All other enzymatic changes in the Se- mice needed a dose of 7 micrograms selenium/kg body wt for 50% restorage . The results demonstrate that processes other than those related to GSH-Px take place in a later phase of selenium deficiency in mouse liver with a chronologically common beginning. The different repletion and depletion kinetics as well as the different need of these processes for the trace element are discussed with respect to the existence of two separate selenium pools.     

Dietary antioxidants and the biochemical response to oxidant inhalation. II. Influence of dietary selenium on the biochemical effects of ozone exposure in mouse lung

We examined the influence of dietary selenium (Se) on the pulmonary biochemical response to ozone (O3) exposure. For 11 weeks, weanling female strain A/St mice were fed a test diet containing Se either at 0 ppm (-Se) or 1 ppm (+Se). Each diet contained 55 ppm vitamin E (vit E). Mice from each dietary group were exposed to 0.8 +/- 0.05 ppm (1568 +/- 98 micrograms/m3) O3 continuously for 5 days. After O3 exposure, they were killed along with a matched number of unexposed controls, and their lungs were analyzed for various biochemical parameters. The Se contents of lung tissue and whole blood were determined, and the levels were seven- to eightfold higher in +Se mice than in -Se mice, reflecting the Se intake of the animals. In unexposed control mice, Se deficiency caused a decline in glutathione peroxidase (GP) activity relative to +Se group. After O3 exposure, the GP activity in the -Se group was associated with a lack of stimulation of glutathione reductase (GR) activity and the pentose phosphate cycle (PPC) as assessed by measuring glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) activities. In contrast, the +Se group after O3 exposure exhibited increases in all four enzyme activities. Other parameters, e.g., lung weight, total lung protein, DNA and nonprotein sulfhydryl contents, and O2 consumption, were not affected by dietary Se in the presence or absence of O3 exposure. The data indicate that dietary Se alters the GP activity, which in turn influences the GR and PPC activities in the lung evidently through a reduced demand for NADPH. The level of vit E in the lung was found to be twofold higher in the -Se group than in the +Se group, suggesting a compensatory relationship between Se and vit E in the lung. With O3 exposure, both Se and vit E contents further increased in the lungs of each dietary group. It is plausible that Se and vit E under oxidant stress are "mobilized" to the lung from other body sites.     

Embryotoxic and teratogenic effects of selenium in the diet of mallards

Mallards (Anas platyrhynchos) were fed a control diet, diets containing 1, 5, 10, or 25 ppm Se as sodium selenite, or a diet containing 10 ppm Se as seleno-DL-methionine in the first of two experiments. Selenium at 10 ppm as selenomethionine or 25 ppm as sodium selenite caused a 40-44% decrease in the total number of eggs that hatched compared to controls. Selenium at 25 ppm (sodium selenite) resulted in a 19% decrease in mean embryonic weight at 18 d of incubation, accompanied by a 6% decrease in crown-rump length. Ten parts per million Se as selenomethionine was more teratogenic than sodium selenite at 25 ppm. Selenomethionine (10 ppm Se) resulted in an incidence of 13.1% malformations that were often multiple, whereas sodium selenite (10 and 25 ppm Se) resulted in 3.6 and 4.2% malformations. The teratogenicity of selenomethionine was confirmed in a second experiment in which mallards received 1, 2, 4, 8, or 16 ppm Se as selenomethionine, resulting in 0.9, 0.5, 1.4, 6.8, and 67.9% malformations, respectively. These malformations included hydrocephaly, microphthalmia, lower bill defects, and foot defects with ectrodactyly. Both forms of selenium increased the incidence of edema and stunted embryonic growth. Selenomethionine (10 ppm Se) resulted in a significant increase of approximately 40% in plasma glutathione peroxidase activity and a 70% increase in sorbitol dehydrogenase activity (indicative of hepatotoxicity) in hatchlings. Sodium selenite (25 ppm Se) resulted in fourfold elevation in plasma uric acid concentration, indicative of renal alteration. Selenomethionine accumulated much better in eggs than did sodium selenite. These findings indicate that selenomethionine is considerably more teratogenic and generally more embryotoxic than sodium selenite, probably due to higher uptake of selenomethionine.     

Role of selenium-dependent glutathione peroxidase in protecting against t-butyl hydroperoxide-induced damage in hepatocytes

The role of the selenoenzyme glutathione peroxidase (Se-GSHPx) in protecting against oxidative injury was studied in hepatocytes isolated from rats fed either a low-selenium (Se-) or a selenium-adequate (Se+, control) diet. In rats fed Se- diet for eight weeks the selenium content of plasma and liver was lowered to 15 and 8%, respectively. No Se-GSHPx and only 5% of total GSHPx activity was detected in Se- hepatocytes. However, the Se- hepatocytes were as resistant as the Se+ cells to oxidative injury by 0.8 mM tert-butyl hydroperoxide (t-BuOOH), or 0.2 mM t-BuOOH plus 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of oxidized glutathione (GSSG) reductase. Only at 1.5 mM t-BuOOH or at 0.5 mM t-BuOOH with BCNU were cell damage and lipid peroxidation more evident in Se- cells. At all t-BuOOH concentrations used the depletion of cellular glutathione (GSH) was similar in magnitude in Se- and Se+ cells, but Se+ cells released more glutathione (mainly GSSG), obviously due to their higher Se-GSHPx activity. These results suggest that hepatocytes devoid of Se-GSHPx activity maintain a high capacity to resist peroxidative attack, either via residual (non-Se)GSHPx activity or other compensatory GSH-associated detoxication mechanisms.     

Non-optimal levels of dietary selenomethionine alter splenocyte response and modify oxidative stress markers in female mice.

Many studies evaluating the effects of selenium (Se) status on immunity utilize inorganic Se, although selenomethionine (Se-Met) has been suggested to be more bioavailable and less toxic. In the current study, we investigated the effects of dietary Se-Met on immune system function and cellular redox status in C57BL/6N female mice fed with low (0.02 ppm), sufficient (0.2 ppm, control group), or excess Se-Met (2 ppm) in the diet for 50 days. Low Se-Met intake reduced glutathione peroxidase (GPx) activity and glutathione concentration without modifying lipoperoxidation. While low Se-Met intake also reduced the number of B cells in the spleen, it increased mitogen-induced proliferation, IL-4 and IL-12 secretion when compared to the sufficient Se-Met intake group. In comparison to controls, excess Se-Met intake increased splenocyte proliferation and reduced B cell numbers, IL-4, and IL-12 secretion without affecting oxidative stress markers. These data suggest that Se-Met supplementation should be carefully evaluated as it many influence immune function.     

Effects of dietary selenium on tissue concentrations, pathology, oxidative stress, and immune function in common eiders (Somateria mollissima)

Common eiders (Somateria mollissima) were fed added Se (as L-selenomethionine) in concentrations increasing from 10 to 80 ppm in a pilot study (Study 1) or 20 (low exposure) and up to 60 (high exposure) ppm Se in Study 2. Body weights of Study 1 ducks and high-exposure ducks in Study 2 declined rapidly. Mean concentrations of Se in blood reached 32.4 ppm wet weight in Study 1 and 17.5 ppm wet weight in high-exposure birds in Study 2. Mean Se concentrations in liver ranged from 351 (low exposure, Study 2) to 1252 ppm dry weight (Study 1). Oxidative stress was evidenced by Se-associated effects on glutathione metabolism. As Se concentrations in liver increased, Se-dependent glutathione peroxidase activity, glutathione reductase activity, oxidized glutathione levels, and the ratio of hepatic oxidized to reduced glutathione increased. In Study 2, the T-cell-mediated immune response was adversely affected in high-exposure eiders, but ducks in the low-exposure group exhibited evidence of an enhanced antibody-mediated immune response. Gross lesions in high-exposure ducks included emaciation, absence of thymus, and loss of nails from digits. Histologic lesions included severe depletion of lymphoid organs, hepatopathy, and necrosis of feather pulp and feather epithelium. Field studies showed that apparently healthy sea ducks generally have higher levels of Se in liver than healthy fresh-water birds, but lower than concentrations found in our study. Data indicate that common eiders and probably other sea ducks possess a higher threshold, or adverse effect level, for Se in tissues than fresh-water species. However, common eiders developed signs of Se toxicity similar to those seen in fresh-water birds.     

Differential effect of dietary selenium on the long-term neurotoxicity induced by MDMA in mice and rats

We examined the effect of dietary selenium (Se) on the long-term effect of 3,4-methylenedioxymethamphetamine (MDMA) on dopamine (DA) and 5-hydroxytryptamine (5-HT) containing neurons in the brain of mice and rats. Animals were fed either a Se-deficient (<0.02 ppm) or Se-replete (0.2 ppm) diet for 8 weeks. On the seventh week mice received three injections of MDMA (15 mg/kg, i.p. 3 h apart) or saline and rats a single dose of MDMA (12.5 mg/kg i.p.) or saline. All animals were sacrificed 7 days later. MDMA administration to mice depleted striatal DA concentration in both dietary groups, although depletion was considerably larger in the Se-deficient mice (64%) than Se-replete mice (30%). In addition, a decrease in 5-HT (17-32%) occurred in brain regions of Se-deficient but not Se-replete mice. In rats, MDMA decreased cortical [(3)H]-paroxetine binding (62%) and 5-HT content, the depletion being similar in the Se-deficient and Se-replete groups. No DA loss occurred in either group. There was no difference in the hyperthermic response induced by MDMA in Se-deficient or Se-replete animals. The Se-deficient diet decreased glutathione peroxidase (GPx) activity by 30% in mouse striatum and cortex and increased the degree of lipid peroxidation in cortical synaptosomes. Se-deficient rats also showed a decrease in brain GPx activity compared with the Se-replete group, but the degree of lipid peroxidation in synaptosomes was similar in both dietary groups. These results suggest that the antioxidant capacity of rats and mice differ leading to a differential susceptibility to the oxidative stress caused by MDMA in situations of low dietary Se.     

Effects of dietary selenium supplementation on serum and liver selenium,serum malondialdehyde and liver glutathione peroxidase activity in rats consuming thermally oxidized sunflower oil

The present study compared the effects of four isocaloric diets containing (1) fresh sunflower oil not supplemented with selenium (Fresh), (2) oxidized sunflower oil not supplemented with selenium (Oxidized), (3) fresh sunflower oil supplemented with 1 ppm selenium as sodium selenite (Fresh + Se), (4) oxidized sunflower oil supplemented with 1 ppm selenium as sodium selenite (Oxidized + Se) on serum MDA concentrations, liver GPx activity and serum and liver selenium contents in growing male Sprague Dawley rats during a period of 43 days. The oxidized oil used was prepared by heating fresh sunflower oil at 180 °C for 48 h. Serum and liver selenium contents and liver GPx activity were significantly higher in the selenium supplemented groups compared to the non-selenium supplemented groups, but these parameters did not differ significantly between the oxidized oil fed groups and the fresh oil fed groups. Serum MDA concentrations increased significantly in the Oxidized group compared to the Fresh group. This suggests that the ingestion of oxidized oil resulted in, in vivo lipid peroxidation. Serum MDA concentrations remained significantly higher even in comparison of the Oxidized + Se group with the Oxidized group. Our results emphasize that the consumption of oxidized oil increases in vivo lipid peroxidation and thus can be deleterious to health. However, we did not observe a significant beneficial effect of selenium supplementation upon the ingestion of thermally oxidized oil on lipid peroxidation.