The genotoxicity of selenium

Selenium at nutritional levels has been shown to have numerous anticarcinogenic or preventative effects against carcinogen-induced breast, colon, liver and skin cancer in animals. Many of these anticarcinogenic effects have been summarized. In addition, numerous mutagenic and antimutagenic effects of selenium compounds have been reported. Some of the selenium compounds frequently tested for mutagenicity are listed in Table 1. Because of the numerous reported anticarcinogenic and preventative effects of selenium, many individuals are supplementing their diets with amounts of selenium that are greater than the recommended daily requirement. Selenium is also used widely in industrial products such as selenium rectifiers, photoelectric batteries, alloys and paints. Because selenium at higher levels is known to be toxic, there should be a greater understanding about its genotoxic as well as its beneficial effect. The object of this review is to summarize experimental evidence both for the antimutagenic and the mutagenic effect of selenium.     

Selenium as an anticancer nutrient: roles in cell proliferation and tumor cell invasion

Selenium is an essential dietary component for animals including humans, and there is increasing evidence for the efficacy of certain forms of selenium as cancer-chemopreventive compounds. In addition, selenium appears to have a protective effect at various stages of carcinogenesis including both the early and later stages of cancer progression. Mechanisms for selenium-anticancer action are not fully understood; however, several have been proposed: antioxidant protection, enhanced carcinogen detoxification, enhanced immune surveillance, modulation of cell proliferation (cell cycle and apoptosis), inhibition of tumor cell invasion and inhibition of angiogenesis. Research has shown that the effectiveness of selenium compounds as chemopreventive agents in vivo correlates with their abilities to affect the regulation of the cell cycle, to stimulate apoptosis and to inhibit tumor cell migration and invasion in vitro. This article reviews the status of knowledge concerning selenium metabolism and its anticancer effects with particular reference to the modulation of cell proliferation and the inhibition of tumor cell invasion.     

Impact of dietary selenium intake on cardiac health: experimental approaches and human studies

Selenium, a dietary trace mineral, essential for humans and animals, exerts its effects mainly through its incorporation into selenoproteins. Adequate selenium intake is needed to maximize the activity of selenoproteins, among which glutathione peroxidases have been shown to play a major role in cellular defense against oxidative stress initiated by excess reactive oxygen species. In humans, a low selenium status has been linked to increased risk of various diseases, including heart disease. The main objective of this review is to present current knowledge on the role of selenium in cardiac health. Experimental studies have shown that selenium may exert protective effects on cardiac tissue in animal models involving oxidative stress. Because of the narrow safety margin of this mineral, most interventional studies in humans have reported inconsistent findings. Major determinants of selenium status in humans are not well understood and several nondietary factors might be associated with reduced selenium status. In this review, we discuss recent studies regarding the role of selenoproteins in the cardiovascular system, the effect of dietary intake on selenium status, the impact of selenium status on cardiac health, and the cellular mechanisms that can be involved in the physiological and toxic effects of selenium.     

Selenium and selenium-antagonistic elements in nutritional cancer prevention

Selenium is an essential trace element with antioxidative, antimutagenic, antiviral and anticarcinogenic properties. There is increasing evidence that the dietary selenium intakes are sub-optimal in the populations of many countries and that human cancer mortalities would significantly decline if additional selenium was made available either through supplementation or the fortification of certain foods. An important property of selenium is its interaction with other elements that may be present in foods, the water, the workplace and the environment, e.g. As, Cu, Ni, Co, Cr, Mn, Zn, Cd, Sn, Pb, Hg, Bi, Mo, Ag, Au, etc. The sequestration of elements by selenium represents an efficient natural detoxification mechanism for some of these elements but also results in the physiological inactivation of selenium. Animal experiments confirm that the chronic exposure to low levels of these elements abolishes the cancer-protective effect of selenium. Human cancer is likewise significantly determined by the interactions of selenium with other elements, as evidenced by epidemiological, ecological and case-control studies. Cadmium, for example, is a key risk-increasing element for prostate cancer; for breast cancer, Cd, Cr, Zn are mainly contributing; for bronchial cancer (in smelter workers), Cd, As, Cr, Sb, Co, La, all these elements are in a reciprocal relationship with Se. While selenium remains the key cancer-protective trace element, the interpretation of its mode of action necessitates consideration of the effects of selenium antagonistic elements.     

The antimutagenic effect of selenium on 7,12-dimethylbenz(a)anthracene and metabolites in the amesSalmonella/microsome system

The antimutagenic effect of selenium as sodium selenite, sodium selenate, selenium dioxide, and seleno-methionine was studied in the AmesSalmonella/microsome mutagenicity test using 7,12-dimethylbenz(a)anthracene (DMBA) and some of its metabolites. Selenium (20 ppm) as sodium selenite reduced the number of histidine revertants on plates containing up to 100 μg DMBA/plate. Increasing concentrations of selenium as sodium selenite, sodium selenate, and selenium dioxide up to 40 ppm Se progressively decreased the number of revertants caused by 50 μg DMBA. DMBA and its metabolites 7-hydroxymethyl-12-methylbenz(a)anthracene, 12-hydroxymethyl-7-methylbenz(a)anthracene, and 3-hydroxy-7,12-dimethylbenz(a)anthracene were mutagenic forSalmonella typhimurium TA100 in the presence of an S-9 mixture. Selenium supplementation as Na₂SeO₃ reduced the number of revertants induced by these metabolites to background levels. The antimutagenic effect of inorganic selenium compounds cannot be explained by toxicity of selenium as determined by viability tests withSalmonella typhimurium TA100. Selenium supplementation in all forms examined, except sodium selenate, decreased the rate of spontaneous reversion. Selenium as sodium selenate was slightly mutagenic at concentrations of 4 ppm or less. Higher concentration of Na₂SeO₄ inhibited the mutagenicity of DMBA. The present studies support the anticarcinogenic potential of selenium and indicate that form and concentration are important factors in this trace element's efficacy.     

The role of selenium in human conception and pregnancy

Selenium (Se) is a trace element essential for the appropriate course of vital processes in the human body. It is also a constituent of the active center of glutathione peroxidase that protects cellular membranes against the adverse effects of H₂O₂ lipid peroxides. Epidemiological surveys have demonstrated that selenium deficiency in the body may contribute to an increased risk for certain neoplasmic diseases (including colonic carcinoma, gastric carcinoma, pulmonary carcinoma and prostate carcinoma), as well as diseases of the cardiovascular, osseous and nervous systems. Apart from its cancer prevention and antioxidative activities, selenium protects the body against detrimental effects of heavy metals and determines the proper functioning of the immunological system.Furthermore, selenium plays a significant role in the undisturbed functioning of the reproductive system. Many studies have addressed correlations between its intake and fertility as well as disorders of procreation processes. Selenium deficiencies may lead to gestational complications, miscarriages and the damaging of the nervous and immune systems of the fetus. A low concentration of selenium in blood serum in the early stage of pregnancy has been proved to be a predictor of low birth weight of a newborn. A deficiency of this element may also cause infertility in men by causing a deterioration in the quality of semen and in sperm motility. For this reason, supplementation in the case of selenium deficiencies in the procreation period of both women and men is of utmost significance.     

Effects of dietary selenium and of lead on the genesis of spontaneous mammary tumors in mice

Selenium added to the diet significantly lowers the incidence of spontaneous mammary adenocarcinoma in female inbred C3H/St mice infected with the Bittner Milk Factor. Lead, 5 ppm, added to the drinking water in the form of the acetate, diminishes the uptake of selenium and reduces its anticarcinogenic effects, causing mammary tumors to appear with the same high incidence as in Se-unsupplemented controls. At higher lead concentrations in the drinking water (25 ppm), the overall tumor incidence is lowered, but tumor growth is significantly accelerated and the survival of tumor-bearing mice is shortened. Under the conditions of administration chosen, lead acts as a selenium antagonist and lowers the concentrations of selenium in liver, kidney, and spleen. The deposition of selenium, copper, and arsenic in bone is increased as compared to lead-unexposed controls.     

Biological effects of selenium compounds with a particular attention to the ontogenetic development

Selenium is a trace element that is essential for living organism. Its beneficial effect is, however, expressed in a very narrow dosage range: the high and low doses of selenium are connected with pathological manifestations. The toxicity depends on the chemical form of selenium, state of organism, interactions with heavy metals and on the stage of ontogenetic development. Whereas one dose of sodium selenite (20 micromol/kg b.w.) is lethal in adult rats, suckling rats are entirely resistant. However, within one week after administration of the same dose, cataract of eye lens developed. The highest incidence of cataract was observed in 10-day-old animals and it decreased until day 20. From postnatal day 20 to day 40 the rats were resistant to both the lethal and cataractogenic effects of selenium. The incidence of cataract may be suppressed by premature weaning, lower hydration of suckling, change of water soluble/water insoluble lens protein ratio, thyroxine treatment, and by interaction with mercury. By means of its oxidative and reduction properties, selenium is involved in the maintenance of the cell redox homeostasis. Typical example is its possible cardioprotective effect: selenium decreased number of arrhythmias, reduced infarct size and improved the contractile recovery after ischemia/reperfusion injury. Selenium supplementation may thus increase cardiac tolerance to ischemic damage.     

Extracellular production of hydrogen selenide accounts for thiol-assisted toxicity of selenite against Saccharomyces cerevisiae

Administration of selenium in humans has anticarcinogenic effects. However, the boundary between cancer-protecting and toxic levels of selenium is extremely narrow. The mechanisms of selenium toxicity need to be fully understood. In Saccharomyces cerevisiae, selenite in the millimolar range is well tolerated by cells. Here we show that the lethal dose of selenite is reduced to the micromolar range by the presence of thiols in the growth medium. Glutathione and selenite spontaneously react to produce several selenium-containing compounds (selenodiglutathione, glutathioselenol, hydrogen selenide, and elemental selenium) as well as reactive oxygen species. We studied which compounds in the reaction pathway between glutathione and sodium selenite are responsible for this toxicity. Involvement of selenodiglutathione, elemental selenium, or reactive oxygen species could be ruled out. In contrast, extracellular formation of hydrogen selenide can fully explain the exacerbation of selenite toxicity by thiols. Indeed, direct production of hydrogen selenide with D-cysteine desulfhydrase induces high mortality. Selenium uptake by S. cerevisiae is considerably enhanced in the presence of external thiols, most likely through internalization of hydrogen selenide. Finally, we discuss the possibility that selenium exerts its toxicity through consumption of intracellular reduced glutathione, thus leading to severe oxidative stress.     

Selenium and Psoriasis

Psoriasis is a chronic, immune-mediated skin disease characterized by production of reactive oxygen species due to the activation of tumor necrosis factor alpha (TNF-??), which is thought to be an important factor in inducing and maintaining psoriatic lesions. As an external factor, ultraviolet B (UVB) radiation stimulates TNF-?? production and secretion by human keratinocytes in vitro and can also reach the upper dermis and suppress endothelial cells in vitro. The selenium level in psoriatic patients has been found to be lower than expected, but studies on its role in the pathogenesis of the disease are scarce. Selenium can influence immune response by changing the expression of cytokines and their receptors or by making immune cells more resistant to oxidative stress. It was reported that selenium supplementation had inhibitory effects on TNF-?? levels in patients with psoriasis, but the details are not completely elucidated. Selenium compounds are also known to prevent the in vitro release of UVB-induced proinflammatory cytokines by inhibition of mRNA in human keratinocytes. In the present review, the protective role of selenium in oxidative stress, lesions, and immune system regulation in patients with psoriasis is summarized.     

Plants,selenium and human health

Selenium is an essential nutrient for animals, microorganisms and some other eukaryotes. Although selenium has not been demonstrated to be essential in vascular plants, the ability of some plants to accumulate and transform selenium into bioactive compounds has important implications for human nutrition and health, and for the environment. Selenium-accumulating plants provide unique tools to help us understand selenium metabolism. They are also a source of genetic material that can be used to alter selenium metabolism and tolerance to help develop food crops that have enhanced levels of anticarcinogenic selenium compounds, as well as plants that are ideally suited for the phytoremediation of selenium-contaminated soils.     

Selenium-mediated inhibition of mammary carcinogenesis

Using the dimethylbenz(a)anthracene-induced mammary tumor model in rats, our studies indicated that there was a dose-response relationship between dietary selenium supplementation and the inhibition of mammary carcinogenesis. The degree of inhibition was proportional to the level of dietary selenium up to 5 ppm, at which point toxicity in the form of a reduction in weight gain was evident. Moreover, it was observed that the chemopreventive efficacy of selenium was influenced by the dose of carcinogen as well as the fat intake of the animals. By supplementing selenium for defined periods of time, we concluded that selenium inhibited both the initiation and the promotion phases of chemical carcinogenesis, and that a continuous intake of selenium was necessary to achieve maximal suppression of tumor growth. In an attempt to improve the efficacy of lower levels of selenium, we conducted another series of experiments in which selenium and vitamin E were tested in combination. Results showed that although vitamin E alone had no prophylactic effect against tumorigenesis, it potentiated the ability of selenium to inhibit the development of mammary tumors. Further investigation suggested that the anticarcinogenic action of selenium could not be explained by its antioxidant function in lipid peroxidation. On the other hand, vitamin E might be able to provide a more favorable climate against oxidant stress to facilitate selenium in exerting its inhibitory effect through some other mechanisms.     

Inhibition of type I and type II iodothyronine deiodinase activity in rat liver, kidney and brain produced by selenium deficiency.

Selenium deficiency for periods of 5 or 6 weeks in rats produced an inhibition of tri-iodothyronine (T3) production from added thyroxine (T4) in brain, liver and kidney homogenate. This inhibition was reflected in plasma T4 and T3 concentrations, which were respectively increased and decreased in selenium-deficient animals. Although plasma T4 levels increased in selenium-deficient animals, this did not produce the normal feedback inhibition on thyrotropin release from the pituitary. Selenium deficiency was confirmed in the animals by decreased selenium-dependent glutathione peroxidase (Se-GSH-Px) activity in all of these tissues. Administration of selenium, as a single intraperitoneal injection of 200 micrograms of selenium (as Na2SeO3)/kg body weight completely reversed the effects of selenium deficiency on thyroid-hormone metabolism and partly restored the activity of Se-GSH-Px. Selenium administration at 10 micrograms/kg body weight had no significant effect on thyroid-hormone metabolism or on Se-GSH-Px activity in any of the tissues studied. The characteristic changes in plasma thyroid-hormone levels that occurred in selenium deficiency appeared not to be due to non-specific stress factors, since food restriction to 75% of normal intake or vitamin E deficiency produced no significant changes in plasma T4 or T3 concentration. These data are consistent with the view that the Type I and Type II iodothyronine deiodinase enzymes are seleno-enzymes or require selenium-containing cofactors for activity.     

富硒益生菌的功效研究进展

硒是人体必需的微量元素,对人体健康有重要作用。益生菌能够将硒元素转化为有机硒,降低硒的毒性,同时硒又提高了益生菌的生物活性,富硒益生菌具备了硒和益生菌的双重功效。本文主要综述了近年来富硒益生菌的功效,如抗氧化、抑制有害菌、调节肠道菌群、抗癌等。     

Environmental impact and bioremediation of seleniferous soils and sediments

Selenium concentrations in the soil environment are directly linked to its transfer in the food chain, eventually causing either deficiency or toxicity associated with several physiological dysfunctions in animals and humans. Selenium bioavailability depends on its speciation in the soil environment, which is mainly influenced by the prevailing pH, redox potential, and organic matter content of the soil. The selenium cycle in the environment is primarily mediated through chemical and biological selenium transformations. Interactions of selenium with microorganisms and plants in the soil environment have been studied in order to understand the underlying interplay of selenium conversions and to develop environmental technologies for efficient bioremediation of seleniferous soils. In situ approaches such as phytoremediation, soil amendment with organic matter and biovolatilization are promising for remediation of seleniferous soils. Ex situ remediation of contaminated soils by soil washing with benign leaching agents is widely considered for removing heavy metal pollutants. However, it has not been applied until now for remediation of seleniferous soils. Washing of seleniferous soils with benign leaching agents and further treatment of Se-bearing leachates in bioreactors through microbial reduction will be advantageous as it is aimed at removal as well as recovery of selenium for potential re-use for agricultural and industrial applications. This review summarizes the impact of selenium deficiency and toxicity on ecosystems in selenium deficient and seleniferous regions across the globe, and recent research in the field of bioremediation of seleniferous soils.     

Interplay between Selenium Levels,Selenoprotein Expression,and Replicative Senescence in WI-38 Human Fibroblasts

Selenium is an essential trace element, which is incorporated as selenocysteine into at least 25 selenoproteins using a unique translational UGA-recoding mechanism. Selenoproteins are important enzymes involved in antioxidant defense, redox homeostasis, and redox signaling pathways. Selenium levels decline during aging, and its deficiency is associated with a marked increase in mortality for people over 60 years of age. Here, we investigate the relationship between selenium levels in the culture medium, selenoprotein expression, and replicative life span of human embryonic lung fibroblast WI-38 cells. Selenium levels regulate the entry into replicative senescence and modify the cellular markers characteristic for senescent cells. Whereas selenium supplementation extends the number of population doublings, its deficiency impairs the proliferative capacity of WI-38 cells. We observe that the expression of several selenoproteins involved in antioxidant defense is specifically affected in response to cellular senescence. Their expression is selectively controlled by the modulation of mRNA levels and translational recoding efficiencies. Our data provide novel mechanistic insights into how selenium impacts the replicative life span of mammalian cells by identifying several selenoproteins as new targets of senescence.     

Glutamate induces mitochondrial dynamic imbalance and autophagy activation: preventive effects of selenium

Glutamate-induced cytotoxicity is partially mediated by enhanced oxidative stress. The objectives of the present study are to determine the effects of glutamate on mitochondrial membrane potential, oxygen consumption, mitochondrial dynamics and autophagy regulating factors and to explore the protective effects of selenium against glutamate cytotoxicity in murine neuronal HT22 cells. Our results demonstrated that glutamate resulted in cell death in a dose-dependent manner and supplementation of 100 nM sodium selenite prevented the detrimental effects of glutamate on cell survival. The glutamate induced cytotoxicity was associated with mitochondrial hyperpolarization, increased ROS production and enhanced oxygen consumption. Selenium reversed these alterations. Furthermore, glutamate increased the levels of mitochondrial fission protein markers pDrp1 and Fis1 and caused increase in mitochondrial fragmentation. Selenium corrected the glutamate-caused mitochondrial dynamic imbalance and reduced the number of cells with fragmented mitochondria. Finally, glutamate activated autophagy markers Beclin 1 and LC3-II, while selenium prevented the activation. These results suggest that glutamate targets the mitochondria and selenium supplementation within physiological concentration is capable of preventing the detrimental effects of glutamate on the mitochondria. Therefore, adequate selenium supplementation may be an efficient strategy to prevent the detrimental glutamate toxicity and further studies are warranted to define the therapeutic potentials of selenium in animal disease models and in human.     

The thioredoxin system as a target for mercury compounds

BackgroundMercury interaction with selenium in vivo has been recognized for >50 years. Several researchers attempted to use selenium to mitigate the detrimental effects of mercurial compounds but the results were controversial. Selenium pools in living organisms are quite low and the high affinity of mercury to bind selenols pointed out selenoproteins as possible targets of toxicity. Such was the case of the selenoenzyme thioredoxin reductase (TrxR) which is an integrant part of the thioredoxin system. Given the important role of this redox system for cellular functioning and the high affinity of mercury for TrxR's active site, this interaction can be key to understand the mechanism by which Hg causes cell death.Scope of the reviewThis review discusses the current state of knowledge concerning the interaction between mercury compounds and the thioredoxin system, its implications for the development of toxicity and the effects of selenium co-exposure.Major conclusionsThe mechanism of toxicity of mercurials is a complex chain of events starting with inhibition of the selenoenzyme, TrxR. Selenium supplementation protects TrxR from the toxicity of inorganic forms of mercury (i.e., Hg(II)) to a certain extent, but not from methylmercury.When TrxR is inhibited, thioredoxin is reduced by alternative mechanisms involving glutathione and glutaredoxin and only when this pathway is hampered does cell death occur.General significanceUnderstanding the molecular mechanism of mercury toxicity and the mechanisms of enzymatic compensation allows the design of mitigation strategies and, since TxrR and Trx exist in the plasma, puts forward the possibility for future use of changes in activity/expression of these enzymes as biomarkers of mercury toxicity, thus refining the risk assessment process.     

Role of selenium on antioxidant capacity in methomyl-treated mice

Methomyl carbamate is a pesticide widely used in the control of insects. The present work aims at studying the effect of selenium on the antioxidant system of methomyl-treated mice. Swiss albino mice were intraperitoneally administered a single dose of methomyl (7 mg/Kg body weight). Mice of another group were injected with sodium selenite (5 pmole/Kg b.wt.) 7 days before methomyl intoxication. After 24 hours, methomyl exposure resulted in significant increase in lactic dehydrogenase activity (LDH). The antioxidant capacity of hepatic cells in terms of the activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione-S-transferase (GST) and glutathione (GSH) content was diminished. It appears that methomyl exerts its toxic effect via peroxidative damage to hepatic, renal and splenic cell membranes. Also, methomyl induced DNA damage in these organs as detected by alkaline filter elution technique. The distribution of methomyl in different organs of mice was detected by HPLC. Selenium administration prior to methomyl injection produced pronounced protective action against methomyl effects. It is observed that selenium enhances the endogenous antioxidant capacity of the cells by increasing the activities of SOD, CAT, GR and GST as well as increasing GSH content. The activity of LDH was decreased in blood and the damage of DNA was suppressed comparable to controls. In conclusion, the adverse effects of methomyl in mice could be ameliorated by selenium.     

The importance of selenium in the prenatal and postnatal development of calves and lambs

Selenium deficiency is responsible for Zenker type muscle degeneration in calves, lambs, and foals in the prenatal and postnatal stages of development. Investigations have shown that the selenium GSH P_x, and vitamin E content of the maternal and fetal parts of the placenta in cattle are different. Similarly, low concentrations of selenium are present in milk from cows and sheep. In addition to an inadquate supply of selenium and vitamin E as a contributory cause of fetal nutritive muscular dystrophy (FNMD), it is assumed that a placental transport block and/or impaired selenium metabolism in the placenta are also responsible. Postnatal nutritive muscular dystrophy, however, is attributed to either acute selenium and vitamin E deficiency in basic feed or impaired plant absorption of selenium as a result of antagonistic elements, such as sulphur.