Selenium:mercury molar ratio in eared grebes (Podiceps nigricollis) as a possible biomarker of exposure

Mercury and selenium have adverse effects on health, and in the past their individual levels in tissues have been used as biomarkers of environmental contamination. These selenium:mercury molar ratios has been proposed as an alternative way to anticipate possible health risks to organisms. We examine selenium and mercury levels, their molar ratios, and variability in the ratios in the brain, liver, muscle, and feathers of a common waterbird, the eared grebe (Podiceps nigricollis), at several locations and phases of their annual cycle. We found: (1) Mean total mercury, for any site or tissue, ranged from 0.15 ppm in the brain to 29.2 ppm in breast feathers; (2) In any tissue, mean mercury levels varied by as much as 10-fold while selenium varied by 3-fold; (3) Mercury and selenium levels were correlated only in liver; (4) Selenium:mercury molar ratios varied significantly in regular patterns among tissues (less than 1 in feathers, up to 23 in brain), sites, and stages of annual cycle; (5) Molar ratios were affected by body weight (but not age), and the heaviest birds had the lowest ratios; and (6) Molar ratios varied more for brain than in other tissues. Low molar ratios are generally considered harmful, although no threshold ratio has been identified. Despite wide variation of molar ratios, field studies of eared grebes have not detected overt adverse effects. Before being adopted as a biomarkers, we suggest that selenium:mercury molar ratios be used in conjunction with studies of individual metal levels, and in accordance with detailed studies of selected species, to provide a baseline of variation in different organisms and tissues.     

Inhibition of rat brain prostaglandin D synthase by inorganic selenocompounds

Various inorganic selenocompounds dose-dependently inhibited the rat brain prostaglandin (PG) D synthase, both in the purified enzyme preparation and in the crude brain supernatant. All of the quadrivalent selenium compounds tested had a very limited range of IC50 values in the purified enzyme (11-12 microM) and in the brain supernatant (9-15 microM). A divalent selenium compound was also inhibitory, but a hexavalent selenium compound was ineffective. In contrast, organic selenocompounds such as selenomethionine and selenourea had no effect on the PGD synthase activity. Furthermore, sodium sulfate and sodium sulfite up to 10 mM did not inhibit the activity. The inhibition by selenium required the preincubation of the metal with sulfhydryl compounds such as dithiothreitol (DTT), indicating that the formation of selenotrisulfide or some other adduct(s) is essential for the inhibition. Furthermore, the inhibition was reversed by an excess amount of dithiothreitol, suggesting that the selenotrisulfide derivative of DTT binds to the SH group of the PGD synthase. The kinetic analysis revealed the inhibition by selenite to be noncompetitive with a Ki value of 10.1 microM. On the other hand, glutathione-dependent PGD synthase from rat spleen was much less inhibited, and PGF synthase and PGD2 11-ketoreductase activities were not inhibited by the selenium compound.     

Synergistic toxicity between arsenic and methylated selenium compounds

Arsenite has been known for half a century to have a protective effect against selenium poisoning. Paradoxically, arsenite inhibits the conversion of inorganic selenium salts to methylated excretory products, although methylation has long been regarded as a detoxification mechanism for selenium. Moreover, there is evidence for a pronounced synergistic toxicity between arsenite and methylated selenium metabolites. We investigated the effect of arsenite on the acute toxicity of a variety of methylated or nonmethylated selenium compounds, as well as methylated forms of sulfur and tellurium. Adult male rats were injected with sodium arsenite (4 mg As/kg bw, s.c.) 10 min prior to injection of the test compounds; at the doses employed, none of the test compounds caused mortality, nor did arsenite, when given alone. When given with arsenite, the following methylated compounds produced toxic signs and high morality at the indicated dosages (mg Se/kg): Methylseleninic acid (2), dimethylselenoxide (2), trimethylselenonium chloride (3), selenobetaine (2), selenobetaine methylester (2, also 1 and 0.5), and Se-methylselenocysteine (2). Toxic signs but not mortality occurred when arsenite was given with selenomethionine (2 mg Se/kg). No enhancement of toxic signs or mortality occurred when arsenite was given with sulfobetaine (0.8 mg S/kg), dimethylsulfide (320 mg S/kg), or the following (nonmethylated) forms of selenium: sodium selenite (2), selenocystine (2), and phenylselenol (2). Arsenite also increased the toxicity of trimethyltelluronium chloride (4.8 mg Te/kg). Like arsenite, periodate-oxidized adenosine (100 mumoles/kg), which is known to inhibit the formation of dimethylselenide and trimethylselenonium ion in vivo, caused increased 24 h mortality when given with various methylated selenium compounds.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioavailability of enterai yeast—selenium in preterm infants

There is no data or literature on the effects of supplementing infants with yeast selenium, although its intestinal absorption and bioavailability are higher in adults compared with other selenium compounds. The aim of the present investigation was to study the impact of selenium enriched yeast on the serum selenium concentration of preterm infants living in a low selenium area (Hungary). Twenty-eight preterm infants with mean ± SD birth weight of 962 ± 129 g and gestational age 27 ± 1 wk were randomized into two groups at birth with respect to selenium supplementation. In the supplemented group (n = 14) infants received 4.8 mg yeast selenium containing 5 μg selenium daily via nasogastric drip during the first 14 postnatal days. The nonsupplemented infants were used as a reference group. In the supplemented group, the serum selenium concentration increased from 32.1 ± 8.5 μg/L to 41.5 ± 6.5 μg/L and in the nonsupplemented group it decreased from 25.9 ± 6.8 μg/L to 18.2 ± 6.4 μg/L from birth in two weeks time. Compared with previous studies, our results suggest that the bioavailability of selenium in the form of yeast selenium is higher than that of other selenium compounds used for preterm infants. We did not observe any complications or side-effects owing to enterai yeast selenium supplementation. We conclude that selenium enriched yeast is a safe and an effective form of short-term enterai selenium supplementation for infants.     

Selenium induces a multi‐targeted cell death process in addition to ROS formation

Selenium compounds inhibit neoplastic growth. Redox active selenium compounds are evolving as promising chemotherapeutic agents through tumour selectivity and multi‐target response, which are of great benefit in preventing development of drug resistance. Generation of reactive oxygen species is implicated in selenium‐mediated cytotoxic effects on cancer cells. Recent findings indicate that activation of diverse intracellular signalling leading to cell death depends on the chemical form of selenium applied and/or cell line investigated. In the present study, we aimed at deciphering different modes of cell death in a single cell line (HeLa) upon treatment with three redox active selenium compounds (selenite, selenodiglutathione and seleno‐DL‐cystine). Both selenite and selenodiglutathione exhibited equipotent toxicity (IC₅₀ 5 μM) in these cells with striking differences in toxicity mechanisms. Morphological and molecular alterations provided evidence of necroptosis‐like cell death in selenite treatment, whereas selenodiglutathione induced apoptosis‐like cell death. We demonstrate that selenodiglutathione efficiently glutathionylated free protein thiols, which might explain the early differences in cytotoxic effects induced by selenite and selenodiglutathione. In contrast, seleno‐DL‐cystine treatment at an IC₅₀ concentration of 100 μM induced morphologically two distinct different types of cell death, one with apoptosis‐like phenotype, while the other was reminiscent of paraptosis‐like cell death, characterized by induction of unfolded protein response, ER‐stress and occurrence of large cytoplasmic vacuoles. Collectively, the current results underline the diverse cytotoxic effects and variable potential of redox active selenium compounds on the survival of HeLa cells and thereby substantiate the potential of chemical species‐specific usage of selenium in the treatment of cancers.     

Absorption and retention characteristics of selenium in dorsal root ganglion neurons

Selenium concentration in the brain tissue is far less variable than those in peripherals, such as the liver and kidneys, in rodents, when fed a selenium-deficient diet. This fact implies the importance of this element for maintaining the integrity of brain functions and the distinctive selenium metabolism and/or the regulatory mechanism in the brain. To obtain basic information concerning the homeostatically maintained selenium store in the brain, we investigated absorption and retention characteristics of selenium from selenious acid (SA) and seleno-l-methionine (SeMet) in rat dorsal root ganglion (DRG) neurons, in comparison to isolated rat hepatocytes and renal cells in vitro. When DRG neurons were cultured in an SA-free medium subsequent to an SA-supplemented one for 24 h, the DRG neurons maintained a higher selenium concentration than that before SA supplementation over a period of 96 h after removal of SA from the culture medium. The cellular glutathione peroxidase activity of the cells increased for 72 h after removal of SA from the culture medium. A similar retention characteristic of selenium was also observed for DRG neurons treated with SeMet-supplemented culture medium. Consequently, selenium from source compounds, in part, was thought to be retained in DRG neurons and then be utilized for the synthesis of selenium-containing proteins, which implied the presence of a neuron-specific selenium retention mechanism.     

Absence of selenoprotein P but not selenocysteine lyase results in severe neurological dysfunction

Dietary selenium restriction in mammals causes bodily selenium to be preferentially retained in the brain relative to other organs. Almost all the known selenoproteins are found in brain, where expression is facilitated by selenocysteine (Sec)-laden selenoprotein P. The brain also expresses selenocysteine lyase (Scly), an enzyme that putatively salvages Sec and recycles the selenium for selenoprotein translation. We compared mice with a genetic deletion of Scly to selenoprotein P (Sepp1) knockout mice for similarity of neurological impairments and whether dietary selenium modulates these parameters. We report that Scly knockout mice do not display neurological dysfunction comparable to Sepp1 knockout mice. Feeding a low-selenium diet to Scly knockout mice revealed a mild spatial learning deficit without disrupting motor coordination. Additionally, we report that the neurological phenotype caused by the absence of Sepp1 is exacerbated in male vs. female mice. These findings indicate that Sec recycling via Scly becomes limiting under selenium deficiency and suggest the presence of a complementary mechanism for processing Sec. Our studies illuminate the interaction between Sepp1 and Scly in the distribution and turnover of body and brain selenium and emphasize the consideration of sex differences when studying selenium and selenoproteins in vertebrate biology.     

Selenium Compounds Prevent Amyloid β-Peptide Neurotoxicity in Rat Primary Hippocampal Neurons

Neuropathological hallmarks of Alzheimer’s disease (AD) include amyloid plaque formation, neurofibrillary tangles, neuronal and synaptic loss. This study aims to identify the neuroprotective effects of the selenium compounds on the neurotoxicity of amyloid β(1–42) in primary cultures of murine hippocampal neurons. Samples were subjected to immunocytochemistry and western blotting techniques to determine the role of treatments on neuronal viability and synaptic protein SNAP-25. We observed a reduced cell viability amyloid β-peptide (1–42)-induced. When cells were co-treated with amyloid β-peptide (1–42) and selenium compounds, we verified a strong increase in relative cell viability and in the level of synaptic marker synaptosomal-associated protein SNAP-25 induced by selenium compounds.     

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.     

Determination of selenium in the human brain by graphite furnace atomic absorption spectrometry

For the investigation of neurological disorders, a development of simple and accessible methods for determining selenium in human brain samples is required. We devised a method of determining selenium using graphite furnace atomic absorption spectrometry (GFAAS). An electrodeless discharge lamp provided the sufficient sensitivity to determine brain selenium. The matrix interferences were avoided by using high temperature, a prolonged pyrolysis step, and a palladium matrix modifier. The technique of standard addition was used to evaluate the sample concentrations. The accuracy of the method was confirmed by a bovine liver reference material. The detection limit of selenium was 0.04 ng. The determined selenium concentrations of human brain cortex and white matter were higher than those of putamen (115–155 and 206–222 ng/g wet wt, respectively). These GFAAS values agreed with those obtained by fluorometric analysis (r=0.91,n=10). Moreover, the GFAAS values were compatible to those reported by other researchers (99–274 ng/g wet wt), in which selenium concentrations in putamen also tended to be higher than the other two regions. We conclude that GFAAS is useful for selenium analysis in brain samples.     

Characteristics of selenazolidine prodrugs of selenocysteine: toxicity, selenium levels, and glutathione peroxidase induction in A/J mice

We have previously reported the synthesis and characterization of two new classes of selenazolidine-4(R)-carboxylic acids (2-oxo and 2-methyl-SCAs) (OSCA and MSCA, respectively), as well as the "parent" compound, selenazolidine-4(R)-carboxylic acid (SCA, selenaproline). These compounds were designed as prodrugs of L-selenocysteine with potential application in cancer chemoprevention or other clinical uses. We will be exploring the chemopreventive activity of the new compounds in the well-established A/J mouse model of tobacco-induced lung carcinogenesis. The objectives of the present study were to investigate several fundamental biochemical endpoints after selenazolidine administration compared with other selenium-containing agents. Groups of mice were fed either AIN-76A diet alone or the diet supplemented with the following selenium compounds (ppm Se): sodium selenite (5), L-selenomethionine (3.75), L-selenocystine (15), Se-methyl-L-selenocysteine (3), MSCA (5, 10, or 15), OSCA (5, 10, or 15), or SCA (5, 10, or 15). After 28 days of supplementation, toxicity of the selenazolidines was not evident, as measured by outward appearance and behavior, body and organ weight changes, and histological evaluation of liver and lung tissue. Select treatment groups showed significant increases in selenium levels in blood and tissues. Increased activity of selenium-dependent glutathione peroxidase (GPx) in blood and liver illustrated that the selenazolidines provided a source of biologically-available selenium.     

Apoptosis induced by selenium in human glioma cell lines

Several studies have shown that selenium can inhibit tumorigenesis in tissues. However, little is known about the mechanism and the effect of selenium on DNA, especially in brain tumor cells. In this study we examined the biological effect of selenium on human glioma cell lines (A172 and T98G). Selenium exhibited an antiproliferative effect on these cell lines (and induced the typical ladder pattern of DNA fragmentation commonly found in apoptosis), which were prevented by catalase. Few effects of selenium on NTI4 fibroblasts were found. These findings demonstrate that selenium may induce, by apoptosis, cell death of human glioma cell lines, which are resulting from free radical oxygen forming.     

Elemental selenium at nano size possesses lower toxicity without compromising the fundamental effect on selenoenzymes: comparison with selenomethionine in mice

Glutathione peroxidase and thioredoxin reductase are major selenoenzymes through which selenium exerts powerful antioxidant effects. Selenium also elicits pro-oxidant effects at toxic levels. The antioxidant and pro-oxidant effects, or bioavailability and toxicity, of selenium depend on its chemical form. Selenomethionine is considered to be the most appropriate supplemental form due to its excellent bioavailability and lower toxicity compared to various selenium compounds. The present studies reveal that, compared with selenomethionine, elemental selenium at nano size (Nano-Se) possesses equal efficacy in increasing the activities of glutathione peroxidase and thioredoxin reductase but has much lower toxicity as indicated by median lethal dose, acute liver injury, and short-term toxicity. Our results suggest that Nano-Se can serve as an antioxidant with reduced risk of selenium toxicity.     

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.     

Selenium and Topiramate Modulates Brain Microsomal Oxidative Stress Values, Ca2+-ATPase Activity, and EEG Records in Pentylentetrazol-Induced Seizures in Rats

It has been suggested that oxidative stress products play an important role in the etiology of epilepsy. We investigated the effects of selenium (Se) administration on topiramate (TPM)- and pentylentetrazol (PTZ)-induced brain toxicity in rats. Forty male Wistar rats were divided into five equal groups. The first and second groups were used as the control and PTZ groups, respectively. TPM, 50 mg, and Se, 0.3 mg, were administered to rats constituting the third and fourth groups, respectively, for 7 days. The combination of 50 mg TPM and Se was given to animals in the fifth group for 7 days. At the end of 7 days all groups except the first received a single dose of PTZ. Brain cortex samples were taken at 3 h of PTZ administration. PTZ resulted in a significant increase in brain cortex and microsomal lipid peroxidation (LP) levels, number of spikes, and epileptiform discharges on the EEG, although brain cortex vitamin E, brain cortex and microsomal reduced glutathione (GSH), and microsomal calcium (Ca) levels, Ca(2+)-ATPase activities, and latency to first spike on the EEG were decreased by PTZ. LP, GSH, vitamin E, and Ca levels and Ca(2+)-ATPase activities were increased by both Se and TPM, although vitamin A and C concentrations were increased by Se only. There were no effects of TPM and Se on brain cortex and microsomal glutathione peroxidase, brain cortex nitric oxide, or beta-carotene levels. In conclusion, TPM and selenium caused protective effects on PTZ-induced brain injury by inhibiting free radical production, regulating calcium-dependent processes, and supporting the antioxidant redox system.     

Chemical form of selenium differentially influences DNA repair pathways following exposure to lead nitrate

Lead, an environmental toxin is known to induce a broad range of physiological and biochemical dysfunctions in humans through a number of mechanisms including the deactivation of antioxidants thus leading to generation of reactive oxygen species (ROS) and subsequent DNA damage. Selenium on the other hand has been proven to play an important role in the protection of cells from free radical damage and oxidative stress, though its effects are thought to be form and dose dependent. As the liver is the primary organ required for metabolite detoxification, HepG2 cells were chosen to assess the protective effects of various selenium compounds following exposure to the genotoxic agent lead nitrate. Initially DNA damage was quantified using a comet assay, gene expression patterns associated with DNA damage and signalling were also examined using PCR arrays and the biological pathways which were most significantly affected by selenium were identified.Interestingly, the organic type selenium compounds (selenium yeast and selenomethionine) conferred protection against lead induced DNA damage in HepG2 cells; this is evident by reduction in the quantity of DNA present in the comet tail of cells cultured in their presence with lead. This trend also followed through the gene expression changes noted in DNA damage pathways analysed. These results were in contrast with those of inorganic sodium selenite which promoted lead induced DNA damage evident in both the comet assay results and the gene expression analysis. Over all this study provided valuable insights into the effects which various selenium compounds had on the DNA damage and signalling pathway indicating the potential for using organic forms of selenium such as selenium enriched yeast to protect against DNA damaging agents.     

Uptake and distribution of sodium selenite in rat brain tumor

Eighteen weanling male Wistar rats with brain gliomas were divided into three groups, which received 0., 2.0, 5.0 ppm selenium (Se) in their drinking water. The accumulation and retention of selenium in the brain bearing tumor was investigated. Significantly higher concentrations of Se were observed in tumor tissue than normal brain tissue after exposure to sodium selenite. Tumors were observed in the 2.0 Μg/g selenium group. The difference in selenium concentration between the tumor tissue and contralateral normal brain tissue was not influenced by the weight of brain or body, and water consumption. We observed that selenium accumulated in tumor tissue more than in normal brain tissue.     

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.     

Mercury and selenium interaction in vivo: effects on thioredoxin reductase and glutathione peroxidase

Mercury compounds exert toxic effects via interaction with many vital enzymes involved in antioxidant regulation, such as selenoenzymes thioredoxin reductase (TrxR) and glutathione peroxidase (GPx). Selenium supplementation can reactivate the mercury-inhibited TrxR and recover the cell viability in vitro. To gain an insight on how selenium supplementation affects mercury toxicity in vertebrates, we investigated the effects of selenium on the mercury accumulation and TrxR and GPx activities in a fish model. Juvenile zebra-seabreams were exposed either to methylmercury (MeHg) or inorganic mercury (Hg(2+)) in the presence or absence of sodium selenite (Se) for 28 days followed by 14 days of depuration. Mercury accumulation was found to be 10-fold higher under MeHg exposure than under Hg(2+) exposure. Selenium supplementation caused a half decrease of the accumulation of MeHg but did not influence Hg(2+) accumulation. Exposure to both mercurials led to a decrease of the activity of TrxR (<50% of control) in all organs. Se supplementation coincident with Hg(2+) exposure protected the thioredoxin system in fish liver. However, supplementation of Se during the depuration phase had no effects. The activity of GPx was only affected in the brain of fishes upon the exposure to MeHg and coexposure to MeHg and Se. Selenium supplementation has a limited capacity to prevent mercury effects in brain and kidney. These results demonstrate that Se supplementation plays a protective role in a tissue-specific manner and also highlight the importance of TrxR as a main target for mercurials in vivo.     

Investigation of the selenium metabolism in cancer cell lines

The aim of this work was to compare different selenium species for their ability to induce cell death in different cancer cell lines, while investigating the underlying chemistry by speciation analysis. A prostate cancer cell line (PC-3), a colon cancer cell line (HT-29) and a leukaemia cell line (Jurkat E6-1) were incubated with five selenium compounds representing inorganic as well as organic Se compounds in different oxidation states. Selenomethionine (SeMet), Se-methylselenocysteine (MeSeCys), methylseleninic acid (MeSeA), selenite and selenate in the concentration range 5-100 μM were incubated with cells for 24 h and the induction of cell death was measured using flow cytometry. The amounts of total selenium in cell medium, cell lysate and the insoluble fractions was determined by ICP-MS. Speciation analysis of cellular fractions was performed by reversed phase, anion exchange and size exclusion chromatography and ICP-MS detection. The selenium compounds exhibited large differences in their ability to induce cell death in the three cell lines and the susceptibilities of the cell lines were different. Full recovery of selenium in the cellular fractions was observed for all Se compounds except MeSeA. Speciation analysis showed that MeSeA was completely transformed during the incubations, while metabolic conversion of the other Se compounds was limited. Production of volatile dimethyl diselenide was observed for MeSeA and MeSeCys. MeSeA, MeSeCys and selenite showed noticeable protein binding. Correlations between cell death induction and the Se compounds transformations could not be demonstrated.