Selenium and selenoproteins in the brain and brain diseases

Over the past three decades, selenium has been intensively investigated as an antioxidant trace element. It is widely distributed throughout the body, but is particularly well maintained in the brain, even upon prolonged dietary selenium deficiency. Changes in selenium concentration in blood and brain have been reported in Alzheimer's disease and brain tumors. The functions of selenium are believed to be carried out by selenoproteins, in which selenium is specifically incorporated as the amino acid, selenocysteine. Several selenoproteins are expressed in brain, but many questions remain about their roles in neuronal function. Glutathione peroxidase has been localized in glial cells, and its expression is increased surrounding the damaged area in Parkinson's disease and occlusive cerebrovascular disease, consistent with its protective role against oxidative damage. Selenoprotein P has been reported to possess antioxidant activities and the ability to promote neuronal cell survival. Recent studies in cell culture and gene knockout models support a function for selenoprotein P in delivery of selenium to the brain. mRNAs for other selenoproteins, including selenoprotein W, thioredoxin reductases, 15-kDa selenoprotein and type 2 iodothyronine deiodinase, are also detected in the brain. Future research directions will surely unravel the important functions of this class of proteins in the brain.     

汞与硒在不同汞暴露水平地区猪肝脏和肾脏蛋白质中的分布

通过对贵州万山汞污染地区及北京地区猪肝脏和肾脏组织上清液进行凝胶过滤色谱分离(SephadexG 10 0 ) ,随后用原子荧光法测定它们蛋白质组分中汞和硒的含量 ,研究在汞暴露水平不同状态下微量元素汞和硒在动物体蛋白质分子水平上的分布 .发现这两个地区猪肝脏和肾脏组织上清液蛋白质组分中汞和硒的分布模式有明显差异 .贵州万山汞污染地区猪肝脏上清液中汞浓度比北京地区高 ,硒浓度也相应高 ,且前者与高分子量和低分子量蛋白结合的硒均明显高于后者 ;而北京地区猪肝脏上清液中的硒主要以与高分子量蛋白结合的形式存在 .贵州汞污染地区猪肝脏上清液中汞主要与高分子量蛋白结合 ,而北京地区猪肝脏上清液中汞则分布较为均匀 .贵州万山地区猪肾脏上清液中 ,含硒峰在高分子量蛋白区和低分子量区都有分布 ;而北京地区猪肾脏上清液中 ,硒则主要集中分布于高分子量蛋白范围 .这两个地区猪肾脏上清液中都有分子量约为 11kD的金属硫蛋白 (MT)存在 ,北京地区猪肾脏上清液中汞主要以与金属硫蛋白结合的形式出现 ,而贵州万山地区猪肾脏上清液中的汞除与金属硫蛋白结合外 ,尚有相当大部分是以与高分子量蛋白结合的形式存在 .研究结果表明 ,由于这两个地区汞暴露水平的差异 ,不仅使这两地区猪肝、肾上清液中的汞与硒含量     

The Influence of Long-term Mercury Exposure on Selenium Availability in Tissues: An Evaluation of Data

The precise mechanisms of mercury accumulation and retention are still unclear. Generally, the association of mercury with selenium is used to explain these phenomena. It seems that the presence of coaccumulated endogenous Se can protect cells from the harmful effects of Hg. However, as speculated by some authors, this binding of Se to Hg can also result in a relative deficiency of biologically available Se needed for selenoenzyme syntheses. Deriving from the assumption that Hg deposited in tissues is bound to Se in a 1:1 ratio, the quantity of non-Hg bound Se could be calculated by the difference between the molar contents of the two elements (Se_mol–Hg_mol). In this study we applied such an approach to the data from our previous investigation, where Hg and Se concentrations were determined in autopsy samples of mercury exposed retired Idrija mercury mine workers, Idrija residents living in a Hg contaminated environment and a control group with no known Hg exposure from the environment. Based on these data we tried to estimate the influence of Hg exposure on the physiologically available selenium content in selected tissues, particularly endocrine glands and brain tissues. Comparing the calculated values of (Se_mol– Hg_mol) it was found that for Idrija residents the values were similar to those of the control group and as expected, diminished values were found in some mercury-loaded organs of retired Idrija miners. It could be speculated that in Idrija residents Hg sequestration of selenium is sufficiently compensated by increased Se levels, but that particularly in active miners and in some organs of retired miners, the activity and/or synthesis of selenoenzymes could be disturbed. Part of the study was presented at the 7th International Conference on Mercury as a Global Pollutant, June 27–July 2, 2004 Ljubljana, Slovenia (Falnoga et al. 2000)     

Protective effects of selenium against mercury toxicity as studied in the rat liver and kidney by nuclear analytical techniques

Mercuric chloride and sodium selenite were separately administered to male rats in the drinking water or in a combination (2.5 mmol Hg/L and 0.1 mmol Se/L). The mercuric chloride group showed histopathological lesions, as evidenced by cell necrosis in the liver and tubular necrosis in the kidney. The sodium selenite group showed some depression in growth, but pathological changes were found neither in the liver nor in the kidney. Simultaneous administration of both compounds produced a protective effect on weight loss and histopathology. These effects were associated with some small structures in the kidney proximal tubules and to some structure in the extracellular space in the liver. Thin, unstained cryosections were freeze-dried and examined in the Studsvik Nuclear Microprobe. The structures observed in the liver and the kidney were shown to contain both selenium and mercury.     

Comparison of mercury levels in various tissues of albino and pigmented mice treated with two different brands of mercury skin-lightening creams

The use of mercury containing skin-lightening creams are becoming increasingly popular among dark-skinned women. The long-term use of certain brands may cause serious health effects over the years. In the present study, we investigated the dermal absorption of mercury and its accumulation in the tissues of albino and pigmented mice treated with two brands of mercury containing skin-lightening creams for a period of one months at different intervals. The mean +/- SD of mercury in the selected brands were: (1) Fair & Lovely (0.304 +/- 0.316 microg/g); and (2) Rose (77513.0 +/- 71063.0 microg/g). Mercury levels were measured in a total of 133 and 144 liver, kidney and brain tissue samples of albino and pigmented mice respectively by the Atomic Absorption Spectrophotometer coupled to Vapour Generator Accessory. In both strains, we found that the mercury concentration in the tissues of mice treated with Rose skin-lightening cream samples was significantly higher than those treated with Fair & Lovely skin lightening cream. Looking at the mercury concentration in the tissue samples with respect to the application of skin lightening creams at different intervals, the highest mercury concentrations were found in the tissues of albino and pigmented mice treated three times a day. On the other hand, the lowest mercury concentrations were found in the tissues of mice treated once a week. Despite the brand of skin-lightening cream that was applied, the study indicated that mercury was readily absorbed through the skin of both albino and pigmented mice as evidenced with its accumulation in the brain, kidney and liver tissues where the kidney had the highest mercury content and brain had the lowest (it P < 0.0001). Significant differences in the mercury levels were observed between the albino and pigmented mice. This emphasizes the protective role of melanin against mercury toxicity. Results of this study stresses the potential harm of these mercury containing skin-lightening creams regardless of their mercury contents especially for women who apply these creams frequently or for extended periods. Permanent nephrological or/and neurological deficits may occur if the damage is severe and diagnosis and treatment are delayed.     

Levels of cadmium, lead, and mercury in human brain tumors

This article reports on the levels of cadmium, lead, and mercury in 21 benign brain tumors and 23 malignant brain tumors. All measurements were performed by atomic absorption spectrometry following digestion by nitric acid. Average concentrations of cadmium, lead, and mercury in brain tumors were 2.02 (ND-72.78), 0.625 (ND-83.13), and 0.118 (ND-1.96) μg/g wet weight, respectively. Our values were higher than data reported by others.     

Interactions of mercury in rat brain

In order to study the metabolism of mercury (Hg), its affinity to metallothionein (MT), and its influence on levels of the essential metals copper and zinc in the brain tissue of rats exposed to elemental mercury (Hg^O) vapor was investigated. The major findings were:

Induction of metallothionein-like proteins by mercury and distribution of mercury and selenium in the cells of hepatopancreas and gill tissues in mussel Mytilus galloprovincialis

The binding of mercury (Hg) to metallothioneins (MTs) and the relation between Hg and selenium in supernatants of hepatopancreas and gill tissues of the common mussel Mytilus galloprovincialis (Lamarck, 1819) was investigated. The mussels were exposed to different Hg concentrations in laboratory conditions: 2.5 μgHg/L, 4 d exposure (short term) and 60 μgHg/L, 33 d exposure (long term). In addition, the results were compared to those found for mussels from nature (polluted and unpolluted region). In control and short-term-exposed mussles, the level of Hg extraction (cytosol) from hepatopancreas and gill cells was very low with respect to the total Hg concentrations in the corresponding tissues, around 10% in control and around 20% after exposure. As expected, Hg exposure was followed by Se increase. For Se, the levels of extraction were higher, around 20% in control and up to 50% (heaptopacrease) of 70% (gills) after exposure. In order to study the distribution of Hg and Se in the cells of these organs, the total Hg and Secconcentrations were analyzed in the subcellular fractions obtained after differential centrifugation. Although after exposure the concentrations of both element increased in all subcellular fractions, their percentages in particular fractions were lower or higher. In this study, the convincing binding of Hg to metallothionein-like proteins was perceived after long-term laboratory exposure (gills, heapatopancreas) and in wild mussels collected near industrial port (hepatopancreas). In latter case, we also detected the traces of Se bound to the MT fractions after size-exclusion chromatography.     

Selenium modifies glutathione peroxidase activity and glutathione concentration in mice exposed to ozone-provoked oxidative stress

The aim of this study was to show the direct effect of selenium on glutathione peroxidase (GSH-Px) activity and GSH/GSSG concentrations in 3- and 6-month-old mice. An ozone-oxygen mixture was used to provoke an oxygen stress. To measure the Se-effect mice were gavaged with sodium selenite. GSH-Px activity and total glutathione concentrations were determined in serum and in the postnuclear fraction of liver and lungs. Additionally glutathione concentrations were determined in whole blood. Both ozone and selenium, administered separately, reduced GSH-Px activity in lungs of 6-month-old animals, while in young mice an opposite effect of Se was observed. Ozone administered jointly with Se did not influence GSH-Px activity in 6-month-old mice, while in young, 3-month-old mice, a stimulatory effect in lungs was observed. There were no significant changes in GSH-Px activity in the liver of 6-month-old mice, but the stimulatory effect occurred in young mice treated with Se and Se & ozone jointly. In young mice, ozone (also ozone with Se) augmented glutathione concentrations. The response to ozone and selenium strictly depended on age and the antagonism between selenium and ozone was observed only in a few cases.     

Selenium addition alters mercury uptake,bioavailability in the rhizosphere and root anatomy of rice (Oryza sativa)

Background and Aims

Mercury (Hg) is an extremely toxic pollutant, especially in the form of methylmercury (MeHg), whereas selenium (Se) is an essential trace element in the human diet. This study aimed to ascertain whether addition of Se can produce rice with enriched Se and lowered Hg content when growing in Hg-contaminated paddy fields and, if so, to determine the possible mechanisms behind these effects.

Methods

Two cultivars of rice (Oryza sativa, japonica and indica) were grown in either hydroponic solutions or soil rhizobags with different Se and Hg treatments. Concentrations of total Hg, MeHg and Se were determined in the roots, shoots and brown rice, together with Hg uptake kinetics and Hg bioavailability in the soil. Root anatonmy was also studied.

Key Results

The high Se treatment (5 μg g^–1) significantly increased brown rice yield by 48 % and total Se content by 2·8-fold, and decreased total Hg and MeHg by 47 and 55 %, respectively, compared with the control treatments. The high Se treatment also markedly reduced ‘water-soluble’ Hg and MeHg concentrations in the rhizosphere soil, decreased the uptake capacity of Hg by roots and enhanced the development of apoplastic barriers in the root endodermis.

Conclusions

Addition of Se to Hg-contaminated soil can help produce brown rice that is simultaneously enriched in Se and contains less total Hg and MeHg. The lowered accumulation of total Hg and MeHg appears to be the result of reduced bioavailability of Hg and production of MeHg in the rhizosphere, suppression of uptake of Hg into the root cells and an enhancement of the development of apoplastic barriers in the endodermis of the roots.     

Understanding hepatitis C viral dynamics with direct-acting antiviral agents due to the interplay between intracellular replication and cellular infection dynamics

The current paradigm for modeling viral kinetics and resistance evolution after treatment initiation considers only the level of circulating virus and cellular infection (CI model), while the intra-cellular level is disregarded. This model was successfully used to explain HIV dynamics and Hepatitis C virus (HCV) dynamics during interferon-based therapy. However, in the new era of direct-acting antiviral agents (DAAs) against HCV, viral kinetics is characterized by a more rapid decline of the wild-type virus as well as an early emergence of resistant strains that jeopardize the treatment outcome. Although the CI model can be extended to describe these new kinetic patterns, this approach has qualitative and quantitative limitations. Instead, we suggest that a more appropriate approach would consider viral dynamics at the cell infection level, as done currently, as well as at the intracellular level. Indeed, whereas in HIV integrated DNA serves as a static replication unit and mutations occur only once per infected cell, HCV replication is deeply affected by DAAs and furthermore processes of resistance evolution can occur at the intra-cellular level with a faster time-scale.We propose a comprehensive model of HCV dynamics that considers both extracellular and intracellular levels of infection (ICCI model). Intracellular viral genomic units are used to form replication units, which in turn synthesize genomic units that are packaged and secreted as virions infecting more target cells. Resistance evolution is modeled intra-cellularly, by different genomic- and replication-unit strains with particular relative-fitness and drug sensitivity properties, allowing for a rapid resistance takeover.Using the ICCI model, we show that the rapid decline of wild-type virus results from the ability of DAAs to destabilize the intracellular replication. On the other hand, this ability also favors the rapid emergence, intracellularly, of resistant virus. By considering the interaction between intracellular and extracellular infection we show that resistant virus, able to maintain a high level of intracellular replication, may nevertheless be unable to maintain rapid enough de novo infection rate at the extracellular level. Hence this model predicts that in HCV, and contrary to our experience with HIV, the emergence of productively resistant virus may not systematically prevent from a viral decline in the long-term. Thus, the ICCI model can explain the transient viral rebounds observed with DAA treatment as well as the viral resistance found in most patients with viral relapse at the end of DAA combination therapy.     

Changes in brain metallothionein and Zinc during development in transgenic mice

The developmental alterations in metallothionein (MT) proteins and zinc (Zn) were investigated in brains of two transgenic strains of mice. MT protein was measured by a cadmium binding assay and Zn by atomic absorption spectrophotometry. MT proteins were expressed at birth (day 1) both in MT-I overexpressing transgenic mouse (MT-I*) and MT-null (expressing only brain specific isoform, MT-III) transgenic mouse. MT proteins level (mainly MT-I) in MT-I* was 16.1 Μ-g/g at birth, and thereafter increased with age to a maximal adult level of 55.3 Μg/g (day 60). Zn level in MT-I* also increased from 8.43 Μg/g (day 1) to 20.7 Μg/g (day 60) with age. MT protein (MT-III) in MT-null mouse was 9.71 Μg/g at birth and remained relatively unchanged during development. Zn level in MT-null mouse at birth was 9.46 Μg/g and also remained unchanged during development. The similar alterations in MT isoforms and Zn in brain during development suggest that MT isoforms may act as a Zn binding protein.     

Selenoprotein P in subjects exposed to mercury and other stress situations such as physical load or metal chelation treatment

In plasma, Se is found in plasma glutathione peroxidase (pGSH-Px), selenoprotein P (Sel-P), and albumins. The aim of the present study was to determine the influence of lifelong exposure to various levels of mercury vapor (Hg⁰) on plasma Se content and the fraction bound to Sel-P. Second, a pilot study was performed on the influence of short-term excessive physical stress and metal chelation (DIMAVAL) treatment. Samples of human plasma/serum obtained from a control group, Idrija residents living in a Hg-polluted environment because of the vicinity of the Idrija mercury mine (closed 1994), a few Idrija residents exposed to excessive physical stress, and two retired miners treated with the drug DIMAVAL were investigated. Selenoprotein P was isolated by affinity chromatography (heparin-Sepharose), and the concentrations of selenium were determined by radiochemical neutron activation analysis and hydride generation-atomic fluorescence spectrometry. Regardless of the group investigated, plasma Se average values were very similar (about 70–90 ngSe/g). A significant change of Sel P (7–24% decrease) was noted only in the group exposed to physical stress as compared to the same subjects before the test, to the control group, and to the Hg exposed group. The decrease of Se bound on Sel-P was accompanied by its increase in fraction of pGSH-Px with albumin.     

The brain selenoproteome: priorities in the hierarchy and different levels of selenium homeostasis in the brain of selenium-deficient rats

The application of radionuclides for the localization of essential trace elements in vivo and the characterization of their binding proteins is a story of intermittently made improvements of the techniques used for their detection. In this study we present the use of neutron activation analysis and different autoradiographic imaging methods including real-time digital autoradiography to reveal new insights in the hierarchy of selenium homeostasis. Selenoproteins containing the essential trace element selenium play important roles in the CNS. Although the CNS does not show the highest selenium concentration in the case of selenium-sufficient supply in comparison with other organs, it shows a high priority for selenium uptake and retention in the case of dietary selenium deficiency. To characterize the hierarchy of selenium supply in the brain, in vivo radiotracer labeling with ⁷⁵Se in rats with different selenium status was combined with autoradiographic detection of ⁷⁵Se in brain tissue sections and ⁷⁵Se-labeled selenoproteins after protein separation by two-dimensional gel electrophoresis. This study demonstrates significant differences in the uptake of ⁷⁵Se into the brain of rats with different selenium status. A brain region-specific uptake pattern of the radiotracer ⁷⁵Se in selenium-deficient rats could be revealed and the CSF was identified as a key part of the brain selenium homeostasis.     

Mercury and selenium concentrations in maternal and neonatal scalp hair: relationship to amalgam-based dental treatment received during pregnancy

Mercury and selenium concentrations were determined in scalp hair samples collected postpartum from 82 term pregnancy mothers and their neonates. Maternal mercury and selenium had median concentrations of 0.39 μg/g (range 0.1–2.13 μg/g) and 0.75 μg/g (range 0.1–3.95 μg/g), respectively, and corresponding median neonatal values were 0.24 μg/g (range 0.1–1.93 μg) and 0.52 μg/g (range (0.1–3.0 μg/g). Amalgam-based restorative dental treatment received during pregnancy by 27 mothers (Group I) was associated with significantly higher mercury concentrations in their neonates (p<0.0001) compared to those born to 55 mothers (Group II) whose most recent history of such dental treatment was dated to periods ranging between 1 and 12 yr prior to pregnancy. In the Group I mother/neonate pairs, amalgam removal and replacement in 10 cases was associated with significantly higher mercury concentrations compared to 17 cases of new amalgam emplacement. Selenium concentrations showed no significant integroup differences. However, the selenium/mercury molar ratio values were lowest in the Group I neonates, compared to their mothers and to the Group II mother/neonate pairs. This ratio decreased as mercury concentration increased, and this interrelation was statistically significant in both groups of mother/neonate pairs. The data from this preliminary study suggest that amalgam-based dental treatment during pregnancy is associated with higher prenatal exposure to mercury, particularly in cases of amalgam removal and replacement. The ability of a peripheral biological tissue, such as hair, to elicit such marked differences in neonatal mercury concentrations provides supporting evidence of high fetal susceptibility to this form of mercury exposure. The data are discussed in relation to the differences between maternal and fetal mercury metabolisms and to mercury—selenium metabolic intereactions in response to mercury exposure.     

Mercury and Selenium in Blood and Epidermis of Bottlenose Dolphins (Tursiops truncatus) from Sarasota Bay, FL: Interaction and Relevance to Life History and Hematologic Parameters

Blood and epidermal biopsies from free-ranging Tursiops truncatus captured and released during either summer or winter health assessments in Sarasota Bay, FL, were evaluated for concentrations of mercury, selenium, stable isotopes (δ¹³C and δ¹⁵N), and blood glutathione peroxidase activity in conjunction with routine hematology and serum chemistry panels. Major objectives were to: 1) quantify and describe relationships among mercury, selenium, glutathione peroxidase, and stable isotopes of C and N in blood and epidermis; 2) elucidate major parameters that influence blood mercury and glutathione peroxidase activity; 3) relate measures of tissue mercury, selenium, and glutathione peroxidase to specific ecological, hematological, morphological, or life history parameters, including season, sex, age, and trophic level. Mercury in both tissues examined is almost exclusively methylmercury. Epidermal concentrations of mercury and selenium reflect their respective amounts in blood, albeit at several times blood concentrations of mercury. The strong association between blood mercury and serum selenium, in conjunction with a lack of significant correlation between blood mercury and glutathione peroxidase, implies that a substantial proportion of blood mercury is affiliated with another selenium-containing moiety or is related to recent dietary intakes (e.g., trophic level, intensive fish consumption). Circulating blood mercury may be described in terms of serum selenium concentration, along with interaction terms among serum selenium, blood δ¹⁵N, and age. Current selenium concentrations in Sarasota Bay dolphins appear adequate for maintenance of blood glutathione peroxidase activity. However, dolphins evidently are subject to seasonal exacerbation of oxidative stress, which might render them more vulnerable to toxic effects of mercury. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Selenium and mercury concentrations in some fish species of the Madeira River, Amazon Basin, Brazil

Samples of 7 species of piscivorous, omnivorous, and herbivorous fish caught at 12 different sites on the Madeira River, Amazon Basin, were analyzed for selenium and mercury. Selenium was determined by anodic stripping voltammetry and mercury by cold vapor atomic absorption spectrophotometry. The means for selenium concentrations ranged from 0.49 to 3.11 nmol/g and for mercury from 0.41 to 6.66 nmol/g depending on the fish species. The molar ratios of Hg:Se increased according to the fish trophic level. Piscivorous species had the highest mean ratio (4.0) and herbivorous species the lowest (0.9). There was a positive and statistically significant correlation between selenium and mercury concentrations for the herbivorous species (r = 0.716;p = 0.0088) not seen for omnivororus and piscivorous species (r = -0.2032;p = 0.3407). These findings are significant for the fish-eating population of the Madeira River because the ingestion of mercury would always be in excess of selenium.     

Arsenic is decreased in target organs during viral infection in mice

Arsenic (As), a potentially toxic trace element, has been shown to influence viral replication and resistance to microbial infection. However, the impact of infection on the normal As status in target organs involved in the disease process has not been studied to date. In the present study, As was measured through inductively coupled plasma mass spectrometry in the plasma, liver, spleen, kidney, heart, pancreas and brain at days 1 and 3 of coxsackievirus B3 infection in female Balb/c mice. The severity of the infection was assessed from clinical signs of disease. The infection changed plasma As in a biphasic pattern with a small increase (n.s.) at day 1 that turned into a decreasing trend (13%, p<0.05) by day 3. In the liver, spleen, heart, pancreas and kidney As was unchanged at day 1 but, at day 3, it had decreased by 71% (p<0.01), 64% (p<0.01), 55% (p<0.01), 63% (p<0.01) and 73% (p<0.01), respectively. In the brain, As went unchanged. The pathophysiological interpretation of these findings requires further research.     

Presynaptic activity and protein turnover are correlated at the single-synapse level

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