Next Article in Journal
Green Tea Consumption Affects Cognitive Dysfunction in the Elderly: A Pilot Study
Next Article in Special Issue
Protein Content and Methyl Donors in Maternal Diet Interact to Influence the Proliferation Rate and Cell Fate of Neural Stem Cells in Rat Hippocampus
Previous Article in Journal
Leucine Supplementation Accelerates Connective Tissue Repair of Injured Tibialis Anterior Muscle
Previous Article in Special Issue
Epigenetic Mechanisms Underlying the Link between Non-Alcoholic Fatty Liver Diseases and Nutrition
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Concept Paper

Selenium-Enriched Foods Are More Effective at Increasing Glutathione Peroxidase (GPx) Activity Compared with Selenomethionine: A Meta-Analysis

1
Food Nutrition & Health, Food & Bio-based Products, AgResearch Grasslands, Private Bag 11008, Tennent Drive, Palmerston North 4442, New Zealand
2
Institute for Cell & Molecular Biosciences, University of Newcastle upon Tyne, Newcastle NE2 4HH, UK
3
Bioinformatics & Statistics AgResearch Grasslands, Private Bag 11008, Tennent Drive, Palmerston North 4442, New Zealand
4
Riddet Institute, Massey University, Palmerston North 4442, New Zealand
5
Gravida: National Centre for Growth and Development, the University of Auckland, Auckland 1142, New Zealand
*
Author to whom correspondence should be addressed.
Nutrients 2014, 6(10), 4002-4031; https://doi.org/10.3390/nu6104002
Submission received: 30 June 2014 / Revised: 20 August 2014 / Accepted: 21 August 2014 / Published: 29 September 2014
(This article belongs to the Special Issue Nutritional Epigenetics)

Abstract

:
Selenium may play a beneficial role in multi-factorial illnesses with genetic and environmental linkages via epigenetic regulation in part via glutathione peroxidase (GPx) activity. A meta-analysis was undertaken to quantify the effects of dietary selenium supplementation on the activity of overall GPx activity in different tissues and animal species and to compare the effectiveness of different forms of dietary selenium. GPx activity response was affected by both the dose and form of selenium (p < 0.001). There were differences between tissues on the effects of selenium supplementation on GPx activity (p < 0.001); however, there was no evidence in the data of differences between animal species (p = 0.95). The interactions between dose and tissue, animal species and form were significant (p < 0.001). Tissues particularly sensitive to changes in selenium supply include red blood cells, kidney and muscle. The meta-analysis identified that for animal species selenium-enriched foods were more effective than selenomethionine at increasing GPx activity.

1. Introduction

Selenium is an essential cofactor for approximately 25 selenoproteins [1,2], including the glutathione peroxidases (GPx1–8 [3]), selenoprotein P and thioredoxin reductases. GPxs are enzymes crucial for detoxification and protecting cells from oxidant damage. To date, eight isoforms of the GPx family have been identified; most of these forms are differentiated by their cellular (or tissue) location and substrates used and whether they incorporate cysteine rather than selenocysteine (Sec) [3,4]. The GPx family has been the focus of many reviews [3,4]. However, briefly, GPx1 (cGPx) is a cytosolic enzyme found in all tissues including blood cells; it reacts with damaging peroxides such as hydrogen peroxide. GPx2 (GSHPx-GI) and GPx3 (pGPx) also use peroxides as substrates but GPx2 is predominantly expressed in gastrointestinal cells whereas GPx3 is a secreted form found in plasma and milk [4,5]. GPx4 (PHGPx) is different in that it uses phospholipid hydroperoxides as substrates and is found in both mitochondria and cytosol; it is expressed in most tissues but is found in a high concentration in the testes. GPx4 has been proposed to have functions in apoptosis and protecting mitochondrial function from damaging radicals [6], sperm development [4] and embryonic development [7]. GPx1–4 all incorporate Sec [3]. GPx5 (eGPx) is found in the epididymis and has roles in fertility [3]. GPx6, also known as Olfactory metabolising protein (OMP), is only classed as a selenoprotein in humans, not in rodents [3], is located in the olfactory epithelium and has possible roles in olfaction [4]. More recently, GPx7 (NPGPx) has been described; like GPx5 it is a cysteine-based isoform, and is thought to prevent oxidative stress in breast cancer cell lines [4] and protein folding in the endoplasmic reticulum [3]. GPx8 was discovered using phylogenetic analyses [4] and also is thought to have a role in protein folding [3]. GPx5–8 are cysteine-based isoforms [3]. Selenium incorporation into selenoproteins (as SEC) occurs during their synthesis by a mechanism involving the 3′ untranslated region of mRNAs and trans-acting proteins [8].
Dietary deficiency of selenium has been shown to redistribute intracellular selenium among the selenoproteins and GPx proteins [9]. Synthesis of the various selenoproteins responds differently to changes in selenium supply [2] with GPx1 being highly sensitive and GPx2 and GPx4 more resistant to changes in selenium supply. In rats, dietary deficiency of selenium has been shown to redistribute intracellular selenium among several selenoproteins including GPxs [9]. There has been much interest in the effects of selenium supplementation on GPx activity (especially red blood cell GPx and plasma GPx3) and mRNA levels since these may provide potential biomarkers of selenium status [10,11,12,13].
Oxidant damage to DNA is a critical event in cancer development [14]. Evidence indicates that a polymorphism of the 3′ untranslated region of the GPx4 gene is functional [15] and associated with colon cancer risk [16]. This suggests that variants in GPx genes increase oxidant-induced DNA damage leading to increased cancer risk. Other studies have shown that, in addition to changes in the DNA sequence, there are changes occurring during cancer that are not in the gene sequence (epigenetic events). Alteration of methylation patterns in CpG islands (often located in DNA promoter) of some GPx genes have been shown in some cancers [17]. Research has shown that another type of epigenetic factor, microRNAs (miRNAs), is also important in human carcinogenesis [18]. These tiny molecules are short, single stranded non-coding RNAs that regulate gene expression by base pairing with target mRNAs at the 3′ untranslated region, leading to mRNA cleavage [19]. The 3′ untranslated region is critical for selenoprotein synthesis and therefore miRNAs (which target such regulatory regions) have the potential to play important roles in regulating GPx expression. In this regard, cell culture studies have recently indicated that changes in selenium supply cause altered expression of a number of miRNA, and altered expression of miR-185 was linked to regulation of GPx2 and Selenophosphate Synthetase 2 (SEPSH2) expression [20]. As a result, there is considerable interest both in the response of selenoprotein activity to selenium supplementation and in finding effective biomarkers of functional selenium status.
The effects of dietary selenium on different GPx activities are complex with differences between enzymes and tissues. Most authors have found an increase in GPx1 in response to dietary selenium in rodents [21,22,23] and selenoprotein expression, including GPx activity, in different tissues is affected by selenium availability to differing extents [24]. While some authors have assessed the effects of different selenium forms on GPx activities, and others have investigated the effects of selenium supplementation on GPx activity in different tissues [25], no one study has attempted to describe quantitatively the nature of the relationship between selenium supplementation and either the different GPx activities or the overall GPx activity (encompassing GPx1–4).
The human epigenome is vital to regulation of tissue functions [26]. The epigenome comprises interconnected, interdependent heritable processes that regulate gene expression (e.g., DNA methylation, histone modifications, non-coding RNAs). There is mounting evidence that these events have a major role in development and function of all cells and in the development of multi-factorial diseases in all stages of life; they allow plasticity of the phenotype in a fixed genotype [27]. Evidence suggests that specific nutrients can modulate epigenetic events [28,29], indicating it may be possible to reduce or even reverse the negative effects in multi-factorial illnesses by diet. Selenium is one nutrient which has been suggested to act through epigenetic mechanisms [30] either by affecting the availability of S-adenosyl methionine or the concentration of S-adenosyl homocysteine (inhibits of DNA methyltransferases) via the methionine-homocysteine cycle [31].
Epigenetic studies require a comprehensive understanding about the dose rate of the nutrient of interest, and the tissue in which to investigate changes in epigenetic regulation. For example, in the case of obesity, epigenetic mechanisms are largely specific to cell type [32]. In the present work, we used a meta-analysis approach to describe tissue differences in overall GPx activity in response to dietary selenium supplementation, and to investigate whether the degree of response varied according to animal species or form of dietary selenium supplementation. The meta-analysis approach, which is a widely used statistical tool to assess treatment effects across similar experiments conducted at different times, gives the advantage of reducing the risk of experimental bias arising from experimental conditions from single experiments. The meta-analysis described here provides essential information for designing appropriate studies in which to investigate the potential role of selenium in the epigenetic regulation of GPx activity.

2. Experimental Section

2.1. Database

This study was a meta-analysis of publications reporting the effects of selenium supplementation on GPx activity, and has been reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement [33] with reference to the explanation and elaboration document [34]. Three of the authors (Nicole C. Roy, John E. Hesketh, Emma N. Bermingham) met in February 2011 to agree in advance on the protocol.

2.2. Information Sources and Searches

The primary author (Emma N. Bermingham) searched the scientific literature electronically in order to identify publications that estimated the effects of selenium supplementation on GPx activity. Online resources searched included OVID databases (Medline, BIOSIS, FSTA, CAB Abstracts), SCOPUS, and PUBMED. The search terms used to identify suitable publications included relevant terms covering selenium supplementation, gluthatione peroxidase, selenoprotein. We limited our database to investigate the effects of selenium supplementation on the activity of selenoproteins in healthy in vivo models. Our literature search was limited to publications reported in English, and those publications which reported selenoprotein activity in table format. Our initial investigations identified that GPx were the predominant selenoproteins investigated therefore a database was constructed using the publications that dealt only with dietary selenium supplementation and activity of GPx in tissues, plasma and red blood cells. The electronic searches commenced on 15 February 2011 and the last search was performed on 31 January 2012.

2.3. Eligibility Criteria

A “publication” was defined as a distinct piece of published work, be it a full paper or research communication (abstract) at a scientific meeting. Only publications in the English language were considered, but no date limits were set for inclusion. In all cases, data on selenium supplementation dose rates and methods and form (e.g., sodium selenite, selenomethionine), methodologies used to determine GPx activities, the animal species (including strain and generation if appropriate), the tissue studied, and the response of selenoprotein activity were recorded. Studies investigating alternative forms of selenium dosing—for example, injection, or dosage via water source—were not included in the analysis. Forms of selenium were classed either as basal diet (control diet), sodium selenite, sodium selenate, selenomethionine, selenium-enriched yeast (selenium-yeast; e.g., SelPlex) or selenium-enriched foods (e.g., mushrooms, animal tissue, onions, milk, etc.).
In order to compare animal species, all dietary supplementation data were normalised to mg/kg selenium for the dose of selenium given. The concentration of selenium in the diet was used as an indicator of selenium supplementation, rather than selenium intake, as few publications recorded intake data. Depletion and repletion studies were not included in the database. In cases where deficiencies of multiple nutrients were investigated, only the treatment groups relating to changes in selenium were used with adequate levels of the other nutrients.
The activity of GPx was standardised to a common unit (nmol NADPH oxidised/min/mg protein in the case of tissues, nmol NADPH oxidised/min/mL for plasma and nmol NADPH oxidised/min/mg haemoglobin for red blood cells). Literature in which the units of selenoprotein activity were not defined in the publication were not included in the database.
Within each publication, treatment groups were coded according to form, tissue and animal as illustrated in Table 1 where treatment groups are shown to be assigned according to the tissue studied. In addition, if appropriate, groups were also coded for length of dosing, as for example in the study of Toshiro et al. [35] in which chickens were fed two levels of selenomethionine for 35 days and tissue samples taken at day 35 of feeding.
Table 1. An example of coding treatments within a publication [35].
Table 1. An example of coding treatments within a publication [35].
ExperimentalTissueLength of DietaryLevel ofSelenium FormPublication Treatment
GroupTreatment (Days)Dose(mg/kg Se)Group
Se−Erythrocyte350SelenomethionineAra_7
Se+Erythrocyte350.3SelenomethionineAra_7
Se−Kidney350SelenomethionineAra_10
Se+Kidney350.3SelenomethionineAra_10
Se−Liver350SelenomethionineAra_9
Se+Liver350.3SelenomethionineAra_9
Se−Muscle (pectoral)350SelenomethionineAra_11
Se+Muscle (pectoral)350.3SelenomethionineAra_11
Se−Muscle (femoral)350SelenomethionineAra_12
Se+Muscle(femoral)350.3SelenomethionineAra_12
Se−Plasma350SelenomethionineAra_8
Se+Plasma350.3SelenomethionineAra_8
Se, selenium.

2.4. Study Selection and Data Collection Process

The primary author (Emma N. Bermingham) reviewed all publications identified from the electronic search, and assessed study eligibility in an unblinded, manner. A copy of all eligible publications was first obtained, either as a portable document format (PDF) file, or as a photocopy of the original paper document.
Two authors (Bruce R. Sinclair and Emma N. Bermingham) extracted relevant data from all eligible publications that were available. Data were entered into a computer spreadsheet (Excel version 2010, Microsoft, Redmond, USA).

2.5. Data Handling and Statistical Analysis

One author (John P. Koolaard) conducted all statistical analyses using computer software (Microsoft Excel 2010, and GenStat Version 14). We determined the effects of selenium form, tissue and animal species on the dose-response relationship between selenium supplementation and GPx activity. In each case, it was the slope of the dose-response relationship that was focussed on.
GPx activity and selenium dose were log (base 10) transformed, and thus the dose-response relationship was linearised. For selenium dose, a small constant of 0.01 was added before taking logs since some dose rates were zero. A weighted linear mixed model analysis using restricted maximum likelihood (REML) (GenStat Version 14) was used, where the weights for each observation were inversely proportional to the stated variance of the mean quoted in the publication. The publication number and coded treatment groups (within publication) were considered to be random effects in the model. The fixed effects were: the (log of) selenium dose, and its interaction with tissue, species and form, as well as the main effects of tissue, species and form group.
Classifications (e.g., animal, tissue, form groups) with less than 5 data points were not included in the meta-analysis.

3. Results

For the animal comparison, 40 publications were identified that met the selection criteria described in the Methods section (Table 2). Data from these were used here to determine the relationship between selenium dose and GPx activity. These publications were coded into 593 treatment groups (see Table S1).

3.1. Overall Relationship between Selenium Supplementation and GPx Activity

As indicated in Table 3, the meta-analysis included treatments groups in birds (59 treatment groups), horses (24 treatment groups), ruminants (14 treatment groups) and rodents (496 treatment groups). In animal species, liver was the predominant tissue investigated (160 treatment groups), followed by the gastrointestinal tract (68 treatment groups), plasma (60 treatment groups) and muscle (55 treatment groups). Sodium selenite (141 treatment groups), selenomethionine (99 treatment groups), and sodium selenate (85 treatment groups) were the predominate forms of selenium supplemented.
REML analysis of data across all the studies showed that the overall relationship between selenium supplementation and GPx activity (ignoring other factors) could be described by the equation: Log GPx activity = 1.822 (SE 0.146) + 0.645 (SE 0.116) × Log Dose. Both the form of selenium (p < 0.001) and tissue studied (p < 0.001) significantly influenced both the intercept and the slope of this relationship (Table 3), whereas animal species only influenced the slope (p = 0.03).
Quantitative analysis indicated that the selenium-enriched foods were more effective at increasing GPx activity compared to other forms of selenium including selenomethionine and selenium-yeast (indicated by the log Dose.Form in Table 3). As indicated by similar log Dose.Form values, sodium selenite, sodium selenate and selenomethionine decreased GPx activity. In addition, GPx activity in the red blood cells, kidney and muscle were least responsive (tissue × dose interaction as indicated by Log Dose.Tissue in Table 3) to selenium supplementation and GPx activity in the gastrointestinal tract most responsive.
Table 2. Description of the form of selenium studied for selenoprotein activity with changing concentrations of selenium in the diet for animal species and average gluthationine peroxidase (GPx) activity. The table indicates the number of treatment groups for each publication. A full description of the data set including methodology used can be found in Table S1.
Table 2. Description of the form of selenium studied for selenoprotein activity with changing concentrations of selenium in the diet for animal species and average gluthationine peroxidase (GPx) activity. The table indicates the number of treatment groups for each publication. A full description of the data set including methodology used can be found in Table S1.
ReferenceAnimal Speciesn Treatment GroupsDiet FormTissueSe Dose Rate (mg/kg)GPx Activity (nmol NADPH ox/min/mg prot)
[23]Rodent5Basal dietGastrointestinal tract0.15850
Selenium-enriched food0.5; 16150–5950
Selenium-yeast18120
[36]Rodent45Basal dietHeart, kidney, liver, plasma, red blood cells0.195–1023
Sodium selenite0.25; 0.5125–1059
Selenomethionine0.25; 0.5125–1063
Selenium-yeast0.25; 0.5127–1011
[37]Rodent16Basal dietPlasma, red blood cells0.02554–476
Sodium selenite0.05; 1; 254–609
[38]Ruminant8Basal dietMuscle, red blood cells0.1614–80
Sodium selenite0.319–97
Selenium-yeast0.324–104
[39]Rodent4Basal dietLiver071–77
Sodium selenite1104–151
[40]Bird8Basal dietLiver, red blood cells0.115192–269
Sodium selenite2308
Selenium-yeast2328–439
[41]Rodent8Basal dietHeart, kidney, liver, plasma0.0223–179
Sodium selenate0.576–672
[42]Rodent9Basal dietLiver, plasma00.6–8.7
Sodium selenate0.75; 0.154–831
[43]Bird12Basal dietLiver, muscle, plasma0.050.7–9.8
Sodium selenate0.1; 0.2; 0.33–58
[44]Rodent6Basal dietLiver022
Sodium selenite0.2; 2743–1101
[45]Rodent5Basal dietLiver021
Sodium selenite0.1; 21097
Selenomethionine0.11046
[46]Bird12Basal dietLiver0.261416–2198
Sodium selenite0.463331–4144
Selenium-yeast0.463114–4771
[47]Ruminant2Basal dietLiver0.1140.00
Sodium selenite0.3152.00
[48]Horse24Basal dietMuscle, plasma, red blood cells0.157–233
Sodium selenite0.67–238
Selenomethionine0.67–360
[49]Rodent10Basal dietBrain, liver, muscle0.00436–105
Sodium selenite1.00463–751
[50]Bird15Basal dietGastrointestinal tract, kidney, liver0.16–12
Sodium selenite0.513–24
Selenium-yeast0.5; 112–24
[51]Rodent2Basal dietBrain0.232
Selenium0.0112523
[52]Rodent40Basal dietLiver, muscle0.022.5
Selenium-enriched food0.05; 0.1; 0.154–937
Sodium selenite0.05; 0.1; 0.154–877
Selenomethionine0.05; 0.1; 0.156–790
[53]Ruminant4Basal dietPlasma0.15810
Sodium selenite0.4860
Selenium-yeast0.4630
[54]Rodent5Basal dietLiver0.01140
Sodium selenite0.1; 0.5; 1; 2880–1250
[55]Rodent6Basal dietLiver, lymph nodes, skin0.005110–675
Sodium selenite0.1645–1732
[56]Rodent15Basal dietBrain, muscle, plasma, reproductive tract, spleen03–250
Sodium selenite0.1; 448–686
[57]Rodent63Basal dietBrain, heart, kidney, liver, muscle, plasma, red blood cells, reproductive tract, spleen02–135
Sodium selenate42–158
Selenomethionine0.5; 1; 2; 42–237
[58]Rodent4Basal dietBrain, liver0.0164–64
Sodium selenite0.1100
[59]Rodent27Basal dietHeart, liver, thyroid0.0031–70
Sodium selenite0.024; 0.052; 0.104; 0.4051–2020
[60]Rodent8Basal dietLiver0.0056–133
Sodium selenite0.10051158–1586
[61]Rodent4Basal dietLiver0.0057
Sodium selenite0.10051262
[62]Rodent8Basal dietKidney, liver0.00519
Sodium selenite0.1005500–1080
[63]Rodent2Basal dietLiver0.0055
Sodium selenite0.10051080
[64]Rodent4Basal dietLiver, plasma013
Sodium selenate0.25340–1500
[65]Rodent16Basal dietKidney, liver0.45455–801
Selenium-yeast0.00717–378
[66]Rodent6Basal dietBrain, kidney, liver09.3
Sodium selenite0.2520–310
[67]Rodent8Basal dietLiver, thyroid010–80
Sodium selenite0.150-890
[68]Rodent68Basal dietAdipose tissue, gastrointestinal tract, liver, plasma, red blood cells03–180
Selenomethionine210–638
[69]Rodent12Basal dietBrain, heart, kidney, liver, lung0.01520
Sodium selenate0.2525–320
[70]Rodent6Basal dietReproductive tract, spleen0.01152
Sodium selenite0.1; 1357
[25]Rodent71Basal dietAdipose, adrenal, brain, diaphragm, eye, heart, gastrointestinal tract, kidney, liver, lung, muscle, oesophagus, pancreas, reproductive tract, skin, spinal cord, spleen, thymus, tongue04–455
Sodium selenate0.1; 432–1502
[35]Bird12Basal dietKidney, liver, muscle, plasma, red blood cells04–143
Selenomethionine0.37–192
[71]Rodent36Basal dietBrain, gastrointestinal tract, heart, kidney, liver, lung, reproductive tract0.0129
Sodium selenite0.510–156
[72]Rodent4Basal dietHeart05
Sodium selenite0.5109
Table 3. Table of effects for the overall relationship between selenium supplementation and gluthathione peroxidase (GPx) activity for animal species. Dose response relationships were determined using the equation: Log GPx activity = [Constant + Form + Tissue + Animal] + [Log Dose.Form + Log Dose.Tissue + Log Dose.Animal]. Model coefficients or effects and the average standard error of difference (SED) between pairs of effects (with the minimum and maximum SEDs where appropriate) are reported.
Table 3. Table of effects for the overall relationship between selenium supplementation and gluthathione peroxidase (GPx) activity for animal species. Dose response relationships were determined using the equation: Log GPx activity = [Constant + Form + Tissue + Animal] + [Log Dose.Form + Log Dose.Tissue + Log Dose.Animal]. Model coefficients or effects and the average standard error of difference (SED) between pairs of effects (with the minimum and maximum SEDs where appropriate) are reported.
ParameterConstantSlopen Treatment Groups
1.822 10.645 2
SE0.1460.116
p-value<0.001
FormLog Dose.Form
Basal diet00232
Sodium selenite0.621−0.366140
Selenomethionine0.390−0.65499
Sodium selenate0.241−0.57869
Selenium-yeast−0.0930.17233
Selenium-enriched foods1.3440.91420
SED
(min SED; max SED)
0.17
(0.124; 0.216)
0.264
(0.111; 0.493)
p-value<0.001<0.001
TissueLog Dose.Tissue
Liver0.0000160
Gastrointestinal tract 3−0.1410.23368
Plasma−0.708−0.15860
Muscle−0.621−0.30255
Brain0.143−0.21934
Heart0.099−0.16841
Kidney0.063−0.31148
Red blood cells 40.516−0.32450
Reproductive tract 50.258−0.15329
Spleen0.690−0.22516
Thyroid0.5320.02611
Adipose tissue 6−0.0950.0057
Lung−0.125−0.2099
Skin0.1210.0085
SED
(min SED; max SED)
0.373
(0.130; 0.756)
0.335
(0.103; 0.653)
p-value<0.001<0.001
AnimalLog Dose.Animal
Rodent 700496
Bird 8−0.042−0.29459
Horse−0.160−0.26224
Ruminant 90.442−0.50214
SED
(min SED; max SED)
0.548
(0.304; 0.729)
0.359
(0.095; 0.506)
p-value0.9480.031
1 This constant value constitutes the combined additive effect (intercept) of the combination of the first categories of Form, Tissue and Animal, namely Basal Diet, Adipose Tissue, and Bird. That is why the coefficients for each of these are zero; 2 This slope value constitutes the coefficient of LogDose (i.e., slope) for the same combination of the first categories of Form, Tissue and Animal, namely Basal Diet, Adipose Tissue, and Bird. Includes the stomach, duodenum, jejunum, ileum, caecum, colon; 3 Includes blood, platelets, erythrocytes, thrombocytes; 4 Includes epididymis, prostate, seminal vesicles and testis. 5 Includes brown and white adipose tissue; 6 Includes mouse, rat and guinea pig; 7 Includes chickens and turkeys; 8 Includes sheep, goat and cow.

3.2. The Effects of Selenium Supplementation on GPx Activity in Humans

The meta-analysis identified 42 treatment groups investigating the effects of selenium supplementation on GPx activity in humans (Table 4). Selenium supplementation was either by selenium-yeast (20 treatment groups) or selenium-enriched food sources (e.g., selenium-enriched onions; 7 treatment groups). Red blood cells (38 treatment groups) and plasma (4 treatment groups) were the tissues studied.
REML analysis of this dataset showed that the overall relationship between selenium supplementation and GPx activity (ignoring other factors) could be described by the equation: Log GPx activity = 2.036 (SE 0.497) – 0.113 (SE 0.128) × Log Dose. The meta-analysis indicated that the slope of the relationship was not significantly affected by form of selenium (p = 0.70) or tissue studied (p = 0.70) (Table 5).
Table 4. Description of the country, form of selenium studied for selenoprotein activity with changing concentrations of selenium in the diet for investigated in human subjects.
Table 4. Description of the country, form of selenium studied for selenoprotein activity with changing concentrations of selenium in the diet for investigated in human subjects.
ReferenceCountryFormTissueSe Dose Rate (mg/kg)GPx Activity (nmol NADPH ox/min/mg prot)Used in Meta-Analysis?
[73]AustraliaBasal dietPlasma15070.9–76.3Yes
Selenium-milk
Selenium-yeast
[74]BritainBasal dietPlasma--No—units
[75]UKBasal dietPlatelet50; 100; 200250–340Yes
Selenium-onions
Selenium-yeast
[76]New ZealandBasal dietBlood3006.49Yes
Selenium-yeast
[77]New ZealandBasal dietPlasma, platelet, whole blood--No-data reported graphically
Sodium selenate--
Selenomethionine--
[78]USABasal dietErythrocyte, plasma--No—data reported graphically
Selenium-glycinate--
[79]SwedenBasal dietPlasma--No—no control (selenium-free) group
[80]DenmarkBasal dietErythocytes, plasma, thrombocytes--No—units
Sodium selenate--
Selenium-milk--
Selenium-yeast--
[81]ChinaBasal dietPlasma, red blood cells--No—data reported graphically
Sodium selenite--
Selenium-yeast--
[82]ItalyBasal dietPlasma--No—units
Sodium selenite--
[12]UKBasal dietErythocytes, platelet50; 100; 20043.0–12800Yes
Enriched Protein
Onions
Selenium-onions
Selenium-yeast
[83]DenmarkBasal dietErythocytes, plasma, thrombocytes--No—units
Selenium-yeast--
[84]USABasal dietPlasma--No—data reported graphically
Selenomethionine--
[85]USABasal dietPlasma--No—no control (selenium-free) group
[86]ChinaBasal dietPlasma--No—data reported graphically
Sodium selenite--
Selenomethionine--
[87]USABasal dietPlasma--No—data reported graphically
Sodium selenite--
Selenomethionine--
Selenium-yeast--
[88]FinlandBasal dietPlasma, platelet, red blood cells-
-
-
-No—units
Sodium selenite-
Selenium-yeast-
Table 5. Table of effects for humans showing the relationship between selenium intake and Glutathione Peroxidase (GPx) activity. Dose response relationships were determined using the equation: Log GPx activity = (Constant + Form + Tissue) + (Log Dose.Form + Log Dose.Tissue). Model coefficients or effects, and the average standard error of difference (SED) between pairs of effects (with the minimum and maximum SEDs where appropriate) are reported.
Table 5. Table of effects for humans showing the relationship between selenium intake and Glutathione Peroxidase (GPx) activity. Dose response relationships were determined using the equation: Log GPx activity = (Constant + Form + Tissue) + (Log Dose.Form + Log Dose.Tissue). Model coefficients or effects, and the average standard error of difference (SED) between pairs of effects (with the minimum and maximum SEDs where appropriate) are reported.
ParameterConstantSlopen Treatment Groups
2.036 2−0.113 3
SE0.4970.128
p-value0.004
FormLog Dose.Form
Basal diet0015
Selenium-enriched foods0.2400.0007
Selenium-yeast0.2310.05020
SED
(min SED; max SED)
0.154
(0.080; 0.226)
0.131
p-value0.0110.703
TissueLog Dose.Tissue
Red blood cells 10.0038
Plasma−0.312−6.74 × 10−44
SED0.9840.019
p-value0.7400.704
1 Includes blood, platelet, erythrocyte; 2 This constant value constitutes the combined additive effect (intercept) of the combination of the first categories of Form and Tissue, namely Basal Diet and Red blood cells. That is why the coefficients for each of these are zero; 3 This slope value constitutes the coefficient of Log Dose (i.e., slope) for the same combination of the first categories of Form and Tissue, namely Basal Diet and Red blood cells.

4. Discussion

GPx synthesis utilises selenium (via selenocysteine) and glutathione derived from transsulfuration of homocysteine; homocysteine is derived from S-adenosylhomocysteine, which is formed as a result of methylation reactions including methylation of selenium [31,89]. Selenium is thought to exert epigenentic effects by altering the relative concentrations of S-adenosyl methionine and S-adenosyl homocysteine, thereby modulating DNA methylation and gene transcription via the methionine-homocysteine cycle [31]. These observations demonstrate an interaction between selenium, GPx enzyme activity, and methylation, although its precise nature remains unclear.
Given the conflicting results in the literature surrounding the effects of selenium supply and selenoprotein activity, it was of interest to attempt to determine quantitatively any differences between the form of selenium and selenoprotein activity. To address one component of this interaction, this meta-analysis quantified the relationship between selenium supplementation and global GPx activity. For all tissues and animal species studied (including humans), selenium supplementation increased GPx activity. The exact relationship between selenium supply and GPx activity depended on the form of selenium used and the tissue being investigated. Importantly, the study suggests that compared with selenomethionine and selenium-yeast in particular, selenium-enriched food are more effective in increasing GPx activity in a range of tissues. These results are discussed in relationship to the role of selenium in epigenetic regulation of DNA methylation, gene expression and histone deacetylase (HDAC) inhibition.

4.1. Form Differences

The dose-response relationships generated in the current study suggest that selenium-enriched foods are the most effective at increasing GPx activity in a range of animal species. However, the selenium-enriched foods group had a smaller number of observations and no higher dose rates were included. Therefore, more data investigating enriched protein sources and using higher levels of selenium would be of value. Interestingly, of the three most common forms of selenium studied (i.e., sodium selenate, sodium selenite and selenomethionine), the inorganic forms of selenium were more effective at increasing GPx activity compared with selenomethionine (see Table 3, Log Dose.Form interactions). As the form of selenium fed was found to affect the relationship between selenium supply and GPx activity, this may explain the apparent contradictory information in the literature concerning the effects of selenium supply on GPx activity [21,90,91,92,93].
Much discussion in the literature exists in terms of the bioavailability of different forms of selenium and their ability to raise selenoprotein activity in humans [75,87]. Traditionally, inorganic forms of selenium (sodium selenite and sodium selenate) have been thought to be less effective at increasing biomarkers of selenium status than organic forms (selenomethionine), based on selenium concentrations in plasma [86,87]. However, a previous meta-analysis suggested that inorganic forms increased platelet GPx activity more effectively than organic forms [94]. More recently, it has been suggested that the response to supplementation varies with baseline status and that this is form dependent. For example, selenomethionine increases plasma selenium in people with either low or optimal selenium status but selenite has little effect unless the subjects are of low status [84]. Recent results have shown that selenium glycinate (an inorganic form of selenium) increased GPx activity in men [78]. Additionally, red blood cell GPx activity increased with short-term (4 weeks) selenate supplementation whereas organic selenium (selenium enriched milk and selenium-yeast) produced no effect in humans [80]. Selenium-yeast increased GPx1 and GPx4 activity in platelets after 12 weeks of supplementation in humans [12]. Interestingly, selenium-enriched onions decreased GPx4 activity after 10 weeks of supplementation [12]. In humans with optimal baseline selenium status, selenomethionine supplementation (50–200 μg/day for 12 months) did not affect GPx3 activity or selenoprotein P levels [84]. Some of these differences may reflect non-specific incorporation of selenomethionine into proteins such as albumin. Additionally, data shows that the chemical form of selenium at nutritional doses can affect the absorption and retention of selenium in a human intestinal Caco-2 cell model [95]. These authors showed that selenomethionine, and digested selenium enriched yeast were transported at comparable efficacy from the apical to basolateral sides, each being about three-fold that of selenite; but that these effects are not directly correlated to the potential to support GPx activity [95].
There is increasing interest in selenium-enriched foods and their impacts on human health, due to the link between selenium status and cancer risk. In the current analysis, selenium-enriched protein sources (e.g., milk, meat; [23,52,73]) enhanced the rate of increase in GPx activity compared to selenium-yeast; unfortunately we were unable to include other inorganic forms of selenium into the meta-analysis due to the format in which GPx activity was reported (graphs, or units). While selenium-enriched rice increased serum GPx activity in humans with normal selenium [96], selenium-enriched onions did not affect platelet GPx activity [75]. Selenium enriched probiotics (containing >90% organic Se; of the organic Se, >75% is selenomethionine) increased GPx activity in the eggs of laying hens [97] and in the blood [98,99] and tissues [99] of pigs. It is important to note that selenium-enriched foods contain multiple forms of selenium, including organic (selenomethionine) and inorganic forms (sodium selenite and sodium selenate) [75]. The effectiveness of selenium-enriched foods in increasing GPx activity observed in the present study is consistent with earlier studies in which selenium enriched milk was more effective than selenium-yeast and more protective against colon tumouriogenesis in mouse models [100]. Furthermore, when mice were fed selenium in the forms of sodium selenite, selenomethionine and selenium-yeast only the selenium-yeast tended to reduce DNA oxidation [101]. Thus, considering both previous and present work, although there are complex and contradictory findings as regards the relative effectiveness of different forms of dietary selenium on GPx activities, in general the greatest effects in both animals and humans are found with protein-based sources of selenium.

4.1.1. Form Effects on Epigenetic Regulation

Epigenetic modifications of genes in response to selenium supplementation have been investigated in vivo and in vitro, with the majority of studies using cell lines to investigate the epigenetic regulation of genes in response to selenium. Of the selenoproteins, only the epigenetic regulation of GPx1 [102,103] and GPx3 [104] have been investigated, but not in relation to selenium supplementation. In terms of the effects of selenium supply on epigenetic regulation, both inorganic and organic forms of selenium have been used to investigate global DNA methylation and gene specific methylation. Investigations on the effect of selenium supplementation have been reported to a lesser extent for HDAC activity and miRNA.
Sodium selenite reduced global DNA methylation in the heart of mice [89]. In the liver and colon mucus of the rat, dietary selenomethionine supplementation has been shown to cause global DNA hypomethylation [22]. Sodium selenite also decreased DNA methylation in human prostate cancer cells [105]. Selenomethione increased DNA methylation of the p53 gene but did not affect the methylation of β-actin gene in the rat [22]. Low levels of methylselenocysteine resulted in increased methylation of the von Hippel-Lindau (VHL) gene in vitro [106]. Selenium methylselenocysteine and selenite supplementation did not affect the methylation of ESR1, p16 (INK4A) or of LINE-1 in vitro [107]. Seleno-DL-methionine did not affect the methylation status of glutathione sulfotransferase pi (GSTP1) nor Ras associated family 1A (RASSF1A) genes in vitro [108]. DNA methylation profile between Keshan Disease patients and normal individuals showed that selenium deficiency decreased methylation of CpG islands in promoter regions of TLR2 and ICAM1, in agreement with results from in vivo and in vitro models of the disease [109].
Methylselenocysteine and selenomethionine are organoselenium compounds that can be converted to beta-methylselenopyruvate and alpha-keto-gamma-methylselenobutyrate. These alpha-keto acid metabolites share structural features with butyrate (an HDAC inhibitor) [110]. Beta-methylselenopyruvate and alpha-keto-gamma-methylselenobutyrate alter HDAC activity and histone acetylation status in vitro [110]. Supplementation of methylseleninic acid inhibited HDAC activity in B-cell lymphoma cell lines [111] and in esophageal squamous cell carcinoma cell lines [112]. Se-Methyl-l-selenocysteine and selenomethionine had no effect on HDAC activity while beta-methylselenopyruvate and alpha-keto-gamma-methylselenobutyrate inhibited HDAC activity in vitro [113]. Selenium-enriched milk has been shown to inhibit HDAC activity in vivo [114]. Furthermore, sodium selenite has recently been shown to regulate the expression of GPx2 and SEPSH2 via miRNA [20]. These observations collectively indicate a potentially important, albeit somewhat unclear, role of several epigenetic mechanisms in modulating the effects of selenium.

4.2. Selenium Supply and GPx Activity in Humans

To our knowledge, there have been two attempts to determine the relationship between selenium supplementation and GPx activity in humans using meta-analysis [94,115], with an additional study published in Chinese that showed supplementation with organic selenium increases the activity of GPx in healthy adults (abstract only [116]). However, no studies have attempted to quantify the relationship between GPx activity and selenium supplementation. Additionally, Ashton et al. [115] excluded selenite on the basis of a supplementation study in the USA which appeared to supplement human subjects who were already selenium replete [87]. This is despite literature supporting an effect of selenite supplementation (100 μg/day) on selenium status in humans [117]. In humans, supplementation of selenomethionine (100 μg) increased whole blood GPx activity [118]. It has been suggested that GPx activity in humans is not sensitive to changes in selenium supply unless the people had low baseline levels of selenium [94]. However, more recently, studies have shown that selenium-enriched milk protein (dairy-selenium) or selenium-rich yeast (yeast-selenium) plasma GPx activity was not changed in humans with low plasma selenium status [73] and in men with high and low selenium status neither prostate tissue nor serum selenium concentrations were associated with prostate tissue GPx activity [119]. Additionally, in healthy males with higher selenium status supplementation with selenized yeast (Selplex, 200 μg/day) reduced red blood cell GPx activity [120].
The current meta-analysis suggests that in humans GPx activity increases with selenium supply (with red blood cells being more responsive than plasma), in agreement with previous observations [115]. This is not unexpected since GPx1, which is more sensitive than GPx3 to selenium supply, is the predominant form in red blood cells and GPx3 the form in plasma. Predicted dose-response relationships suggest the same would hold true of other tissues; however these relationships need to be strengthened by more information on the effects of selenium supplementation and the various GPx activities in other tissues [115].

4.3. GPx Activity/Expression as a Biomarker of Selenium Requirements

Currently, there is debate as to the appropriateness of GPx1 and GPx3 activities or mRNA levels as biomarkers for selenium requirements [10,11,12,13]. Interestingly, results from single studies indicate that GPx activity is not an appropriate biomarker for selenium status [10,11,12,13] whereas the conclusion from a systematic review was that GPx activity may have a role as a biomarker of selenium status [115].
Initially, we had planned to assess the effects of selenium supplementation on mRNA expression of GPx, however our literature search identified that few publications provided quantitative effects of selenium supplementation on GPx mRNA. Therefore, we were unable to include this parameter in our study and instead focussed on GPx activity. Although the activity of selenoproteins does not always reflect changes in mRNA levels [83], previous work indicates that levels of selenoprotein mRNAs respond to selenium supplementation in a differential manner [11,23] that partly reflects the selenoprotein hierarchy due to different effects of low Se supply on mRNA [73]. Interestingly, the complexity of selenium form also carries through to mRNA expression. For example, selenium-enriched onions (12 weeks study with humans) increased the expression of selenoprotein W1, S1 and R mRNA in humans [12] and selenium-enriched milk increased the expression of GPx1 and GPx2 mRNA in humans (compared to selenium-yeast) after 6 weeks of supplementation [73]. However, there was no effect of short-term (4 weeks) inorganic (selenite) and organic (selenium-yeast and selenium-enriched milk) selenium supplementation on the expression of selenoprotein mRNA (GPx1, thioredoxin reductase-1 and selenoprotein P) in leucocytes in humans [80]. More research in this area is needed to clarify this relationship.

4.4. GPx Activity Is Dependent on the Tissue Studied

The current analysis identifies that there is a hierarchy in terms of the responsiveness of tissue GPx activity to selenium supplementation [31], in agreement with previous studies reporting the effects of GPx activity in multiple tissue beds concurrently [25,57,71] and consistent with the previously described selenoprotein hierarchy [68,121,122,123]. For example, Sun et al. [25] observed that GPx activity was present in 28 tissues in the rat (compared to selenoprotein W which was not detected in all tissues) and that different tissues react differently to alterations in selenium supply. Other studies have shown that supplementation with selenomethionine had no effects on the activity of GPx in brain, testis, heart, muscle and plasma whereas spleen and red blood cells had increased GPx activity [57].
In another study [68], it was observed that supplementation with selenomethionine increased the activity of GPx in the gastrointestinal tract, liver and adipose tissue. The present study also indicates that GPx activity in the gastrointestinal tract is sensitive to selenium supply and this may reflect the presence of GPx2, a selenoprotein that ranks highly in the selenoprotein hierarchy. In addition, the current dataset indicates that there are no decreases in tissue GPx activity associated with higher levels of selenium supplementation. However, this could be due to the relatively small number of treatments investigating the effects of high levels of selenium supplementation.

4.5. Limitations of the Meta-Analysis

As there was limited information on all forms of GPx (i.e., GPx 1–8), the present analysis considered GPx1–8 isoforms occurring in a tissue as a single, combined variable of global GPx activity. Given that there are differences in terms of biochemistry, physiology and metabolism of the different GPx, this affects how the data can be interpreted, and more information on individual forms would be of value. Additionally, the present study did not consider selenoproteins other than GPx1–8, including selenoprotein P which is known to respond to selenium supplementation in a dose-responsive manner [75]. This largely reflects both the relatively few publications in this area with data on these other selenoproteins in the quantitative format required for meta-analysis and the bulk of literature with appropriate data focussing on GPx activity. Human studies suggest that both GPx3 and selenoprotein P levels in plasma exhibit a linear relation to selenium intake following supplementation but that GPx3 reaches a maximal level at a lower selenium intake than selenoprotein P [87,124].
While we identified 17 publications that reported GPx activity in response to selenium supplementation in humans (see Table S2), for a variety of reasons, including issues around units (not reported or compatible), only four publications (42 treatment groups) were included in the current meta-analysis. With such small numbers of publications over a small range of selenium forms (selenium-enriched protein and selenium-yeast), this analysis can therefore only be regarded as preliminary in terms of the situation in humans. A recent review assessing the selenium status of humans indicated a number of key issues in terms of interpreting selenium supplementation data which are in agreement with the findings from the current analysis, namely a lack of consistency between the units of measurement for key analyses including selenium concentration in urine and selenoprotein activity [115]. Inconsistency in units measuring selenoprotein activity has been pointed out previously [125], and it appears that the unit of activity may impact the interpretation of the data. For example, when GPx activity in platelets was measured in μmol NADPH oxidised/min/g protein it showed a significant response to selenium supplementation whereas those measured in nmol NADPH oxidised/min/mL plasma did not [115].
In many publications, the basal diet was not analysed for the final selenium concentration. Therefore, for the purposes of this analysis we assumed that all basal diets (control diets) contained no selenium. While this assumption may not be completely accurate (for example, the basal diet of Sun et al. [25] contained 4 ng selenium per kg diet), it enables us to determine the dose-response relationships between increases in selenium intake and GPx activity. Additionally it is highly probable that the content of the basal diet is much less than the amount of selenium added (e.g., 0.1 or 4 mg/kg) [25].
The present study excluded data sets from “depletion-repletion” studies and it assumed that at the start of the study all animals had an adequate selenium status. Results from individual human studies suggest that baseline selenium status may affect the relationship between GPx activity and selenium supply. Selenomethionine increases plasma selenium in people with both low and optimal selenium status but selenite has little effect unless subjects are of low status [84]. For example, selenomethionine did not affect GPx3 activity in humans with optimal selenium intake [84], whereas selenite increases plasma GPx activity and plasma selenium concentration in humans with sub-optimal baseline selenium status [117]. In addition, our meta-analysis shows that plasma GPx activity is relatively resistant to selenium supplementation and that activity in other tissues is more sensitive and may be more appropriate to measure as a biomarker of status.
As the overall meta-analysis includes data on GPx activity in non-blood tissues, it is also possible that the selenium-enriched proteins are effective in supplying selenium to the non-blood tissues for humans. Indeed, supplementation with selenium-enriched dairy protein increased rectal biopsy GPx activity without concurrent increases in plasma GPx activity [50]. Overall, the relative effectiveness of the different forms at delivering selenium to non-blood tissues in humans with suboptimal selenium status is not clear and should be investigated further.

5. Conclusions

In conclusion, this study indicates that in animals selenium-enriched food is more effective in increasing GPx activity in a range of tissues compared with other forms of selenium including selenomethionine. Such an analysis will provide essential information regarding selenium dosage and form a basis for subsequent studies that aim to investigate how selenium interacts with epigenetic mechanisms to exert its effects, in particular those which involve GPx enzymes and other selenoproteins.

Supplementary Files

Supplementary File 1

Acknowledgments

Emma N. Bermingham was funded by a Foundation Research Science and Technology Postdoctoral Fellowship (AGRX0703), as part of Nutrigenomics New Zealand. The authors acknowledge the assistance of David Baird for statistical advice (VSN (New Zealand) Ltd) and Matthew Barnett (AgResearch Limited) for advice on the manuscript. The writing of this manuscript was facilitated by an EU-funded IRSES grant (PIRSES-GA-2010-269210) and NZ-EU funded IRS ES counterpart fund established by MBIE and operated by the Royal Society of New Zealand.

Author Contributions

Emma N. Bermingham and Bruce R. Sinclair compiled the database. John P. Koolaard conducted the statistical analysis. Emma N. Bermingham, John E. Hesketh, Nicole C. Roy planned and designed the study. All authors contributed to the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lu, J.; Holmgren, A. Selenoproteins. J. Biol. Chem. 2009, 284, 723–727. [Google Scholar]
  2. Fairweather-Tait, S.J.; Bao, Y.; Broadley, M.R.; Collings, R.; Ford, D.; Hesketh, J.E.; Hurst, R. Selenium in human health and disease. Antioxid. Redox Signal. 2011, 14, 1337–1383. [Google Scholar]
  3. Brigelius-Flohe, R.; Maiorino, M. Glutathione peroxidases. Biochim. Biophys. Acta 2013, 1830, 3289–3303. [Google Scholar]
  4. Toppo, S.; Vanin, S.; Bosello, V.; Tosatto, S.C. Evolutionary and structural insights into the multifaceted glutathione peroxidase (GPx) superfamily. Antioxid. Redox Signal. 2008, 10, 1501–1514. [Google Scholar]
  5. Bellinger, F.P.; Raman, A.V.; Reeves, M.A.; Berry, M.J. Regulation and function of selenoproteins in human disease. Biochem. J. 2009, 422, 11–22. [Google Scholar]
  6. Cole-Ezea, P.; Swan, D.; Shanley, D.; Hesketh, J. Glutathione peroxidase 4 has a major role in protecting mitochondria from oxidative damage and maintaining oxidative phosphorylation complexes in gut epithelial cells. Free Radic. Biol. Med. 2012, 53, 488–497. [Google Scholar]
  7. Ufer, C.; Wang, C.C. The roles of glutathione peroxidases during embryo development. Front. Mol. Neurosci. 2011, 4, 12. [Google Scholar]
  8. Hesketh, J. Nutrigenomics and selenium: Gene expression patterns, physiological targets, and genetics. Annu. Rev. Nutr. 2008, 28, 157–177. [Google Scholar]
  9. Bermano, G.; Nicol, F.; Dyer, J.A.; Sunde, R.A.; Beckett, G.J.; Arthur, J.R.; Hesketh, J.E. Selenoprotein gene expression during selenium-repletion of selenium-deficient rats. Biol. Trace Elem. Res. 1996, 51, 211–223. [Google Scholar]
  10. Sunde, R.A. Molecular biomarker panels for assessment of selenium status in rats. Exp. Biol. Med. 2010, 235, 1046–1052. [Google Scholar]
  11. Barnes, K.M.; Evenson, J.K.; Raines, A.M.; Sunde, R.A. Transcript analysis of the selenoproteome indicates that dietary selenium requirements of rats based on selenium-regulated selenoprotein mRNA levels are uniformly less than those based on glutathione peroxidase activity. J. Nutr. 2009, 139, 199–206. [Google Scholar]
  12. Goldson, A.J.; Fairweather-Tait, S.J.; Armah, C.N.; Bao, Y.; Broadley, M.R.; Dainty, J.R.; Furniss, C.; Hart, D.J.; Teucher, B.; Hurst, R. Effects of selenium supplementation on selenoprotein gene expression and response to influenza vaccine challenge: A randomised controlled trial. PLoS One 2011, 6, e14771. [Google Scholar]
  13. Sunde, R.A.; Thompson, K.M.; Evenson, J.K.; Thompson, B.M. Blood glutathione peroxidase-1 mRNA levels can be used as molecular biomarkers to determine dietary selenium requirements in rats. Exp. Biol. Med. Maywood 2009, 234, 1271–1279. [Google Scholar]
  14. Federico, A.; Morgillo, F.; Tuccillo, C.; Ciardiello, F.; Loguercio, C. Chronic inflammation and oxidative stress in human carcinogenesis. Int. J. Cancer 2007, 121, 2381–2386. [Google Scholar]
  15. Méplan, C.; Crosley, L.K.; Nicol, F.; Horgan, G.W.; Mathers, J.C.; Arthur, J.R.; Hesketh, J.E. Functional effects of a common single-nucleotide polymorphism (GPx4c718t) in the glutathione peroxidase 4 gene: Interaction with sex. Am. J. Clin. Nutr. 2008, 87, 1019–1027. [Google Scholar]
  16. Bermano, G.; Pagmantidis, V.; Holloway, N.; Kadri, S.; Mowat, N.A.; Shiel, R.S.; Arthur, J.R.; Mathers, J.C.; Daly, A.K.; Broom, J.; et al. Evidence that a polymorphism within the 3′UTR of glutathione peroxidase 4 is functional and is associated with susceptibility to colorectal cancer. Genes Nutr. 2007, 2, 225–232. [Google Scholar]
  17. Peng, D.F.; Razvi, M.; Chen, H.; Washington, K.; Roessner, A.; Schneider-Stock, R.; El-Rifai, W. DNA hypermethylation regulates the expression of members of the Mu-class glutathione S-transferases and glutathione peroxidases in Barrett’s adenocarcinoma. Gut 2009, 58, 5–15. [Google Scholar]
  18. Webster, R.J.; Giles, K.M.; Price, K.J.; Zhang, P.M.; Mattick, J.S.; Leedman, P.J. Regulation of Epidermal Growth Factor Receptor Signaling in Human Cancer Cells by MicroRNA-7. J. Biol. Chem. 2009, 284, 5731–5741. [Google Scholar]
  19. Millar, A.A.; Waterhouse, P.M. Plant and animal microRNAs: Similarities and differences. Funct. Integr. Genomics 2005, 5, 129–135. [Google Scholar]
  20. Maciel-Dominguez, A.; Swan, D.; Ford, D.; Hesketh, J. Selenium alters miRNA profile in an intestinal cell line: Evidence that miR-185 regulates expression of GPx2 and SEPSH2. Mol. Nutr. Food Res. 2013, 57, 2195–2205. [Google Scholar]
  21. Qin, S.; Huang, K.; Gao, J.; Huang, D.; Cai, T.; Pan, C. Comparison of glutathione peroxidase 1 and iodothyronine deiodinase 1 mRNA expression in murine liver after feeding selenite or selenized yeast. J. Trace Elem. Med. Biol. 2009, 23, 29–35. [Google Scholar]
  22. Zeng, H.; Yan, L.; Cheng, W.-H.; Uthus, E.O. Dietary selenomethionine increases exon-specific DNA methylation of the p53 gene in rat liver and colon mucosa. J. Nutr. 2011, 141, 1464–1468. [Google Scholar]
  23. Hu, Y.; McIntosh, G.H.; Le Leu, R.K.; Young, G.P. Selenium-enriched milk proteins and selenium yeast affect selenoprotein activity and expression differently in mouse colon. Br. J. Nutr. 2010, 104, 17–23. [Google Scholar]
  24. Allan, C.B.; Lacourciere, G.M.; Stadtman, T.C. Responsiveness of selenoproteins to dietary selenium. Annu. Rev. Nutr. 1999, 19, 1–16. [Google Scholar]
  25. Sun, Y.; Ha, P.C.; Butler, J.A.; Ou, B.R.; Yeh, J.Y.; Whanger, P. Effect of dietary selenium on selenoprotein W and glutathione peroxidase in 28 tissues of the rat. J. Nutr. Biochem. 1998, 9, 23–27. [Google Scholar]
  26. Gallou-Kabani, C.; Vige, A.; Gross, M.; Junien, C. Nutri-epigenomics: Lifelong remodelling of our epigenomes by nutritional and metabolic factors and beyond. Clin. Chem. Lab. Med. 2007, 45, 321–327. [Google Scholar]
  27. Gluckman, P.D.; Lillycrop, K.A.; Vickers, M.H.; Pleasants, A.B.; Phillips, E.S.; Beedle, A.S.; Burdge, G.C.; Hanson, M.A. Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proc. Natl. Acad. Sci. USA 2007, 104, 12796–12800. [Google Scholar]
  28. Cooney, C.A.; Dave, A.A.; Wolff, G.L. Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J. Nutr. 2002, 132, 2393S–2400S. [Google Scholar]
  29. Wolff, G.L.; Kodell, R.L.; Moore, S.R.; Cooney, C.A. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J. 1998, 12, 949–957. [Google Scholar]
  30. Ho, E.; Beaver, L.M.; Williams, D.E.; Dashwood, R.H. Dietary factors and epigenetic regulation for prostate cancer prevention. Adv. Nutr. 2011, 2, 497–510. [Google Scholar]
  31. Joseph, J.; Loscalzo, J. Selenistasis: epistatic effects of selenium on cardiovascular phenotype. Nutrients 2013, 5, 340–358. [Google Scholar]
  32. Waterland, R.A. Epigenetic mechanisms affecting regulation of energy balance: Many questions, few answers. Annu. Rev. Nutr. 2014, 34, 337–355. [Google Scholar]
  33. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009, 6, e1000097. [Google Scholar]
  34. Liberati, A.; Altman, D.G.; Tetzlaff, J.; Mulrow, C.; Gotzsche, P.C.; Ioannidis, J.P.; Clarke, M.; Devereaux, P.J.; Kleijnen, J.; Moher, D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. BMJ 2009, 339, b2700. [Google Scholar]
  35. Toshiro, A.; Moriyuki, S.; Toshinori, S.; Shigekatsu, M.; Takeo, S.; Naoyuki, T.; Tsutomu, K. Glutathione peroxidase activity in tissues of chickens supplemented with dietary selenium. Comp. Biochem. Physiol. 1994, 107, 245–248. [Google Scholar]
  36. Smith, A.M.; Picciano, M.F. Relative bioavailability of seleno-compounds in the lactating rat. J. Nutr. 1987, 117, 725–731. [Google Scholar]
  37. Smith, A.M.; Picciano, M.F. Evidence for increased selenium requirement for the rat during pregnancy and lactation. J. Nutr. 1986, 116, 1068–1079. [Google Scholar]
  38. Juniper, D.T.; Phipps, R.H.; Ramos-Morales, E.; Bertin, G. Effect of dietary supplementation with selenium-enriched yeast or sodium selenite on selenium tissue distribution and meat quality in beef cattle. J. Anim. Sci. 2008, 86, 3100–3109. [Google Scholar]
  39. Tabatabaei, N.; Jamalian, J.; Owji, A.A.; Ramezani, R.; Karbalaie, N.; Rajaeifard, A.R. Effects of dietary selenium supplementation on serum and liver selenium, serum malondialdehyde and liver glutathione peroxidase activity in rats consuming thermally oxidized sunflower oil. Food Chem. Toxicol. 2008, 46, 3501–3505. [Google Scholar]
  40. Upton, J.R.; Edens, F.W.; Ferket, P.R. The effects of dietary oxidized fat and selenium source on performance, glutathione peroxidase, and glutathione reductase activity in broiler chickens. J. Appl. Poult. Res. 2009, 18, 193–202. [Google Scholar]
  41. Zhu, Z.; Kimura, M.; Itokawa, Y. Effect of selenium and protein deficiency on selenium and glutathione peroxidase in rats. Biol. Trace Elem. Res. 1993, 36, 15–23. [Google Scholar]
  42. Mueller, A.S.; Klomann, S.D.; Wolf, N.M.; Schneider, S.; Schmidt, R.; Spielmann, J.; Stangl, G.; Eder, K.; Pallauf, J. Redox regulation of protein tyrosine phosphatase 1B by manipulation of dietary selenium affects the triglyceride concentration in rat liver. J. Nutr. 2008, 138, 2328–2336. [Google Scholar]
  43. Mueller, A.S.; Fischer, J.; Most, E.; Pallauf, J. Investigation into selenium requirement of growing turkeys offered a diet supplemented with two levels of vitamin E. J. Anim. Physiol. Anim. Nutr. 2009, 93, 313–324. [Google Scholar]
  44. Uthus, E.; Ross, S. Dietary selenium affects homoscysteine metabolism differently in Fisher-344 rats and CD-1 mice. J. Nutr. 2007, 137, 1132–1136. [Google Scholar]
  45. Davis, C.; Uthus, E.; Finley, J. Dietary selenium and arsenic affect DNA methylation in vitro in Caco-2 cells and in vitro in rat liver and colon. J. Nutr. 2000, 130, 2903–2909. [Google Scholar]
  46. Mahmoud, K.Z.; Edens, F.W. Influence of selenium sources on age-related and mild heat stress-related changes of blood and liver glutathione redox cycle in broiler chickens (Gallus domesticus). Comp. Biochem. Physiol. 2003, 136, 921–934. [Google Scholar]
  47. Chadio, S.E.; Kotsampasi, B.M.; Menegatos, J.G.; Zervas, G.P.; Kalogiannis, D.G. Effect of selenium supplementation on thyroid hormone levels and selenoenzyme activities in growing lambs. Biol. Trace Elem. Res. 2006, 109, 145–154. [Google Scholar]
  48. Richardson, S.M.; Siciliano, P.D.; Engle, T.E.; Larson, C.K.; Ward, T.L. Effect of selenium supplementation and source on the selenium status of horses. J. Anim. Sci. 2006, 84, 1742–1748. [Google Scholar]
  49. Sun, Y.; Butler, J.A.; Whanger, P.D. Glutathione peroxidase activity and selenoprotein W levels in different brain regions of selenium-depleted rats. J. Nutr. Biochem. 2001, 12, 88–94. [Google Scholar]
  50. Petrovič, V.; Boldižárová, K.; Faix, S.; Mellen, M.; Arpášová, H.; Leng, L. Antioxidant and selenium status of laying hens fed with diets supplemented with selenite or Se-yeast. J. Anim. Feed Sci. 2006, 15, 435–444. [Google Scholar]
  51. Castaño, A.; Ayala, A.; Rodriguez-Gomez, J.A.; de La Cruz, C.P.; Revilla, E.; Machado, J.C.A. Increase in dopamine turnover and tyrosine hydroxylase enzyme in hippocampus of rats fed on low selenium diet. J. Neurosci. Res. 1995, 42, 684–691. [Google Scholar]
  52. Butler, J.A.; Deagen, J.T.; Van Ryssen, J.B.J.; Rowe, K.E.; Whanger, P.D. Bioavailability to rats of selenium in ovine muscle, liver and hemoglobin. Nutr. Res. 1991, 11, 1293–1305. [Google Scholar]
  53. Chung, J.Y.; Kim, J.H.; Ko, Y.H.; Jang, I.S. Effects of dietary supplemented inorganic and organic selenium on antioxidant defense systems in the intestine, serum, liver and muscle of Korean native goats. Asian-Aust. J. Anim. Sci. 2007, 20, 52–59. [Google Scholar]
  54. Debski, B.; Milner, J.A. Influence of dietary selenium and cytochrome P450 modifiers on liver selenium content and cytochrome P450 activity in rats. Trace Elem. Electrolytes 2002, 19, 209–214. [Google Scholar]
  55. Rafferty, T.S.; Norval, M.; El-Ghorr, A.; Beckett, G.J.; Arthur, J.R.; Nicol, F.; Hunter, J.A.A.; McKenzie, R.C. Dietary selenium levels determine epidermal langerhans cell numbers in mice. Biol. Trace Elem. Res. 2003, 92, 161–171. [Google Scholar]
  56. Yeh, J.Y.; Vendeland, S.C.; Gu, Q.; Butler, J.A.; Ou, B.R.; Whanger, P.D.; Yeh, J.Y.; Vendeland, S.C.; Gu, Q.; Butler, J.A.; et al. Dietary selenium increases selenoprotein W levels in rat tissues. J. Nutr. 1997, 127, 2165–2172. [Google Scholar]
  57. Gu, Q.-P.; Xia, Y.-M.; Ha, P.-C.; Butler, J.A.; Whanger, P.D. Distribution of selenium between plasma fractions in guinea pigs and humans with various intakes of dietary selenium. J. Trace Elem. Med. Biol. 1998, 12, 8–15. [Google Scholar]
  58. Chanoine, J.P.; Safran, M.; Farwell, A.P.; Tranter, P.; Ekenbarger, D.M.; Dubord, S.; Alex, S.; Arthur, J.R.; Beckett, G.J.; Braverman, L.E. Selenium deficiency and type II 5′-deiodinase regulation in the euthyroid and hypothyroid rat: Evidence of a direct effect of thyroxine. Endocrinology 1992, 131, 479–484. [Google Scholar]
  59. Bermano, G.; Nicol, F.; Dyer, J.A.; Sunde, R.A.; Beckett, G.J.; Arthur, J.R.; Hesketh, J.E. Tissue-specific regulation of selenoenzyme gene expression during selenium deficiency in rats. Biochem. J. 1995, 311, 425–430. [Google Scholar]
  60. Arthur, J.R.; Morrice, P.C.; Nicol, F.; Beddows, S.E.; Boyd, R.; Hayes, J.D.; Beckett, G.J. The effects of selenium and copper deficiencies on glutathione S-transferase and glutathione peroxidase in rat liver. Biochem. J. 1987, 248, 539–544. [Google Scholar]
  61. Beckett, G.J.; Beddows, S.E.; Morrice, P.C.; Nicol, F.; Arthur, J.R. Inhibition of hepatic deiodination of thyroxine is caused by selenium deficiency in rats. Biochem. J. 1987, 248, 443–447. [Google Scholar]
  62. Beckett, G.J.; Nicol, F.; Proudfoot, D.; Dyson, K.; Loucaides, G.; Arthur, J.R. The changes in hepatic enzyme expression caused by selenium deficiency and hypothyroidism in rats are produced by independent mechanisms. Biochem. J. 1990, 266, 743–747. [Google Scholar]
  63. Beckett, G.J.; Russell, A.; Nicol, F.; Sahu, P.; Wolf, C.R.; Arthur, J.R. Effect of selenium deficiency on hepatic type I 5-iodothyronine deiodinase activity and hepatic thyroid hormone levels in the rat. Biochem. J. 1992, 282, 483–486. [Google Scholar]
  64. Chittum, H.S.; Hill, K.E.; Carlson, B.A.; Lee, B.J.; Burk, R.F.; Hatfield, D.L. Replenishment of selenium deficient rats with selenium results in redistribution of the selenocysteine tRNA population in a tissue specific manner. Biochim. Biophys. Acta 1997, 1359, 25–34. [Google Scholar]
  65. Nakane, T.; Asayama, K.; Kodera, K.; Hayashibe, H.; Uchida, N.; Nakazawa, S. Effect of selenium deficiency on cellular and extracellular glutathione peroxidases: Immunochemical detection and mRNA analysis in rat kidney and serum. Free Radic. Biol. Med. 1998, 25, 504–511. [Google Scholar]
  66. Hill, K.E.; McCollum, G.W.; Boeglin, M.E.; Burk, R.F. Thioredoxin reductase activity is decreased by selenium deficiency. Biochem. Biophys. Res. Commun. 1997, 234, 293–295. [Google Scholar]
  67. Mitchell, J.H.; Nicol, F.; Beckett, G.J.; Arthur, J.R.; Mitchell, J.H.; Nicol, F.; Beckett, G.J.; Arthur, J.R. Selenoprotein expression and brain development in preweanling selenium- and iodine-deficient rats. J. Mol. Endocrinol. 1998, 20, 203–210. [Google Scholar]
  68. Reddy, K.; Tappel, A.L. Effect of dietary selenium and autoxidized lipids on the glutathione peroxidase system of gastrointestinal tract and other tissues in the rat. J. Nutr. 1974, 104, 1069–1078. [Google Scholar]
  69. Moskovitz, J. Prolonged selenium-deficient diet in MsrA knockout mice causes enhanced oxidative modification to proteins and affects the levels of antioxidant enzymes in a tissue-specific manner. Free Radic. Res. 2007, 41, 162–171. [Google Scholar]
  70. Berggren, M.M.; Mangin, J.F.; Gasdaska, J.R.; Powis, G. Effect of selenium on rat thioredoxin reductase activity: Increase by supranutritional selenium and decrease by selenium deficiency. Biochem. Pharmacol. 1999, 57, 187–193. [Google Scholar]
  71. Masukawa, T.; Nishimura, T.; Iwata, H. Differential changes of glutathione S-transferase activity by dietary selenium. Biochem. Pharmacol. 1984, 33, 2635–2639. [Google Scholar]
  72. Xia, Y.; Hill, K.E.; Burk, R.F. Effect of selenium deficiency on hydroperoxide-induced glutathione release from the isolated perfused rat heart. J. Nutr. 1985, 115, 733–742. [Google Scholar]
  73. Hu, Y.; McIntosh, G.H.; Le Leu, R.K.; Upton, J.M.; Woodman, R.J.; Young, G.P. The influence of selenium-enriched milk proteins and selenium yeast on plasma selenium levels and rectal selenoprotein gene expression in human subjects. Br. J. Nutr. 2011, 106, 572–582. [Google Scholar]
  74. Sunde, R.A.; Paterson, E.; Evenson, J.K.; Barnes, K.M.; Lovegrove, J.A.; Gordon, M.H. Longitudinal selenium status in healthy British adults: Assessment using biochemical and molecular biomarkers. Br. J. Nutr. 2008, 2008, S37–S47. [Google Scholar]
  75. Hurst, R.; Armah, C.N.; Dainty, J.R.; Hart, D.J.; Teucher, B.; Goldson, A.J.; Broadley, M.R.; Motley, A.K.; Fairweather-Tait, S.J. Establishing optimal selenium status: Results of a randomized, double-blind, placebo-controlled trial. Am. J. Clin. Nutr. 2010, 91, 923–931. [Google Scholar]
  76. Karunasinghe, N.; Ferguson, L.R.; Tuckey, J.; Masters, J. Hemolysate thioredoxin reductase and glutathione peroxidase activities correlate with serum selenium in a group of New Zealand men at high prostate cancer risk. J. Nutr. 2006, 136, 2232–2235. [Google Scholar]
  77. Thomson, C.D.; Robinson, M.F.; Butler, J.A.; Whanger, P.D. Long-term supplementation with selenate and selenomethionine: Selenium and glutathione peroxidase (EC 1.11.1.9) in blood components of New Zealand women. Br. J. Nutr. 1993, 69, 577–588. [Google Scholar]
  78. Zhang, W.; Joseph, E.; Hitchcock, C.; DiSilvestro, R.A. Selenium glycinate supplementation increases blood glutathione peroxidase activities and decreases prostate-specific antigen readings in middle-aged US men. Nutr. Res. 2011, 31, 165–168. [Google Scholar]
  79. Åkesson, B.; Huang, W.; Persson-Moschos, M.; Marchaluk, E.; Jacobsson, L.; Lindgärde, F. Glutathione peroxidase, selenoprotein P and selenium in serum of elderly subjects in relation to other biomarkers of nutritional status and food intake. J. Nutr. Biochem. 1997, 8, 508–517. [Google Scholar]
  80. Ravn-Haren, G.; Bugel, S.; Krath, B.N.; Hoac, T.; Stagsted, J.; Jorgensen, K.; Bresson, J.R.; Larsen, E.H.; Dragsted, L.O. A short-term intervention trial with selenate, selenium-enriched yeast and selenium-enriched milk: Effects on oxidative defence regulation. Br. J. Nutr. 2008, 99, 883–892. [Google Scholar]
  81. Alfthan, G.; Xu, G.L.; Tan, W.H.; Aro, A.; Wu, J.; Yang, Y.X.; Liang, W.S.; Xue, W.L.; Kong, L.H. Selenium supplementation of children in a selenium-deficient area in China: Blood selenium levels and glutathione peroxidase activities. Biol. Trace Elem. Res. 2000, 73, 113–125. [Google Scholar]
  82. Bellisola, G.; Perona, G.; Galassini, S.; Moschini, G.; Guidi, G.C. Plasma selenium and glutathione peroxidase activities in individuals living in the Veneto region of Italy. J. Trace Elem. Electrolytes Health Dis. 1993, 7, 242–244. [Google Scholar]
  83. Ravn-Haren, G.; Krath, B.N.; Overvad, K.; Cold, S.; Moesgaard, S.; Larsen, E.H.; Dragsted, L.O. Effect of long-term selenium yeast intervention on activity and gene expression of antioxidant and xenobiotic metabolising enzymes in healthy elderly volunteers from the Danish Prevention of Cancer by Intervention by Selenium (PRECISE) pilot study. Br. J. Nutr. 2008, 99, 1190–1198. [Google Scholar]
  84. Combs, G.F.; Jackson, M.I.; Watts, J.C.; Johnson, L.K.; Zeng, H.; Idso, J.; Schomburg, L.; Hoeg, A.; Hoefig, C.S.; Chiang, E.C.; et al. Differential responses to selenomethionine supplementation by sex and genotype in healthy adults. Br. J. Nutr. 2012, 107, 1514–1525. [Google Scholar]
  85. Combs, G.F., Jr.; Watts, J.C.; Jackson, M.I.; Johnson, L.K.; Zeng, H.; Scheett, A.J.; Uthus, E.O.; Schomburg, L.; Hoeg, A.; Hoefig, C.S.; et al. Determinants of selenium status in healthy adults. Nutr. J. 2011, 10, 75. [Google Scholar]
  86. Xia, Y.; Hill, K.E.; Byrne, D.W.; Xu, J.; Burk, R.F. Effectiveness of selenium supplements in a low-selenium area of China. Am. J. Clin. Nutr. 2005, 81, 829–834. [Google Scholar]
  87. Burk, R.F.; Norsworthy, B.K.; Hill, K.E.; Motley, A.K.; Byrne, D.W. Effects of chemical form of selenium on plasma biomarkers in a high-dose human supplementation trial. Cancer Epidemiol. Biomark. Prev. 2006, 15, 804–810. [Google Scholar]
  88. Alfthan, G.; Aro, A.; Arvilommi, H.; Huttunen, J.K. Selenium metabolism and platelet glutathione peroxidase activity in healthy Finnish men: Effects of selenium yeast, selenite, and selenate. Am. J. Clin. Nutr. 1991, 53, 120–125. [Google Scholar]
  89. Metes-Kosik, N.; Luptak, I.; Dibello, P.M.; Handy, D.E.; Tang, S.S.; Zhi, H.; Qin, F.; Jacobsen, D.W.; Loscalzo, J.; Joseph, J. Both selenium deficiency and modest selenium supplementation lead to myocardial fibrosis in mice via effects on redox-methylation balance. Mol. Nutr. Food Res. 2012, 56, 1812–1824. [Google Scholar]
  90. Mahan, D.C.; Cline, T.R.; Richert, B. Effects of dietary levels of selenium-enriched yeast and sodium selenite as selenium sources fed to growing-finishing pigs on performance, tissue selenium, serum glutathione peroxidase activity, carcass characteristics, and loin quality. J. Anim. Sci. 1999, 77, 2172–2179. [Google Scholar]
  91. Mahan, D.C.; Parrett, N.A. Evaluating the efficacy of selenium-enriched yeast and sodium selenite on tissue selenium retention and serum glutathione peroxidase activity in grower and finisher swine. J. Anim. Sci. 1996, 74, 2967–2974. [Google Scholar]
  92. Cases, J.; Vacchina, V.; Napolitano, A.; Caporiccio, B.; Besancon, P.; Lobinski, R.; Rouanet, J.-M. Selenium from selenium-rich spirulina is less bioavailable than selenium from sodium selenite and selenomethionine in selenium-deficient rats. J. Nutr. 2001, 131, 2343–2350. [Google Scholar]
  93. Guyot, H.; Spring, P.; Andrieu, S.; Rollin, F. Comparative responses to sodium selenite and organic selenium supplements in Belgian Blue cows and calves. Livest. Sci. 2007, 111, 259–263. [Google Scholar]
  94. Nève, J. Human selenium supplementation as assessed by changes in blood selenium concentration and gluthathione peroxidase activity. J. Trace Elem. Med. Biol. 1995, 9, 65–73. [Google Scholar]
  95. Zeng, H.; Jackson, M.I.; Cheng, W.H.; Combs, G.F., Jr. Chemical form of selenium affects its uptake, transport, and glutathione peroxidase activity in the human intestinal Caco-2 cell model. Biological Trace Elem. Res. 2011, 143, 1209–1218. [Google Scholar]
  96. Giacosa, A.; Faliva, M.A.; Perna, S.; Minoia, C.; Ronchi, A.; Rondanelli, M. Selenium fortification of an Italian rice cultivar via foliar fertilization with sodium selenate and its effects on human serum selenium levels and on erythrocyte glutathione peroxidase activity. Nutrients 2014, 6, 1251–1261. [Google Scholar]
  97. Pan, C.; Zhao, Y.; Liao, S.F.; Chen, F.; Qin, S.; Wu, X.; Zhou, H.; Huang, K. Effect of selenium-enriched probiotics on laying performance, egg quality, egg selenium content, and egg glutathione peroxidase activity. J. Agric. Food Chem. 2011, 59, 11424–11431. [Google Scholar]
  98. Gan, F.; Chen, X.; Liao, S.F.; Lv, C.; Ren, F.; Ye, G.; Pan, C.; Huang, D.; Shi, J.; Shi, X.; et al. Selenium-Enriched probiotics improve antioxidant status, immune function, and selenoprotein gene expression of piglets raised under high ambient temperature. J. Agric. Food Chem. 2014, 62, 4502–4508. [Google Scholar]
  99. Gan, F.; Ren, F.; Chen, X.; Lv, C.; Pan, C.; Ye, G.; Shi, J.; Shi, X.; Zhou, H.; Shituleni, S.A.; et al. Effects of selenium-enriched probiotics on heat shock protein mRNA levels in piglet under heat stress conditions. J. Agric. Food Chem. 2013, 61, 2385–2391. [Google Scholar]
  100. Hu, Y.; McIntosh, G.H.; Le Leu, R.K.; Woodman, R.; Young, G.P. Suppression of colorectal oncogenesis by selenium-enriched milk proteins: Apoptosis and K-ras mutations. Cancer Res. 2008, 68, 4936–4944. [Google Scholar]
  101. Barger, J.L.; Kayo, T.; Pugh, T.D.; Vann, J.A.; Power, R.; Dawson, K.; Weindruch, R.; Prolla, T.A. Gene expression profiling reveals differential effects of sodium selenite, selenomethionine, and yeast-derived selenium in the mouse. Genes Nutr. 2012, 7, 155–165. [Google Scholar]
  102. Barroso, M.; Florindo, C.; Kalwa, H.; Silva, Z.; Turanov, A.A.; Carlson, B.A.; de Almeida, I.T.; Blom, H.J.; Gladyshev, V.N.; Hatfield, D.L.; et al. Inhibition of cellular methyltransferases promotes endothelial cell activation by suppressing glutathione peroxidase 1 protein expression. J. Biol. Chem. 2014, 289, 15350–15362. [Google Scholar]
  103. Kulak, M.V.; Cyr, A.R.; Woodfield, G.W.; Bogachek, M.; Spanheimer, P.M.; Li, T.; Price, D.H.; Domann, F.E.; Weigel, R.J. Transcriptional regulation of the GPX1 gene by TFAP2C and aberrant CpG methylation in human breast cancer. Oncogene 2013, 32, 4043–4051. [Google Scholar]
  104. Yu, Y.P.; Yu, G.; Tseng, G.; Cieply, K.; Nelson, J.; Defrances, M.; Zarnegar, R.; Michalopoulos, G.; Luo, J.H. Glutathione peroxidase 3, deleted or methylated in prostate cancer, suppresses prostate cancer growth and metastasis. Cancer Res. 2007, 67, 8043–8050. [Google Scholar]
  105. Xiang, N.; Zhao, R.; Song, G.; Zhong, W. Selenite reactivates silenced genes by modifying DNA methylation and histones in prostate cancer cells. Carcinogenesis 2008, 29, 2175–2181. [Google Scholar]
  106. Uthus, E.; Begaye, A.; Ross, S.; Zeng, H. The von Hippel-Lindau (VHL) tumor-suppressor gene is down-regulated by selenium deficiency in Caco-2 cells and rat colon mucosa. Biol. Trace Elem. Res. 2011, 142, 223–231. [Google Scholar]
  107. Barrera, L.N.; Johnson, I.T.; Bao, Y.; Cassidy, A.; Belshaw, N.J. Colorectal cancer cells Caco-2 and HCT116 resist epigenetic effects of isothiocyanates and selenium in vitro. Eur. J. Nutr. 2013, 52, 1327–1341. [Google Scholar]
  108. Ramachandran, K.; Navarro, L.; Gordian, E.; Das, P.M.; Singal, R. Methylation-mediated silencing of genes is not altered by selenium treatment of prostate cancer cells. Anticancer Res. 2007, 27, 921–925. [Google Scholar]
  109. Yang, G.; Zhu, Y.; Dong, X.; Duan, Z.; Niu, X.; Wei, J. TLR2-ICAM1-Gadd45alpha axis mediates the epigenetic effect of selenium on DNA methylation and gene expression in keshan disease. Biol. Trace Elem. Res. 2014, 159, 69–80. [Google Scholar]
  110. Nian, H.; Bisson, W.H.; Dashwood, W.M.; Pinto, J.T.; Dashwood, R.H. Alpha-keto acid metabolites of organoselenium compounds inhibit histone deacetylase activity in human colon cancer cells. Carcinogenesis 2009, 30, 1416–1423. [Google Scholar]
  111. Kassam, S.; Goenaga-Infante, H.; Maharaj, L.; Hiley, C.T.; Juliger, S.; Joel, S.P. Methylseleninic acid inhibits HDAC activity in diffuse large B-cell lymphoma cell lines. Cancer Chemother. Pharmacol. 2011, 68, 815–821. [Google Scholar]
  112. Hu, C.; Liu, M.; Zhang, W.; Xu, Q.; Ma, K.; Chen, L.; Wang, Z.; He, S.; Zhu, H.; Xu, N. Upregulation of KLF4 by methylseleninic acid in human esophageal squamous cell carcinoma cells: Modification of histone H3 acetylation through HAT/HDAC interplay. Mol. Carcinog. 2014. [Google Scholar] [CrossRef]
  113. Lee, J.I.; Nian, H.; Cooper, A.J.; Sinha, R.; Dai, J.; Bisson, W.H.; Dashwood, R.H.; Pinto, J.T. Alpha-keto acid metabolites of naturally occurring organoselenium compounds as inhibitors of histone deacetylase in human prostate cancer cells. Cancer Prev. Res. Phila 2009, 2, 683–693. [Google Scholar]
  114. Hu, Y.; McIntosh, G.H.; Le Leu, R.K.; Nyskohus, L.S.; Woodman, R.J.; Young, G.P. Combination of selenium and green tea improves the efficacy of chemoprevention in a rat colorectal cancer model by modulating genetic and epigenetic biomarkers. PLoS One 2013, 8, e64362. [Google Scholar]
  115. Ashton, K.; Hooper, L.; Harvey, L.J.; Hurst, R.; Casgrain, A.; Fairweather-Tait, S.J. Methods of assessment of selenium status in humans: A systematic review. Am. J. Clin. Nutr. 2009, 89, 2025S–2039S. [Google Scholar]
  116. Jiang, X.; Dong, J.; Wang, B.; Yin, X.; Qin, L. Effects of organic selenium supplement on glutathione peroxidase activities: A meta-analysis of randomized controlled trials. Wei Sheng Yan Jiu 2012, 41, 120–123. (in Chinese). [Google Scholar]
  117. Méplan, C.; Crosley, L.K.; Nicol, F.; Beckett, G.J.; Howie, A.F.; Hill, K.E.; Horgan, G.; Mathers, J.C.; Arthur, J.R.; Hesketh, J.E. Genetic polymorphisms in the human selenoprotein P gene determine the response of selenoprotein markers to selenium supplementation in a gender-specific manner (the SELGEN study). FASEB J. 2007, 21, 3063–3074. [Google Scholar]
  118. Miller, J.C.; Thomson, C.D.; Williams, S.M.; van Havre, N.; Wilkins, G.T.; Morison, I.M.; Ludgate, J.L.; Skeaff, C.M. Influence of the glutathione peroxidase 1 Pro200Leu polymorphism on the response of glutathione peroxidase activity to selenium supplementation: A randomized controlled trial. Am. J. Clin. Nutr. 2012, 96, 923–931. [Google Scholar]
  119. Takata, Y.; Morris, J.S.; King, I.B.; Kristal, A.R.; Lin, D.W.; Peters, U. Correlation between selenium concentrations and glutathione peroxidase activity in serum and human prostate tissue. Prostate 2009, 69, 1635–1642. [Google Scholar]
  120. Karunasinghe, N.; Han, D.Y.; Zhu, S.; Duan, H.; Ko, Y.J.; Yu, J.F.; Triggs, C.M.; Ferguson, L.R. Effects of supplementation with selenium, as selenized yeast, in a healthy male population from New Zealand. Nutr. Cancer 2013, 65, 355–366. [Google Scholar]
  121. Zhang, L.P.; Maiorino, M.; Roveri, A.; Ursini, F. Phospholipid hydroperoxide glutathione peroxidase: Specific activity in tissues of rats of different age and comparison with other glutathione peroxidases. Biochim. Biophys. Acta 1989, 1006, 140–143. [Google Scholar]
  122. Lei, X.G.; Ross, D.A.; Roneker, K.R. Comparison of age-related differences in expression of phospholipid hydroperoxide glutathione peroxidase mRNA and activity in various tissues of pigs. Comp. Biochem. Physiol. Biochem. Mol. Biol. 1997, 117, 109–114. [Google Scholar]
  123. Kuhbacher, M.; Bartel, J.; Hoppe, B.; Alber, D.; Bukalis, G.; Brauer, A.U.; Behne, D.; Kyriakopoulos, A. The brain selenoproteome: Priorities in the hierarchy and different levels of selenium homeostasis in the brain of selenium-deficient rats. J. Neurochem. 2009, 110, 133–142. [Google Scholar]
  124. Xia, Y.; Hill, K.E.; Li, P.; Xu, J.; Zhou, D.; Motley, A.K.; Wang, L.; Byrne, D.W.; Burk, R.F. Optimization of selenoprotein P and other plasma selenium biomarkers for the assessment of the selenium nutritional requirement: A placebo-controlled, double-blind study of selenomethionine supplementation in selenium-deficient Chinese subjects. Am. J. Clin. Nutr. 2010, 92, 525–531. [Google Scholar]
  125. Reilly, C. Selenium in Food and Health, 1st ed.; Blackie Academic & Professional: London, UK, 1996; p. 338. [Google Scholar]

Share and Cite

MDPI and ACS Style

Bermingham, E.N.; Hesketh, J.E.; Sinclair, B.R.; Koolaard, J.P.; Roy, N.C. Selenium-Enriched Foods Are More Effective at Increasing Glutathione Peroxidase (GPx) Activity Compared with Selenomethionine: A Meta-Analysis. Nutrients 2014, 6, 4002-4031. https://doi.org/10.3390/nu6104002

AMA Style

Bermingham EN, Hesketh JE, Sinclair BR, Koolaard JP, Roy NC. Selenium-Enriched Foods Are More Effective at Increasing Glutathione Peroxidase (GPx) Activity Compared with Selenomethionine: A Meta-Analysis. Nutrients. 2014; 6(10):4002-4031. https://doi.org/10.3390/nu6104002

Chicago/Turabian Style

Bermingham, Emma N., John E. Hesketh, Bruce R. Sinclair, John P. Koolaard, and Nicole C. Roy. 2014. "Selenium-Enriched Foods Are More Effective at Increasing Glutathione Peroxidase (GPx) Activity Compared with Selenomethionine: A Meta-Analysis" Nutrients 6, no. 10: 4002-4031. https://doi.org/10.3390/nu6104002

Article Metrics

Back to TopTop