Selenoprotein P (SELENOP) is a liver-derived transporter of selenium (Se) in blood, and a meaningful biomarker of Se status. Se is an essential trace element for the biosynthesis of ...enzymatically-active selenoproteins, protecting the organism from oxidative damage. The usage of uncalibrated assays hinders the comparability of SELENOP concentrations and their pathophysiological interpretation across different clinical studies. On this account, we established a new sandwich SELENOP-ELISA and calibrated against a standard reference material (SRM1950). The ELISA displays a wide working range (11.6–538.4µg/L), high accuracy (2.9%) and good precision (9.3%). To verify whether SELENOP correlates to total Se and to SELENOP-bound Se, serum samples from healthy subjects and age-selected participants from the Berlin Aging Study II were analyzed by SELENOP-ELISA and Se quantification. SELENOP was affinity-purified and its Se content was determined from a subset of samples. There was a high correlation of total Se and SELENOP concentrations in young and elderly men, and in elderly women, but not in young women, indicating a specific sexual dimorphism in these biomarkers of Se status in young subjects. The Se content of isolated SELENOP was independent of sex and age (mean±SD: 5.4±0.5). By using this calibrated SELENOP-ELISA, prior reports on pathological SELENOP concentrations in diabetes and obesity are challenged as the reported values are outside reasonable limits. Biomarkers of Se status in clinical research need to be measured by validated assays in order to avoid erroneous data and incorrect interpretations, especially when analyzing young women. The Se content of circulating SELENOP differs between individuals and may provide some important diagnostic information on Se metabolism and status.
•A calibrated SELENOP-ELISA identifies sex-specific differences in Se status.•The calibration challenges reported pathological status in diabetes or obesity.•Among healthy adults, young females show a particular high Se to SELENOP ratio.•Number of Se atoms per SELENOP molecule are 5.4 instead of the predicted 10.
Selenium is essential for expression and proper function of a set of redox active selenoproteins implicated in aging-relevant diseases, e.g. type 2 diabetes mellitus (T2D) and hypertension. However, ...data in cohorts of older adults, particularly with respect to different Se biomarkers and sex-specific analyses are sparse.
To assess associations of serum Se and selenoprotein P (SELENOP) concentrations with T2D and hypertension in a cohort of older females and males.
This study included 1500 participants from the Berlin Aging Study II. Diagnosis of T2D was made in case of antidiabetic medication, self-reported T2D, or laboratory parameters. Diagnosis of hypertension was based on self-report, blood pressure measurement, or anti-hypertensive medication. Se was measured by spectroscopy, and SELENOP by ELISA. Multiple adjusted regression models quantified dose-dependent associations.
Participants had a median(IQR) age of 68 (65,71) years, and 767 (51%) were women. 191 (13%) participants had T2D and 1126 (75%) had hypertension. Se and SELENOP correlated significantly (r = 0.59, p < 0.001), and were elevated in those with self-reported Se supplementation. Serum Se and SELENOP were not associated with T2D in the whole cohort. In men, SELENOP was positively associated with T2D, OR (95%CI) for one mg/L increase in SELENOP was 1.22 (1.00,1.48). Se was non-linearly associated with hypertension, comparing to the lowest quartile (Q1), and participants with higher Se levels (Q3) had a lower OR (95%CI) of 0.66 (0.45,0.96), which was specific for men. SELENOP positively associated with hypertension, and OR (95%CI) per one mg/L increase was 1.15 (1.01,1.32).
The data suggest a sex-specific interrelationship of Se status with T2D and hypertension, with apparent biomarker-specific associations.
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•This study included 1500 senior subjects from the Berlin Aging Study II.•Selenium displayed a U-shaped association with hypertension in men.•SELENOP dose-dependently associated with hypertension in women.•SELENOP dose-dependently associated with T2D in men.
Selenoproteins are a unique group of proteins that contain selenium in the form of selenocysteine (Sec) co-translationally inserted in response to a UGA codon with the help of cis- and trans-acting ...factors. Mammalian selenoproteins contain single Sec residues, with the exception of selenoprotein P (SelP) that has 7-15 Sec residues depending on species. Assessing an individual's selenium status is important under various pathological conditions, which requires a reliable selenium biomarker. Due to a key role in organismal selenium homeostasis, high Sec content, regulation by dietary selenium, and availability of robust assays in human plasma, SelP has emerged as a major biomarker of selenium status. Here, we found that Cys is present in various Sec positions in human SelP. Treatment of cells expressing SelP with thiophosphate, an analog of the selenium donor for Sec synthesis, led to a nearly complete replacement of Sec with Cys, whereas supplementation of cells with selenium supported Sec insertion. SelP isolated directly from human plasma had up to 8% Cys inserted in place of Sec, depending on the Sec position. These findings suggest that a change in selenium status may be reflected in both SelP concentration and its Sec content, and that availability of the SelP-derived selenium for selenoprotein synthesis may be overestimated under conditions of low selenium status due to replacement of Sec with Cys.
Selenium deficiency constitutes a risk factor for the incidence and negative course of severe diseases including sepsis, stroke, autoimmune diseases or cancer. In this study, hypoxia is identified as ...a powerful stimulus to redirect selenoprotein biosynthesis causing reduced selenoprotein P expression and diminished selenium export from hepatocytes in favour of increased biosynthesis of the essential protective intracellular phospholipid hydroperoxide glutathione peroxidase GPX4. Specifically, hypoxia decreases transcript concentrations of central factors controlling selenium and selenocysteine metabolism including selenophosphate synthetase-2, phosphoseryl-tRNA(SerSec) kinase and selenocysteine lyase, which are all proven to be rate-limiting enzymes in selenoprotein biosynthesis. These effects are paralleled by a general decline of selenoprotein expression; however, not all selenoproteins are affected to the same extent by hypoxia, and GPX4 constitutes an exception as its expression becomes slightly increased. Supplemental selenium is able to overcome the hypoxia-dependent down regulation of selenoprotein expression in our cell culture model system, supporting the concept of using selenium as an adjuvant treatment option in severe diseases. Although it remains to be tested whether these effects constitute a hepatocyte-specific response, the selenium-dependent decline of selenoprotein P biosynthesis under hypoxic conditions may explain the progressive selenium deficit developing in severe diseases.
Selenoprotein biosynthesis relies on the co-translational insertion of selenocysteine in response to UGA codons. Aminoglycoside antibiotics interfere with ribosomal function and may cause codon ...misreading. We hypothesized that biosynthesis of the selenium (Se) transporter selenoprotein P (SELENOP) is particularly sensitive to antibiotics due to its ten in frame UGA codons. As liver regulates Se metabolism, we tested the aminoglycosides G418 and gentamicin in hepatoma cell lines (HepG2, Hep3B and Hepa1-6) and in experimental mice. In vitro, SELENOP levels increased strongly in response to G418, whereas expression of the glutathione peroxidases GPX1 and GPX2 was marginally affected. Se content of G418-induced SELENOP was dependent on Se availability, and was completely suppressed by G418 under Se-poor conditions. Selenocysteine residues were replaced mainly by cysteine, tryptophan and arginine in a codon-specific manner. Interestingly, in young healthy mice, antibiotic treatment failed to affect Selenop biosynthesis to a detectable degree. These findings suggest that the interfering activity of aminoglycosides on selenoprotein biosynthesis can be severe, but depend on the Se status, and other parameters likely including age and general health. Focused analyses with aminoglycoside-treated patients are needed next to evaluate a possible interference of selenoprotein biosynthesis by the antibiotics and elucidate potential side effects.
Background
Selenium is an essential trace mineral. The main function of selenoprotein P (SELENOP) is to transport selenium but it has also been ascribed anti-oxidative effects.
Methods
To assess the ...association of repeated measurements of serum SELENOP concentration with all-cause and cause-specific mortality serum SELENOP was measured at baseline and 5-year follow-up in 7,186 and 4,164 participants of the ESTHER study, a German population-based cohort aged 50–74 years at baseline.
Results
During 17.3 years of follow-up, 2,126 study participants (30%) died. The relationship of serum SELENOP concentration with all-cause mortality was L-shaped, with mortality being significantly higher at SELENOP concentrations < 4.1 mg/L, which is near the bottom tertile’s cut-off (4.2 mg/L). All-cause mortality of participants in the bottom SELENOP tertile was significantly increased compared to subjects in the top tertile (hazard ratio 95% confidence interval: 1.35 1.21–1.50). SELENOP in the bottom tertile was further associated with increased cardiovascular mortality (1.24 1.04–1.49), cancer mortality (1.31 1.09–1.58), respiratory disease mortality (2.06 1.28–3.32) and gastrointestinal disease mortality (2.04 1.25–3.32). The excess risk of all-cause mortality for those in the bottom SELENOP tertile was more than twice as strong in men as in women (interaction of SELENOP and sex;
p
= 0.008).
Conclusions
In this large cohort study, serum SELENOP concentration was inversely associated with all-cause and cause-specific mortality. Consistent inverse associations with multiple mortality outcomes might be explained by an impaired selenium transport and selenium deficiency in multiple organs. Trials testing the efficacy of selenium supplements in subjects with low baseline SELENOP concentration are needed.
Trial registration
Retrospectively registered in the German Clinical Trials Register on Feb 14, 2018 (ID: DRKS00014028).
•Polish pregnant women presented with low selenium status.•Selenium concentration declined throughout pregnancy.•TPO-aAb and TG-aAb declined throughout pregnancy.•Both observations were unrelated.
...Selenium (Se) deficiency is related to an increased risk of preterm labor, miscarriage, preeclampsia, gestational diabetes, and other obstetric complications. As the Se status declines during pregnancy, we hypothesized that the decline may be exacerbated in women with autoimmune thyroid disease (AITD).
Pregnant women (n=74; 30 23–38 years) were consecutively recruited from the district of Warsaw, Poland, and divided into healthy subjects (HS, n=45), and women with a diagnosis of AITD (AITD, n=29). Thyroglobulin antibodies (TG-aAb), thyroid peroxidase antibodies (TPO-aAb), TSH, free T3, free T4, total T3, and total T4, as well as urine iodine excretion were determined. Se status was assessed by serum Se and selenoprotein P (SELENOP) concentrations. Thyroid volume was evaluated by ultrasonography.
Serum Se and SELENOP concentrations were relatively low in both control and AITD women. A Se deficit according to WHO definition (<45μg/l) was observed in 0%, 3.4%, 28.6% and 4.5%, 18.2%, 35.5% of women in the AITD and HS group, respectively, during the 1st, 2nd, and 3rd trimester. From first to third trimester, TPO-aAb and TG-aAb declined in AITD by 71% and 60%, respectively. The decline in TPO- and TG-aAb was unrelated to the Se status.
In this area of habitual low Se intake, a high proportion of women developed a severe Se deficit during pregnancy, irrespective of AITD status. This decline must be considered as a preventable risk factor for pregnancy complications of relevance to both the unborn child and the pregnant mother.
Infectious diseases impair Se metabolism, and low Se status is associated with mortality risk in adults with critical disease. The Se status of neonates is poorly characterised, and a potential ...impact of connatal infection is unknown. We hypothesised that an infection negatively affects the Se status of neonates. We conducted an observational case-control study at three intensive care units at the Charité-Universitätsmedizin Berlin, Germany. Plasma samples were collected from forty-four neonates. On the basis of clinical signs for bacterial infection and concentrations of IL-6 or C-reactive protein, neonates were classified into control (n 23) and infected (n 21) groups. Plasma Se and selenoprotein P (SePP) concentrations were determined by X-ray fluorescence and ELISA, respectively, at day of birth (day 1) and 48 h later (day 3). Se and SePP showed a positive correlation in both groups of neonates. Se concentrations indicative of Se deficit in adults (500 ng/l). During antibiotic therapy, SePP increased significantly from day 1 (1·03 (sd 0·10) mg/l) to day 3 (1·34 (sd 0·10) mg/l), indicative of improved hepatic Se metabolism. We conclude that both Se and SePP are suitable biomarkers for assessing Se status in neonates and for identifying subjects at risk of deficiency.
Background and objectives: Suboptimal intakes of the essential micronutrient selenium (Se) and selenoprotein genetic variation may contribute to colorectal cancer (CRC). Here, we examined the ...associations of single nucleotide polymorphisms (SNPs) in the Se pathway and their Se status interactions with CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Methods: Using an Illumina Goldengate assay, we simultaneously genotyped all SNPs in 164 Se pathway genes (comprising all 25 selenoprotein genes, selenoprotein biosynthesis / transport genes, and metabolic pathway genes) using 1264 candidate functional and common tagging SNPs. From these assays, 1040 variants in 154 genes were successfully assayed in DNA samples from 1478 CRC case-control pairs matched within EPIC. Multivariate logistic regression was used to determine the association of SNPs in the Se pathway with CRC risk. Pathway and gene based analyses were also performed using the PIGE package Adaptive Rank Truncated test. Results: Genotypes for 144 SNPs in 63 genes were associated with an altered CRC risk However, none of the associations in the selenoprotein genes remained significant after Benjamini-Hochberg multiple-testing correction, although the Thioredoxin Reductase 1 (TXNRD1) rs11111979 SNP retained significance with gene-wide PACT (P values adjusted for correlated tests) considerations. SNP genotypes in cell-signaling pathway genes (FRZB, SMAD3, and SMAD7) known to be affected by Se intake were also significantly associated with CRC risk after multiple testing adjustments. Additionally, genetic variations were shown to interact with biomarkers of Se status (as assessed by serum Se and Selenoprotein P concentration) to alter CRC risk. Pathway analyses also suggest that SNP only and SNP X Se interactions in selenoprotein, antioxidant, apoptosis and TGF-beta signaling pathways may alter CRC susceptibility risk. Conclusions: Detailed investigation of Se intake levels and metabolism is needed to further explore relevance for CRC etio-pathogenesis, especially for individuals of particular Se pathway genotypes and/or those with suboptimal Se status.
Background: Selenium status is suboptimal in many Europeans and may be a risk factor for the development of various cancers, including those of the liver and biliary tract.
Objective: We wished to ...examine whether selenium status in advance of cancer onset is associated with hepatobiliary cancers in the EPIC (European Prospective Investigation into Cancer and Nutrition) study.
Design: We assessed prediagnostic selenium status by measuring serum concentrations of selenium and selenoprotein P (SePP; the major circulating selenium transfer protein) and examined the association with hepatocellular carcinoma (HCC; n = 121), gallbladder and biliary tract cancers (GBTCs; n = 100), and intrahepatic bile duct cancer (IHBC; n = 40) risk in a nested case-control design within the EPIC study. Selenium was measured by total reflection X-ray fluorescence, and SePP was determined by a colorimetric sandwich ELISA. Multivariable ORs and 95% CIs were calculated by using conditional logistic regression.
Results: HCC and GBTC cases, but not IHBC cases, showed significantly lower circulating selenium and SePP concentrations than their matched controls. Higher circulating selenium was associated with a significantly lower HCC risk (OR per 20-μg/L increase: 0.41; 95% CI: 0.23, 0.72) but not with the risk of GBTC or IHBC. Similarly, higher SePP concentrations were associated with lowered HCC risk only in both the categorical and continuous analyses (HCC: P-trend ≤ 0.0001; OR per 1.5-mg/L increase: 0.37; 95% CI: 0.21, 0.63).
Conclusion: These findings from a large prospective cohort provide evidence that suboptimal selenium status in Europeans may be associated with an appreciably increased risk of HCC development.
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