Emerging evidence on selenoneine and its public health relevance in coastal populations: a review and case study of dietary Se among Inuit populations in the Canadian Arctic.

Selenium is an essential mineral yet both deficiency and excess are associated with adverse health effects. Dietary intake of Se in humans varies greatly between populations due to food availability, dietary preferences, and local geological and ecosystem processes impacting Se accumulation into agricultural products and animal populations. We argue there is a need to evaluate and reconsider the relevance of public health recommendations on Se given recent evidence, including the metabolic pathways and health implications of Se. This argument is particularly pertinent for Inuit populations in Northern Canada, who often exceed dietary tolerable upper intake levels and exhibit very high whole blood Se concentrations due to their dependence on local country foods high in the newly discovered Se compound, selenoneine. Since selenoneine appears to have lower toxicity compared to other Se species and does not contribute to the circulating pools of Se for selenoprotein synthesis, we argue that total dietary Se or total Se in plasma or whole blood are poor indicators of Se adequacy for human health in these populations. Overall, this review provides an overview of the current evidence of Se speciation, deficiency, adequacy, and excess and implications for human health and dietary recommendations, with particular reference to Inuit populations in the Canadian Arctic and other coastal populations consuming marine foods.

Simultaneous determination of ergothioneine, selenoneine, and their methylated metabolites in human blood using ID-LC-MS/MS.

Ergothioneine and selenoneine are structurally related dietary antioxidants and cytoprotectants that may help prevent several chronic diseases associated with inflammation and aging. Both compounds share pharmacokinetic characteristics such as cellular uptake through the ergothioneine transporter, accumulation in red blood cells, and biotransformation to methylated metabolites. A rapid, sensitive, specific, precise, and cost-effective analytical method is required to further investigate the potential health benefits of these compounds, individually or combined, in large epidemiological studies. We developed and validated an isotope-dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) method for the simultaneous specific quantification of these analytes in human blood following a simple sample preparation consisting of dilution in aqueous dithiothreitol followed by centrifugal filtration. Chromatographic separation of the analytes is achieved using a reversed-phase chromatography within an 8-min run. Analyte detection is performed using triple quadrupole mass spectrometry in multiple reaction monitoring mode. Each analyte is quantified against its corresponding isotopically labeled internal standard either commercially available or synthesized in-house (77Se-labeled selenoneine compounds). The validated method demonstrates excellent linearity and very good precision (all CV < 10%). Matrix effects are minimal, suggesting that this method could easily be adapted to other matrices. Freeze/thaw cycles have little effect on methylated metabolites but significantly reduced concentrations of the parent compounds. The method was successfully applied to a small set of volunteer blood samples containing low levels of the analytes. The developed ID-LC-MS/MS method opens new avenues for exploring the roles of these bioactive compounds and their metabolites in human health and disease.

Selenoneine is a major selenium species in beluga skin and red blood cells of Inuit from Nunavik.

Nunavimmiut (Inuit of Nunavik, Northern Quebec, Canada) exhibit a high selenium (Se) status because of their frequent consumption of marine mammal foods. Indirect evidence from our previous studies had suggested that selenoneine - a novel selenocompound - may be accumulating in the blood of Nunavimmiut. We used a liquid-chromatography/inductively coupled tandem mass spectrometry (LC-ICP-MS/MS) method to measure concentrations of selenoneine and its methylated metabolite Se-methylselenoneine in archived red blood cells (RBC) obtained from 210 Nunavimmiut living in communities along the Hudson Strait, where marine mammal hunting and consumption are most frequent in Nunavik. This method was adapted to quantify selenoneine and its methylated metabolite in beluga mattaaq, an Inuit delicacy consisting of the skin with the underlying layer of fat and the major dietary source of Se for Nunavimmiut. Total selenium concentration was also measured in RBC and beluga mattaaq samples by isotope dilution ICP-MS/MS. The median selenoneine concentration in RBC was 413 µg Se/L (range = 3.20-3230 µg Se/L), representing 54% (median) of total Se content (range = 1.6-91%). Quantification of selenoneine in five beluga mattaaq samples (skin layer) from Nunavik revealed a median concentration of 1.8 µg Se/g wet wt (range = 1.2-7.4 µg Se/g), constituting 54% (median) of the total Se content (range = 44-74%). Se-methylselenoneine was also detected in Inuit RBC but not in beluga mattaaq, suggesting that selenoneine undergoes methylation in humans. Selenoneine may protect Nunavimmiut from methylmecury toxicity by increasing its demethylation in RBC and in turn decreasing its distribution to target organs.

Determinants of selenoneine concentration in red blood cells of Inuit from Nunavik (Northern Québec, Canada).

Selenium (Se) is a trace mineral essential to human health, and is especially abundant in marine foods consumed by Inuit populations in Nunavik (northern Quebec, Canada), leading to exceptionally high whole blood Se levels. While most epidemiological studies to date examine plasma or whole blood Se, little is known about the health implications of specific Se biomarkers (e.g. selenoproteins and small Se compounds). Selenoneine, a novel Se compound, is found in high concentrations in marine foods (and particularly beluga mattaaq) and the red blood cells (RBCs) of populations that consume them. We report here RBC selenoneine concentrations in a population of Inuit adults (n = 885) who participated in the Qanuippitaa? 2004 survey. Simple associations between RBC selenoneine and other Se and mercury (Hg) biomarkers were assessed using Spearman correlations and linear regressions. Wilcoxon ranksum tests were used to examine differences in biomarkers and characteristics between tertiles of RBC selenoneine concentration. A multiple linear regression analysis was used to determine factors (sociodemographic, lifestyle, and dietary) associated with RBC selenoneine concentrations. Selenoneine comprised a large proportion of whole blood Se and RBC Se in this population. Age and sex-adjusted geometric mean RBC selenoneine concentration was 118 µg/L (range: 1-3226 µg/L) and was much higher (p = 0.001) among women (150.3 µg/L) than men (87.6 µg/L) across all regions of Nunavik after controlling for age, region, and diet. RBC selenoneine was highly correlated with RBC Se (rs = 0.96, p < 0.001) and whole blood Se (rs = 0.89, p < 0.001), but only weakly correlated with plasma Se (rs = 0.13, p < 0.001). Overall, increasing age (standardized ß = 0.24), higher body-mass index (BMI; ß = 0.08), female sex (ß = 0.10), living in a Hudson Strait community (compared to Hudson Bay and Ungava Bay; ß = 0.38), and consuming beluga mattaaq (g/day; ß = 0.19) were positively associated with RBC selenoneine. Meanwhile, consumption of market meats (g/day; ß = -0.07) was negatively associated with RBC selenoneine. RBC selenoneine is an important biomarker of Se dietary intake from local marine foods in Inuit populations. Further studies are needed to examine the health effects of selenoneine intake and the underlying mechanisms for sex differences among Inuit populations.

Plasma levels of selenium-containing proteins in Inuit adults from Nunavik.

Selenium (Se) is highly abundant in marine foods traditionally consumed by Inuit of Nunavik (Northern Quebec, Canada) and accordingly, their Se intake is among the highest in the world. However, little is known regarding the biological implications of this high Se status in this Arctic indigenous population. We used a method combining affinity chromatography and inductively coupled plasma-mass spectrometry with quantification by post-column isotope dilution to determine total Se levels and concentrations of Se-containing proteins in archived plasma samples of Inuit adults who participated to the 2004 Nunavik Inuit Health Survey (N = 852). Amounts of mercury (Hg) associated with Se-containing proteins were also quantified. Results show that glutathione peroxidase 3 (GPx3), selenoprotein P (SelP) and selenoalbumin (SeAlb) represented respectively 25%, 52% and 23% of total plasma Se concentrations. In addition, small amounts of Hg co-eluted with each Se-containing protein and up to 50% of plasma Hg was associated to SelP. Total plasma Se concentrations (median = 139 µg L− 1; interquartile range (IQR) = 22.7 µg L− 1) were markedly lower and less variable than whole blood Se concentration (median = 261 µg L− 1, IQR = 166 µg L− 1). A non linear relation was observed between whole blood Se and plasma Se levels, with plasma Se concentrations leveling off at approximately 200 µg L− 1, whereas 16% and 3% of individuals exhibited whole blood concentrations higher than 500 µg L− 1 and 1000 µg L− 1, respectively. In contrast, a linear relationship was previously reported in communities consuming Brazil nuts which are rich Se, mainly present as selenomethionine. This suggests that a different selenocompound, possibly selenoneine, is present in the Arctic marine food chain and accumulates in the blood cellular fraction of Inuit.

Rosiglitazone-induced heart remodelling is associated with enhanced turnover of myofibrillar protein and mTOR activation.

We investigated cardiac hypertrophy elicited by rosiglitazone treatment at the level of protein synthesis/degradation, mTOR, MAPK and AMPK signalling pathways, cardiac function and aspects of carbohydrate/lipid metabolism. Hearts of rats treated or not with rosiglitazone (15 mg/kg day) for 21 days were evaluated for gene expression, protein synthesis, proteasome and calpain activities, signalling pathways, and function by echocardiography. Rosiglitazone induced eccentric heart hypertrophy associated with increased expression of ANP, BNP, collagen I and III and fibronectin, reduced heart rate and increased stroke volume. Rosiglitazone robustly increased heart glycogen content ( approximately 400%), an effect associated with increases in glycogenin and UDPG-PPL mRNA levels and glucose uptake, and a reduction in glycogen phosphorylase expression and activity. Cardiac triglyceride content, lipoprotein lipase activity and mRNA levels of enzymes involved in fatty acid oxidation were also reduced by the agonist. Rosiglitazone-induced cardiac hypertrophy was associated with an increase in myofibrillar protein content and turnover (increased synthesis and an enhancement of calpain-mediated myofibrillar degradation). In contrast, 26S beta5 chymotryptic proteasome activity and mRNA levels of 20S beta2 and beta5 and 19S RPN 2 proteasome subunits along with the ubiquitin ligases atrogin and CHIP were all reduced by rosiglitazone. These morphological and biochemical changes were associated with marked activation of the key growth-promoting mTOR signalling pathway, whose pharmacological inhibition with rapamycin completely blocked cardiac hypertrophy induced by rosiglitazone. The study demonstrates that both arms of protein balance are involved in rosiglitazone-induced cardiac hypertrophy, and establishes the mTOR pathway as a novel important mediator therein.