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Scope: Selenoneine, a recently discovered selenium (Se) species mainly present in marine fish, is the Se analogue of ergothioneine, a sulfurcontaining purported antioxidant. Although similar properties have been proposed for selenoneine, data on its relevance to human health are yet scarce. Here, the transfer and presystemic metabolism of selenoneine in an in vitro model of the human intestinal barrier are investigated. Methods and results: Selenoneine and the reference species Semethylselenocysteine (MeSeCys) and selenite are applied to the Caco2 intestinal barrier model. Selenoneine is transferred in higher amounts, but with similar kinetics as selenite, while MeSeCys shows the highest permeability. In contrast to the reference species, transfer of selenoneine is directed toward the blood side. Cellular Se contents demonstrate that selenoneine is efficiently taken up by Caco2 cells. Moreover, HPLC/MSbased Se speciation studies reveal a partial metabolism to Semethylselenoneine, a metabolite previously detected in human blood and urine. Conclusions: Selenoneine is likely to pass the intestinal barrier via transcellular, carriermediated transport, is highly bioavailable to Caco2 cells and undergoes metabolic transformations. Therefore, further studies are needed to elucidate its possible health effects and to characterize the metabolism of selenoneine in humans. Accepted version

Scope: Small selenium (Se) species play a key role in Se metabolism and act as dietary sources of the essential trace element. However, they are redoxactive and trigger pro and antioxidant responses. As health outcomes are strongly speciesdependent, speciesspecific characteristics of Se compounds are tested in vivo. Methods and results: In the model organism Caenorhabditis elegans (C. elegans), immediate and sustained effects of selenite, selenomethionine (SeMet), and Semethylselenocysteine (MeSeCys) are studied regarding their bioavailability, incorporation into proteins, as well as modulation of the cellular redox status. While all tested Se compounds are bioavailable, only SeMet persistently accumulates and is nonspecifically incorporated into proteins. However, the protection toward chemicallyinduced formation of reactive species is independent of the applied Se compound. Increased thioredoxin reductase (TXNRD) activity and changes in mRNA expression levels of antioxidant proteins indicate the activation of cellular defense mechanisms. However, in txnrd1 deletion mutants, no protective effects of the Se species are observed anymore, which is also reflected by differential gene expression data. Conclusion: Se species protect against chemicallyinduced reactive species formation. The identified immediate and sustained systemic effects of Se species give rise to speculations on possible benefits facing subsequent periods of inadequate Se intake. Accepted version

The possible relevance to human health of selenoneine and its sulfur-analogue ergothioneine has generated interest in their quantitative determination in biological samples. To gain more insight into the similarities and differences of these two species, a method for their simultaneous quantitative determination in human blood cells using reversed-phase high performance liquid chromatography (RPHPLC) coupled to inductively coupled plasma triple quadrupole mass spectrometry (ICP-QQQ-MS) is presented. Spectral interferences hampering the determination of sulfur and selenium by ICPMS are overcome by introducing oxygen to the reaction cell. To access selenoneine and ergothioneine in the complex blood matrix, lysis of the cells with cold water followed by cut-off filtration (3000 Da) is performed. Recoveries based on blood cells spiked with selenoneine and ergothioneine were between 80% and 85%. The standard deviation of the method was around 0.10 mg S per L for ergothioneine (corresponding to relative standard deviations (RSD) between 101% for ergothioneine concentrations of 110 mg S per L) and 0.25 mg Se per L for selenoneine (RSDs of 252% for concentrations of 110 mg Se per L). The method was applied to blood cell samples from three volunteers which showed selenoneine and ergothioneine concentrations in the range of 3.25 to 7.35 mg Se per L and 0.86 to 6.44 mg S per L, respectively. The method is expected to be of wide use in future studies investigating the dietary uptake of selenoneine and ergothioneine and their relevance in human health. (VLID)5840961 Accepted version

Scope Selenoneine (2-selenyl-N, N, N-trimethyl-L-histidine), the selenium (Se) analogue of the ubiquitous thiol compound and putative antioxidant ergothioneine, is the major organic selenium species in several marine fish species. Although its antioxidant efficacy has been proposed, selenoneine has been poorly characterized, preventing conclusions on its possible beneficial health effects. Methods and results Treatment of Caenorhabditis elegans (C. elegans) with selenoneine for 18h attenuated the induction of reactive oxygen and nitrogen species (RONS). However, the effect was not immediate, occurring 48h post-treatment. Total Se and Se speciation analysis revealed that selenoneine was efficiently taken up and present in its original form directly after treatment, with no metabolic transformations observed. 48h post-treatment, total Se in worms was slightly higher compared to controls and no selenoneine could be detected. Conclusion The protective effect of selenoneine may not be attributed to the presence of the compound itself, but rather to the activation of molecular mechanisms with consequences at more protracted time points. (VLID)5900096 Accepted version

Selenoneine, a naturally occurring form of selenium, is the selenium analogue of ergothioneine, a sulfur species with health relevance not only as a purported antioxidant but likely also beyond. Selenoneine has been speculated to exhibit similar effects. To study selenoneines health properties as well as its metabolic transformation, the pure compound is required. Chemical synthesis of selenoneine, however, is challenging and biosynthetic approaches have been sought. We herein report the biosynthesis and isolation of selenoneine from genetically modified fission yeast Schizosaccharomyces pombe grown in a medium containing sodium selenate. After cell lysis and extraction with methanol, selenoneine was purified by three consecutive preparative reversed-phase HPLC steps. The product obtained at the mg level was characterised by high resolution mass spectrometry, NMR and HPLC/ICPMS. Biosynthesis was found to be a promising alternative to chemical synthesis, and should be suitable for upscaling to produce higher amounts of this important selenium species in the future. (VLID)5840958 Accepted version

The essential micronutrient selenium (Se) is required for various systemic functions, but its beneficial range is narrow and overexposure may result in adverse health effects. Additionally, the chemical form of the ingested selenium contributes crucially to its health effects. While small Se species play a major role in Se metabolism, their toxicological effects, bioavailability and metabolic transformations following elevated uptake are poorly understood. Utilizing the tractable invertebrate Caenorhabditis elegans allowed for an alternative approach to study species-specific characteristics of organic and inorganic Se forms in vivo, revealing remarkable species-dependent differences in the toxicity and bioavailability of selenite, selenomethionine (SeMet) and Se-methylselenocysteine (MeSeCys). An inverse relationship was found between toxicity and bioavailability of the Se species, with the organic species displaying a higher bioavailability than the inorganic form, yet being less toxic. Quantitative Se speciation analysis with HPLC/mass spectrometry revealed a partial metabolism of SeMet and MeSeCys. In SeMet exposed worms, identified metabolites were Se-adenosylselenomethionine (AdoSeMet) and Se-adenosylselenohomocysteine (AdoSeHcy), while worms exposed to MeSeCys produced Se-methylselenoglutathione (MeSeGSH) and -glutamyl-MeSeCys (-Glu-MeSeCys). Moreover, the possible role of the sole selenoprotein in the nematode, thioredoxin reductase-1 (TrxR-1), was studied comparing wildtype and trxr-1 deletion mutants. Although a lower basal Se level was detected in trxr-1 mutants, Se toxicity and bioavailability following acute exposure was indistinguishable from wildtype worms. Altogether, the current study demonstrates the suitability of C. elegans as a model for Se species dependent toxicity and metabolism, while further research is needed to elucidate TrxR-1 function in the nematode. Accepted version

Methyl-2-acetamido-2-deoxy-1-seleno-β -D-galactopyranoside (selenosugar 1) was recently identified as the major urinary selenium metabolite. To obtain information on biological availability and metabolism of selenosugar 1 in relation to biologically available selenite male Wistar strain rats at 8 weeks of age were exposed during 48h to sodium selenite, trimethylselenonium iodide (TMSe), selenosugar 1 or methyl-2-acetamido-2-deoxy-1-seleno-β -D-glucopyranoside (selenosugar 2) in drinking water. Selenium speciation analysis by HPLC/ICPMS was performed on urine samples collected during the exposure. Total selenium in liver, kidney, small intestine and blood was analysed at the end of the experiment by ICPMS following microwave-assisted acid digestion. The major species found in background urine of rats not supplemented with selenium were selenosugar 1 (major metabolite) and TMSe (minor metabolite). The majority of selenium excreted in the urine after ingestion of selenosugars was excreted unchanged, while one part was metabolised, resulting in selenosugar 1 and TMSe as urinary metabolites. As previously reported, ingested TMSe was excreted rapidly and unchanged. Selenium after ingestion of selenite was excreted as selenosugar 1 and TMSe and excretion was slower when compared to selenosugars or TMSe. Ingestion of selenite resulted in increased selenium in the blood and organs, whereas no significant increases in selenium concentration were observed after ingestion of selenosugars or TMSe. The work indicates that selenosugar 1 and selenosugar 2 are at least partly biologically available to rats and undergo metabolism resulting with selenosugar 1 and TMSe as the end products excreted in the urine.