Selenium toxicity but not deficient or super-nutritional selenium status vastly alters the transcriptome in rodents

Abstract

BackgroundProtein and mRNA levels for several selenoproteins, such as glutathione peroxidase-1 (Gpx1), are down-regulated dramatically by selenium (Se) deficiency. These levels in rats increase sigmoidally with increasing dietary Se and reach defined plateaus at the Se requirement, making them sensitive biomarkers for Se deficiency. These levels, however, do not further increase with super-nutritional or toxic Se status, making them ineffective for detection of high Se status. Biomarkers for high Se status are needed as super-nutritional Se intakes are associated with beneficial as well as adverse health outcomes. To characterize Se regulation of the transcriptome, we conducted 3 microarray experiments in weanling mice and rats fed Se-deficient diets supplemented with up to 5 μg Se/g diet.ResultsThere was no effect of Se status on growth of mice fed 0 to 0.2 μg Se/g diet or rats fed 0 to 2 μg Se/g diet, but rats fed 5 μg Se/g diet showed a 23% decrease in growth and elevated plasma alanine aminotransferase activity, indicating Se toxicity. Rats fed 5 μg Se/g diet had significantly altered expression of 1193 liver transcripts, whereas mice or rats fed ≤ 2 μg Se/g diet had < 10 transcripts significantly altered relative to Se-adequate animals within an experiment. Functional analysis of genes altered by Se toxicity showed enrichment in cell movement/morphogenesis, extracellular matrix, and development/angiogenesis processes. Genes up-regulated by Se deficiency were targets of the stress response transcription factor, Nrf2. Multiple regression analysis of transcripts significantly altered by 2 μg Se/g and Se-deficient diets identified an 11-transcript biomarker panel that accounted for 99% of the variation in liver Se concentration over the full range from 0 to 5 μg Se/g diet.ConclusionThis study shows that Se toxicity (5 μg Se/g diet) in rats vastly alters the liver transcriptome whereas Se-deficiency or high but non-toxic Se intake elicits relatively few changes. This is the first evidence that a vastly expanded number of transcriptional changes itself can be a biomarker of Se toxicity, and that identified transcripts can be used to develop molecular biomarker panels that accurately predict super-nutritional and toxic Se status.

Selenoprotein H Suppresses Cellular Senescence through Genome Maintenance and Redox Regulation

“…SelH may confer the interaction between selenium and Nrf2 as this selenoprotein is among the few most sensitive ones to dietary selenium deficiency (19,76). Consistent with this observation, SelH-deficient cells display increased nuclear pNrf2 expression endogenously or dose-dependently after H 2 O 2 treatment.…”

Insights for Setting of Nutrient Requirements, Gleaned by Comparison of Selenium Status Biomarkers in Turkeys and Chickens versus Rats, Mice, and Lambs

“…Thus, selenoprotein biomarkers cannot be used effectively as indicators of high selenium status. By using transcriptomics, however, we identified in rats a limited number of nonselenoprotein transcripts that have potential as biomarkers for supernutritional and toxic selenium status (23,46).…”

“…These additional selenoproteins expanded the array of both biochemical and transcript-based biomarkers of selenium status in our studies (14)(15)(16)(17)(18). The identification of the complete selenoproteome (19) further expanded the number of selenoprotein transcripts as "molecular biomarkers" for the assessment of selenium status and requirements in rodents (20)(21)(22)(23) and is helping researchers to better understand the hierarchy of selenium incorporation into selenoproteins.…”

Purification and characterization of glutathione peroxidase 1 in the red muscle of Pacific bluefin tuna Thunnus orientalis

“…Protein and mRNA levels for several selenoproteins, such as GPx1, are downregulated dramatically by selenium deficiency [23]. GPx1 activities in rat tissues increase with increasing dietary selenium and reach defined plateaus at the selenium requirement [23]. Thus, GPx1 may be a sensitive biomarker for selenium deficiency and redox status in fish.…”

“…It is not known, however, whether the selenoneine that is abundant in fish cells and tissues is used in selenoprotein synthesis. Protein and mRNA levels for several selenoproteins, such as GPx1, are downregulated dramatically by selenium deficiency [23]. GPx1 activities in rat tissues increase with increasing dietary selenium and reach defined plateaus at the selenium requirement [23].…”