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.
Highlights
Protein and mRNA levels for several selenoproteins, such as glutathione peroxidase-1 (Gpx1), are down-regulated dramatically by selenium (Se) deficiency
The resulting Se requirements based on selenoprotein mRNAs (0.03 to 0.07 μg Se/g diet) are slightly lower than requirements based on selenoenzyme activity (0.06 to 0.13 μg Se/g diet), but importantly, none of these mRNAs are further increased in rats fed supernutritional levels of dietary Se up to 8-times the requirement
Se Status of Animals using Conventional Biomarkers Se concentration in liver, Gpx1 activity in liver and red blood cells (RBCs), and glutathione peroxidase-3 (Gpx3) activity in plasma were measured for each study to determine the Se status of the animals
Summary
Protein 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. The resulting Se requirements based on selenoprotein mRNAs (0.03 to 0.07 μg Se/g diet) are slightly lower than requirements based on selenoenzyme activity (0.06 to 0.13 μg Se/g diet), but importantly, none of these mRNAs are further increased in rats fed supernutritional levels of dietary Se up to 8-times the requirement These studies demonstrated that selenoprotein mRNAs are useful molecular biomarkers for Se deficiency, but are not effective in assessing high Se status
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