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

<p>Abstract</p> <p>Background</p> <p>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. 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.</p> <p>Results</p> <p>There 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.</p> <p>Conclusion</p> <p>This 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.</p

Selenoprotein gene nomenclature

The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4 and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine-R-sulfoxide reductase 1) and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15 kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV) and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates

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Peer reviewe

Selenium regulation of selenoprotein enzyme activity and transcripts in a pilot study with Founder strains from the Collaborative Cross - Fig 3

<p>Relative expression of plasma Gpx3 activity (A), RBC Gpx1 activity (B), liver Gpx1 activity (C), liver Gpx4 activity (D), and liver Txnrd (E) activity. Activities are expressed as a percentage of activities in Se-adequate B6 mice. Left portion of each panel shows the relative activity in B6 mice fed 0 μg Se/g (-Se) and 0.2 μg Se/g (+Se) relative to +Se B6 mice; values are mean ± SEM (n = 3/treatment). Right portion of each panel shows the relative activities in -Se and +Se Founder mice as box-and-whisker plots, where the box delineates 25 to 75%, the bar in the box the median, and the error bars 10 and 90%; also shown are individual values linked by lines for each of the 8 strains. Means with asterisks are significantly different from Se-adequate values (P<0.05).</p

Relative expression of liver selenoprotein transcripts not altered significantly by Se deficiency in B6 or Founder mice.

<p>Shown are expression levels for <i>Msrb1</i>, <i>Selenos</i>, <i>Selenoo</i>, <i>Selenot</i>, <i>Txnrd1</i>, <i>Selenom</i>, and <i>Selenon</i>, expressed relative to the level in +Se B6 mice. Details as described for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0191449#pone.0191449.g004" target="_blank">Fig 4</a>.</p

Effect of Se deficiency on selenoprotein transcript expression in Founder mouse liver.

<p>Shown are expression levels for 18 selenoprotein transcripts, shown as percentage of expression of that transcript in Se-adequate mice. Box-and-whisker plots indicate the median as the bar in the box, the box delineates 25 to 75%, and the error bars 10 and 90%; also shown are individual values for each of the 8 strains. Horizontal dashed lines separate transcripts regulated significantly both for B6 and Founder mice (*, P<0.05, left), regulated only significantly for Founder mice (#, P<0.05, middle), and not regulated significantly (P>0.05) for B6 or Founder mice (right), determined using t-tests as described for Figs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0191449#pone.0191449.g003" target="_blank">3</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0191449#pone.0191449.g006" target="_blank">6</a>.</p

Growth of Founder mice.

<p>Eight strains of male mice starting at the indicated age were fed for 56 d, and weighed biweekly. B6 mice (n = 3/treatment), and AJ, 129S, NOD, NZO, CAST, WSB, and PWK (n = 1/treatment) were fed a Se-deficient basal diet (0.005 μg Se/g) or that diet supplemented with 0.2 μg Se/g as selenite. B6 values are the mean weight ± SEM; values for other strains are the mean weight. There was no significant effect (P>0.05) of dietary Se level at any timepoint for B6 mice or for Founder mice.</p