Department of Nutritional Sciences, University of Wisconsin, Madison, WI, USA.
J Nutr. 2021 Apr 8;151(4):772-784. doi: 10.1093/jn/nxaa333.
Better biomarkers of selenium (Se) status and a better understanding of toxic Se biochemistry are needed to set safe dietary upper limits. In previous studies, differential expression (DE) of individual liver transcripts in rats and turkeys failed to identify a single transcript that was consistently and significantly (q < 0.05) altered by high Se.
To evaluate the effect of Se status on rat liver transcript expression data at the level of gene sets, and to compare transcript expression in rats with that in turkeys to identify common regulated transcripts.
Gene set enrichment analysis (GSEA) was conducted on liver from weanling rats fed an Se-deficient basal diet (0.005 μg Se/g) supplemented with 0, 0.24 (Se-adequate), 2, or 5 μg Se/g diet as selenite for 28 d. In addition, transcript expression was compared with liver expression in turkeys fed 0, 0.4, 2, or 5 μg Se/g diet as selenite.
Se deficiency significantly downregulated the rat selenoprotein gene set but also upregulated gene sets for a variety of pathways, processes, and disease states. GSEA of 2 compared with 0.24 μg Se/g found no significantly up- or downregulated gene sets, showing that 2 μg Se/g is not particularly toxic to the rat. GSEA analysis of 5 compared with 0.24 μg Se/g transcripts, however, found 27 significantly upregulated gene sets for a wide variety of conditions. Cross-species GSEA comparison of transcript expression, however, identified no common gene sets significantly and consistently regulated by high Se in rats and turkeys. In addition, comparison of individual marginally significant (unadjusted P < 0.05) DE transcripts between rats and turkeys also failed to find common transcripts.
The dramatic increase in significant liver transcript DE and GSEA gene sets in rats fed 5 compared with 2 μg Se/g clearly appears to be a biomarker for Se toxicity, albeit not Se-specific. These analyses, however, failed to identify specific transcripts or pathways, biological states, or processes that were directly linked with high Se status, strongly indicating that adaptation to high Se lies outside transcriptional regulation.
为了制定安全的膳食上限，我们需要更好的硒（Se）状态生物标志物，并深入了解有毒 Se 的生物化学。在之前的研究中，大鼠和火鸡肝脏中单个转录本的差异表达（DE）未能鉴定出一个始终显著（q < 0.05）受高 Se 改变的单一转录本。
在基因集水平上评估 Se 状态对大鼠肝脏转录本表达数据的影响，并比较大鼠和火鸡的转录本表达，以鉴定共同调节的转录本。
对 28 天内用亚硒酸钠补充 0.005μg Se/g（硒缺乏）基础饮食、0.24（硒充足）、2 或 5μg Se/g 饮食的断奶大鼠的肝脏进行基因集富集分析（GSEA）。此外，还比较了火鸡用亚硒酸钠补充 0、0.4、2 或 5μg Se/g 饮食的肝脏转录本表达。
Se 缺乏显著下调了大鼠的硒蛋白基因集，但也上调了多种途径、过程和疾病状态的基因集。与 0.24μg Se/g 相比，2 比较 2 与 0.24μg Se/g 时，未发现明显上调或下调的基因集，表明 2μg Se/g 对大鼠并无特别毒性。然而，与 0.24μg Se/g 相比，5 比较 2 时，发现了 27 个与多种情况显著上调的基因集。然而，对大鼠和火鸡中高 Se 显著且一致调节的基因集进行跨物种 GSEA 比较，未发现共同的基因集。此外，比较大鼠和火鸡之间略微显著（未调整 P < 0.05）的 DE 转录本，也未发现共同的转录本。
与 2μg Se/g 相比，大鼠肝脏中显著增加的 DE 转录本和 GSEA 基因集，显然是 Se 毒性的生物标志物，尽管不是 Se 特异性的。然而，这些分析未能确定与高 Se 状态直接相关的特定转录本或途径、生物状态或过程，这强烈表明对高 Se 的适应超出了转录调控的范围。
