Analyses of Selenotranscriptomes and Selenium Concentrations in Response to Dietary Selenium Deficiency and Age Reveal Common and Distinct Patterns by Tissue and Sex in Telomere-Dysfunctional Mice

Abstract

The hierarchies of tissue selenium distribution and selenotranscriptomes are thought to critically affect healthspan and longevity. We determined selenium status and selenotranscriptomes in response to long-term dietary selenium deficiency and age in tissues of male and female mice. Weanling telomerase RNA component knockout C57BL/6 mice were fed a selenium-deficient (0.03 mg Se/kg) Torula yeast-based AIN-93G diet or a diet supplemented with sodium selenate (0.15 mg Se/kg) until age 18 or 24 mo. Plasma, hearts, kidneys, livers, and testes were collected to assay for selenotranscriptomes, selected selenoproteins, and tissue selenium concentrations. Data were analyzed with the use of 2-factor ANOVA (diet × age) in both sexes. Dietary selenium deficiency decreased ( ≤ 0.05) selenium concentrations (65-72%) and glutathione peroxidase (GPX) 3 (82-94%) and selenoprotein P (SELENOP) (17-41%) levels in the plasma of both sexes of mice and mRNA levels (9-68%) of 4, 4, and 12 selenoproteins in the heart, kidney, and liver of males, respectively, and 5, 16, and 14 selenoproteins, respectively, in females. Age increased selenium concentrations and SELENOP levels (27% and 30%, respectively; ≤ 0.05) in the plasma of males only but decreased (12-46%; < 0.05) mRNA levels of 1, 5, and 13 selenoproteins in the heart, kidney, and liver of males, respectively, and 6, 5, and 0 selenoproteins, respectively, in females. Among these mRNAs, selenoprotein H (), selenoprotein M (), selenoprotein W (), methionine--sulfoxide reductase 1 (), ,, thioredoxin reductase 1 (), , selenoprotein S (), selenoprotein F (), and selenoprotein O () responded in parallel to dietary selenium deficiency and age in ≥1 tissue or sex, or both. Dietary selenium deficiency upregulated (40-160%; ≤ 0.05) iodothyronine deiodinase 2 () and selenoprotein N () in the kidneys of males. Age upregulated (11-44%; < 0.05) in the kidneys of males, selenoprotein K () and selenoprotein I () in the kidneys of females, and and in the testes. These results illustrate tissue-specific sexual dimorphisms of selenium status and selenotranscriptomes because of dietary selenium deficiency and age.

Dietary Selenium Supplementation Ameliorates Female Reproductive Efficiency in Aging Mice

“…As expected, a significantly lower whole-blood Se concentration was observed in Se-deficient mice compared to the Se-adequate and Se-supplemented groups at the study endpoint i.e., week 8. This finding is supported, to some extent, by a recent report [57] where it was shown that plasma Se concentration significantly declined in telomere-dysfunctional aged female mice (C57BL/6) fed a Se-deficient diet (Se-yeast 0.03 mg Se/kg) compared to those fed an adequate inorganic-Se diet (0.15 mg Se/kg) until aged 18 or 24 months; this decline was more pronounced in the latter age group. Similarly, in two very recent studies [42,43] on young female BALB/c mice, a significant reduction in whole-blood Se levels was reported following a three-month long feeding with a Se-deficient (0.02 mg Se/kg) diet.…”

“…Similarly, recently it was shown that Se deficiency downregulated several selenoproteins, including Gpx1, Gpx3, and Gpx4, in an organ-specific manner in mice [89]. Interestingly, long-term Se deficiency and age also significantly downregulated mRNA levels of many selenoproteins such as Gpx1, Gpx3, and Gpx4 in a tissue-specific manner in aged female G3 Terc −/− C57BL/6 mice [57]. In any case, precise fundamental basis of this tissue-specific hierarchical selenotranscriptomic regulation by dietary Se deficiency still remains poorly elucidated [57].…”

“…Interestingly, long-term Se deficiency and age also significantly downregulated mRNA levels of many selenoproteins such as Gpx1, Gpx3, and Gpx4 in a tissue-specific manner in aged female G3 Terc −/− C57BL/6 mice [57]. In any case, precise fundamental basis of this tissue-specific hierarchical selenotranscriptomic regulation by dietary Se deficiency still remains poorly elucidated [57]. In general, GPX1, GPX3, and GPX4 are well-recognized for their antioxidant and redox regulatory roles, and have been implicated in playing significant roles in mammalian fertility and reproduction [9,10].…”

“…Indeed, SELENOF has been implicated in mitigating tunicamycin-induced apoptosis in human lens epithelial (hLE) cells, potentially via inhibiting mitochondria-dependent oxidative stress [104]. In a recent selenotranscriptomic study, it was shown that long-term Se deficiency and age downregulated the mRNA expression of Selenof in a sex-and tissue-specific pattern in telomere-dysfunctional mouse model [57]. Moreover, an upregulated mRNA expression of SELENOF was reported in growing lambs supplemented with inorganic Se [105].…”

Analysis of Selenoprotein Expression in Response to Dietary Selenium Deficiency During Pregnancy Indicates Tissue Specific Differential Expression in Mothers and Sex Specific Changes in the Fetus and Offspring

“…In mice, selenium deficiency has been previously demonstrated to increase expression of GPx2 in the gastrointestinal tract [40]; however, this is the first study to investigate the effects of dietary selenium deficiency on foetal selenoprotein expression. Expression of DIO2 and SelenoN in kidneys has also been recognised to upregulate in response to dietary selenium deficiency [41], with age also playing a factor in upregulation of several others. Cao et.…”