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Title: Selenium and selenoprotein deficiencies induce widespread pyogranuloma formation in mice, while high levels of dietary selenium decrease liver tumor size driven by TGFa

Author
item MOUSTAFA, MOHAMED - National Cancer Institute (NCI, NIH)
item CARLSON, BRADLEY - National Cancer Institute (NCI, NIH)
item ANVER, MIRIAM - National Cancer Institute (NCI, NIH)
item BOBE, GERD - National Cancer Institute (NCI, NIH)
item ZHONG, NIANXIN - National Cancer Institute (NCI, NIH)
item WARD, JERROLD - National Institutes Of Health (NIH)
item PARELLA, CHRISTINE - National Cancer Institute (NCI, NIH)
item HOFFMANN, VICTORIA - National Cancer Institute (NCI, NIH)
item ROGERS, KEITH - National Cancer Institute (NCI, NIH)
item Combs, Gerald
item SCHWEIZER, ULRICH - Charite' University Hospital Berlin
item MERLINO, GLENN - National Cancer Institute (NCI, NIH)
item GLADYSHEV, VADIM - Harvard Medical School
item HATFIELD, DOLPH - National Cancer Institute (NCI, NIH)

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/21/2013
Publication Date: 2/27/2013
Citation: Moustafa, M., Carlson, B.A., Anver, M.R., Bobe, G., Zhong, N., Ward, J.M., Parella, C.M., Hoffmann, V.J., Rogers, K., Combs, G.F., Schweizer, U., Merlino, G.T., Gladyshev, V.N., Hatfield, D.L. 2013. Selenium and selenoprotein deficiencies induce widespread pyogranuloma formation in mice, while high levels of dietary selenium decrease liver tumor size driven by TGFa . PLoS One. 8(2): e57389. doi:10.1371/journal.pone.0057389.

Interpretive Summary: This paper addressed the fact that changes in dietary selenium and selenoprotein status can influence both anti- and pro-cancer pathways, making the outcome of interventions different from one study to another. It reports the results of an experiment in which several levels of dietary selenium were fed to mice carrying a either or both of two mutant transgenes: one for selenocysteine tRNA and another that predisposed them to liver cancer. This allowed us to alter selenoprotein expression in individuals fed adequate dietary levels of selenium. We found that mice deprive of selenium developed early morbidity and mortality and showed a characteristic neurologically lethal phenotype. Pathological examination showed inflammatory changes in liver, lungs, heart, spleen, small and large intestine, and mesenteric lymph nodes. Neither dietary selenium nor selenium status, separately or in combination, influenced the development of liver cancer in predisposed mice.

Technical Abstract: Changes in dietary selenium and selenoprotein status may influence both anti- and pro-cancer pathways, making the outcome of interventions different from one study to another. To characterize such outcomes in a defined setting, we undertook a controlled hepatocarcinogenesis study involving varying levels of dietary selenium and altered selenoprotein status using mice carrying a mutant (A37G) selenocysteine tRNA transgene (TrsptG37) and/or TGFa. The use of TrsptG37 allowed us to alter selenoprotein expression in a selenoprotein and tissue specific manner and, at sufficient dietary selenium, separate the effect of diet and selenoprotein status, whereas TGFa was employed as the driver of hepatocarcinogenesis. We subjected these mice to diets deficient in selenium (0.02 ppm selenium) or supplemented with 0.1, 0.4 or 2.25 ppm selenium as selenite or 30 ppm triphenylselenonium chloride (TPSC), a non-metabolized selenium compound. TrsptG37 transgenic and TGFa/TrsptG37 bi-transgenic mice maintained on selenium-deficient or TPSC diets developed early morbidity and mortality prior to tumor formation, and showed a characteristic neurologically lethal phenotype. Pathological analyses revealed widespread disseminated pyogranulomatous inflammation, wherein pyrogranulomas occurred in liver, lungs, heart, spleen, small and large intestine, and mesenteric lymph nodes in the TrsptG37 transgenic and TGFa/TrsptG37 bi-transgenic mice fed the selenium-deficient or TPSC diets. The incidence of hepatocarcinogenesis was significantly increased in mice carrying the TGFa transgene; however, neither dietary selenium nor selenium status, separately or in combination, influenced hepatocarcinogenesis in these animal models. Thus, dietary selenium and selenoprotein status do not affect hepatocarcinogenesis driven by TGFa, but their deficiency leads to widespread pyogranuloma formation.