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 (Trsp(tG37) ) and/or a
cancer driver TGFα transgene. The use of Trsp(tG37) altered
selenoprotein expression in a
selenoprotein and tissue specific manner and, at sufficient dietary
selenium levels, separate the effect of diet and
selenoprotein status. Mice were maintained on diets deficient in
selenium (0.02 ppm
selenium) or supplemented with 0.1, 0.4 or 2.25 ppm
selenium or 30 ppm
triphenylselenonium chloride (TPSC), a non-metabolized
selenium compound. Trsp(tG37) transgenic and TGFα/Trsp(tG37) bi-transgenic mice subjected to
selenium-deficient or TPSC diets developed a neurological phenotype associated with early morbidity and mortality prior to hepatocarcinoma development. Pathology analyses revealed widespread disseminated pyogranulomatous
inflammation. Pyogranulomas occurred in liver, lungs, heart, spleen, small and large intestine, and mesenteric lymph nodes in these transgenic and bi-transgenic mice. The incidence of liver
tumors was significantly increased in mice carrying the TGFα transgene, while dietary
selenium and
selenoprotein status did not affect
tumor number and multiplicity. However,
adenoma and
carcinoma size and area were smaller in TGFα transgenic mice that were fed 0.4 and 2.25 versus 0.1 ppm of
selenium. Thus,
selenium and
selenoprotein deficiencies led to widespread pyogranuloma formation, while high
selenium levels inhibited the size of TGFα-induced liver
tumors.