Abstract
We explored the potential role of zinc (Zn) and zinc transporters in protection against cytotoxicity of cadmium (Cd) in a cell culture model of human urothelium, named UROtsa. We used real-time qRT-PCR to quantify transcript levels of 19 Zn transporters of the Zrt-/Irt-like protein (ZIP) and ZnT gene families that were expressed in UROtsa cells and were altered by Cd exposure. Cd as low as 0.1 µM induced expression of ZnT1, known to mediate efflux of Zn and Cd. Loss of cell viability by 57% was seen 24 h after exposure to 2.5 µM Cd. Exposure to 2.5 µM Cd together with 10–50 µM Zn prevented loss of cell viability by 66%. Pretreatment of the UROtsa cells with an inhibitor of glutathione biosynthesis (buthionine sulfoximine) diminished ZnT1 induction by Cd with a resultant increase in sensitivity to Cd cytotoxicity. Conversely, pretreatment of UROtsa cells with an inhibitor of DNA methylation, 5-aza-2’-deoxycytidine (aza-dC) did not change the extent of ZnT1 induction by Cd. The induced expression of ZnT1 that remained impervious in cells treated with aza-dC coincided with resistance to Cd cytotoxicity. Therefore, expression of ZnT1 efflux transporter and Cd toxicity in UROtsa cells could be modulated, in part, by DNA methylation and glutathione biosynthesis. Induced expression of ZnT1 may be a viable mechanistic approach to mitigating cytotoxicity of Cd.
Highlights
Exposure to cadmium (Cd) is inevitable for most people because this toxic metal is present in virtually all foodstuffs, cigarette smoke, and polluted air from combustion of fossil fuels and biomass [1,2,3]
Our studies have indicated that the UROtsa cell line is suitable for studying urothelial cancer; prolonged exposure to 1 μM Cd induced UROtsa cells to transform to cancer cells [21] and the tumors derived from transformed cells displayed gene expression profiles similar to the basal subtype of muscle invasive bladder cancer [22]
Lower expression levels of ZIP8 than ZIP14 suggested that ZIP14 and ZnT1 could potentially be involved in Cd accumulation and its cytotoxicity in this human urothelial cell line
Summary
Exposure to cadmium (Cd) is inevitable for most people because this toxic metal is present in virtually all foodstuffs, cigarette smoke, and polluted air from combustion of fossil fuels and biomass [1,2,3]. Cd has no known biological role in humans, but it has a similar ionic radius to that of calcium (Ca) and electronegativity similar to that of zinc (Zn). Cd can be taken up by the same transporter systems and pathways the body uses to acquire Ca, Zn, and other essential metals including iron (Fe) and manganese (Mn) [2,4,5,6]. Members of zinc transporters of the Zrt- and Irt-related protein (ZIP). Family, such as ZIP8 and ZIP14, have been shown to mediate Cd uptake by various cell types [7,8,9,10,11,12,13]. High blood Cd has been associated with certain variants of the ZIP8 and ZIP14 genes [14]
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