Chromium (VI)-induced transformation is enhanced by Zn deficiency in BALB/c 3T3 cells

Hexavalent chromium [Cr(VI)] is a carcinogenic heavy metal that is reduced to intermediate oxidation states, such as Cr(V) and Cr(IV), in the process of forming stable Cr(III) forms; it is these intermediate forms that are thought to be responsible for much of the DNA damage and mutations that are induced by Cr(VI). Metallothionein (MT), a heavy metal-binding protein, is induced by zinc and other heavy metals and protects cells from the toxic effects of these metals by sequestering them. MT cannot bind Cr, but by scavenging reactive oxygen species through its cysteine residues, it may act as a protective factor against Cr(VI)-induced DNA lesions by reducing Cr(VI) directly to Cr(III), thereby avoiding the creation of the toxic intermediates. Here, we showed that Zn deficiency decreased MT expression in BALB/3T3 clone A31-1-1 cells and caused them to become highly susceptible to Cr(VI)-induced transformation. To obtain Zn-deficient cultures, cells were cultured in medium supplemented with 10% Chelex(®)-100 chelating resin-treated FBS. The increase in susceptibility to transformation was abolished by culturing the cells with supplemental Zn (50 µM). Previously, we reported that Cr(VI) inhibits MT transcription by preventing the zinc-dependent formation of a complex of metal response element-binding transcription factor-1 (MTF-1) and the co-activator p300. Our results suggest that the carcinogenicity of Cr(VI) is enhanced by MTF-1 dysfunction.