We will study the intracellular distribution of chromium and the mechanisms of chromium toxicity in mammalian cells. With Cr(VI), increased SCE frequency occurred at 0.01 micromolar, whereas the inhibition of cell proliferation occurred at 1.0 micromolar. Cr(III) was much less effective. Our working hypothesis is that the genotoxic effects of Cr(VI) are causually related to the antiproliferative effects. We will study the transport of 51-Cr (VI and III) into cells and of their distribution in intracellular organelles. We expect that chromium toxicity is associated with changes in chromatin conformation (DNA superstructure). Our plan is to: study cytogenetic changes by chromium by using assays which measure chromatid aberrations, chromosomal aberrations and SCE; utilize computer-aided cell sizing equipment to detect small changes in cell growth and cell size; develop chromium- resistent and chromium - transformed cells; use a variety of analyses to monitor alterations in these cell variants; study the effects of chromium on the uptake of nucleotide precursors and cellular nucleotide pools; use the following preparations for biochemical studies: intact cells, permeabilized cells, nucleoids and isolated chromosomes; study the effects of chromium on the fidelity of DNA synthesis, and on the conformation of chromatin in these preparations.
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