The overall objective of this research project is to understand the mechanism by which chromium(VI) compounds affect gene expression. The approaches we plan to use in attacking this problem are: (1) examine the ability of chromium(IV) to differentially affect gene expression in rats and chick embryos, two well-characterized, yet developmentally different, in vivo systems; (2) compare the effects of chromium(IV) on different types of genes, i.e., constitutive genes, tissue-specific genes, inducible genes, and quiescent genes; and (3) determine possible mutations in genes affected by chromium(IV). The long-range objective of this research project is to understand the mechanism by which chromium(IV) compounds act as carcinogens. We plan to test the hypothesis that chromium(IV) - induced DNA damage will adversely affect the expression of genes containing repetitive sequences and inducible genes.
The specific aims of the proposed research are: (1) Determination of the effects of chromium(IV) - induced DNA damage in rat liver and kidney and in chick embryo liver and blood cells on the steady-state mRNA levels (using liquid hybridization) and rate of transcription (using nuclear """"""""run-off"""""""" transcription) of specific genes in vivo. The genes which will be examined are: a. constitutive inducible genes - chick delta-aminolevulinate synthase, rat and chick cytochromes P-450, rat and chick metallothioneins, and rat glutathione S - transferases (contain repetitive sequences); b. constitutive noninducible gene - chick transferrin (contains repetitive sequences); c. oncongenes - rat ras, chick myc; and d. constitutive noninducible gene - rat and chick actin. (2) Determination of possible chromium(IV) - induced mutations in specific genes in vivo using amplification and hybridization mismatch analysis.
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