The broad long term objective of this study is to better understand benzene toxicity relative to hematopoiesis and v-Ha-ras transgene activation in bone marrow cells and hematopoietic progenitor cells (HPC) that lead to the onset of leukemia. The v-Ha-ras transgenic Tg.AC mouse is used to investigate environmental determinants of carcinogenesis. The transgene construct is composed of a zeta-globin promoter fused to a v-Ha-ras coding sequence and a 3'SV40 polyadenylation sequence. Procedures for clonal selection of murine HPC from bone marrow cells using defined culture media for quantification and characterization of erythroid and myeloid lineage of HPC are evaluated. Transgene expression in bone marrow cells and HPC derived from them is assayed by RT-PCR. The effect of benzene on hematopoiesis and transgene expression is studied by exposing groups of experimental and control mice to benzene (34 mg/kg body weight/day) in their drinking water for extended time periods. It is hypothesized that benzene will have a significant negative effect on hematopoiesis and will activate transgene expression beyond basal levels. It is also hypothesized that benzene toxicity cooperates with the expressed transgene to drive selection proliferation and differentiation of transformed neoplastic HPC.
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