Although benzene requires metabolic activation in order to exert its myelotoxic effects, the metabolic mechanisms underlying toxicity are not defined. Bone marrow stroma has been implicated as a potential target of benzene metabolites. Stroma represents a hemopoietic microenvironment which is critical to the regulation of normal hemopoiesis. Toxic effects of benzene at the level of bone marrow stroma provide a potential mechanism for benzene-induced myelotoxicity and leukemogenicity. The experiments proposed will focus on the metabolism and toxicity of benzene and its metabolites at the level of the target organ, the bone marrow. More specifically mechanisms of toxicity at the level of bone marrow stroma will be investigated. Studies of metabolic activation and detoxification of benzene and its metabolites will be combined with an analysis of the effects of benzene and its metabolites on stromal-derived regulators of differentiation and proliferation. The effects of benzene and its metabolites on eicosanoid and lymphokine homeostasis in murine bone marrow stroma will be examined together with effects on proteases responsible for lymphokine processing. In order to assess the relevance of any effects observed in-vitro, whether similar effects are observed after benzene administration to mice in-vivo will also be examined. Metabolic and mechanistic studies will also be extended to the human situation by examining the effect of benzene and its metabolites on human bone marrow and stroma in-vitro.

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University of Colorado Denver
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