Occupational exposure to benzene represents a significant hazard to certain individuals in the workplace. Chronic exposure to benzene can cause multiple clinical disorders that are related to the general hematotoxicity of benzene. However, benzene itself is not considered the ultimate toxicant but is transformed in vivo into metabolites that react with cellular macromolecules and interfere with normal development of bone marrow precursor cells. Experiments in this proposal are designed to investigate the cellular mechanism of toxicity of benzene and benzene metabolites on bone marrow immuno/hemopoiesis. The polyhydroxy metabolites of benzene to be studied include benzoquinone, benzenetriol, catechol, hydroquinone and phenol. A primary objective of these studies is to examine the relationship between the in vivo and in vitro effects of benzene metabolites on marrow precursor cell proliferation and differentiation. In this study, it will be determined how benzene and its metabolites can alter precursor T- and B- lymphocyte development as well as precursor granulocyte/ionocyte development. Emphasis will be applied to discerning changes between maturational development versus cellular proliferation. An important part of the study will be to investigate the role of stromal cells of the marrow hemopoietic microenvironment in metabolite-induced marrow toxicity. Stromal cells constitute cells that are capable of promoting specific hemopoietic proliferation and development. A detailed examination of alterations in the normal process of precursor cell differentiation and maturation will result in greater understanding of the molecular events triggering myelotoxicity in individuals exposed to benzene or benzene metabolites.
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