Polymorphonuclear (PMNs) and mononuclear leukocytes play important roles in host defense mechanisms against infections and neoplasms. Thus, any alteration in either the production or function of these cells would result in suppressed host defenses. A likely site at which such alterations could occur is in the bone marrow. While there is an appreciation of the bone marrow being a target organ for chemical-induced toxicity, the mechanisms and determinants of bone marrow toxicity by environmental agents are not well understood. The overall aim of this project is to investigate biochemical and molecular mechanisms which could contribute to the altered production and function of PMNs and mononuclear cells by the environmental pollutant benzo(a)pyrene (BP). It is our hypothesis that there are biochemical factors within specific bone marrow cell populations which determine their susceptibility for toxic reactions by BP and its metabolites. In this regard, we will; (1) continue to investigate the activation of BP and BP-7, 8-dihydrodiol to reactive intermediates by myeloperoxidase and bone marrow-derived cells; (2) investigate the biochemical and molecular interactions of BP-derived metabolites with bone marrow myeloid and stromal cells and human cell lines which could result in the altered production or function of leukocytes; and (3) evaluate the function and activity of bone marrow cell populations following the oral administration of BP to mice. These studies bring together a spectrum of analytical, biochemical and cell biology approaches to analyze the consequences of BP's interactions with bone marrow cells both in vitro and in vivo. The successful completion of this project will result in a greater understanding of biochemical and molecular interactions and determinants of cellular susceptibility which could contribute to the bone marrow toxic effects of BP. Further knowledge of the mechanisms of toxicity within the bone marrow by environmental agents will contribute to our ability to predict risk and to develop protective and treatment regimes against toxicity to this critical organ.

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National Institute of Environmental Health Sciences (NIEHS)
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Toxicology Subcommittee 2 (TOX)
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Johns Hopkins University
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