Polymorphonuclear (PMN's) and mononuclear leukocytes are important cells in host defense mechanisms. An alteration in either the production or function of these cells could result in suppressed host defenses against infection and neoplasms. A likely site at which such alterations could occur is in the bone marrow. Studies have shown that the oral administration of the environmental pollutant benzo(a)pyrene (BP) to Ah nonresponsive DBA/2 mice with an Ahd/Ahd genotype, results in acute and severe hematotoxicity, resembling aplastic anemia. This is of human relevance considering that diet is a major route of exposure to polycyclic aromatic hydrocarbons (PAHs). The overall aim of this project is to investigate biochemical and cellular mechanisms which could contribute to the altered production and function of PMNs and mononuclear cells by BP. It is the investigator's hypothesis that xenobiotic processing within specific bone marrow cell populations, such as the stromal microenvironment and committed myeloid progenitors, underlie their susceptibility for toxic reactions by BP and its metabolites. Enzymes that are pertinent to this investigation include cytochrome P-450, myeloperoxidase and those of the mitochondrial electron transport chain. Based on this hypothesis, the specific aims of this project will continue to: investigate biochemical and molecular interactions of BP-derived quinones and BP-7,8-dihydrodiol (BP-diol) which occur as a result of their interactions with organelles and enzymes from bone marrow cells; investigate the mechanisms of toxicity of BP and its metabolites to DBA/2 bone marrow stromal cells in vitro and in vivo; examine the ability of BP and its metabolites to alter the differentiation of human myeloid cell lines, ML-1 and HL-60, and progenitor cells from DBA/2 mice; and evaluate if a peroxide-dependent mechanism is involved in the bioactivation of BP-diol in vitro and in vivo. Fulfillment of these aims will result in a greater understanding of biochemical and molecular interactions, determinants of cellular susceptibility, and mechanisms of potentiation which could contribute to the bone marrow toxic effects of BP. Knowledge of these mechanisms of toxicity within the bone marrow will contribute to the ability to develop biomarkers of effect to better assess the potential risk for hematotoxicity in humans exposed to PAHs through their diet, especially those that are Ah nonresponsive.
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