Polymorphonuclear leukocytes (PMNs) respond to various stimuli with respiratory burst. The role of the products of that burst is to combat invading bacteria or other opsonized particles. When instead of natural stimuli chemicals capable of PMN activation are used, products released during the respiratory burst cause damage to neighboring cells. Conversely, some toxic agents could impair a normal PMN response to bacterial infection. We have previously found that stimulation of human PMNs by tumor promoters causes formation of H2O2, the amounts of which correlate with the first stage tumor-promoting potency of those promoters. Production of H2O2 by activated PMNs is paralleled by formation of 5-hydroxymethyl-2'-deoxyuridine (HMdU) and thymidine glycol (dTG) in DNA exposed to those PMNs. Catalase inhibits formation of the oxidized DNA bases, whereas chymotrypsin-specific inhibitors decrease H2O2 production. The major objective of this proposal is to determine whether exposure to carcinogenic and toxic agents impairs the normal functions of PMNs. The agents under study are benzene and some of its metabolites, chloroform, NiCl2, K2CrO4 and methyl mercury chloride. 1) We will determine whether rat and human PMNs cause formation of comparable amounts of H2O2, HMdU and dTG in response to the same tumor promoters. 2) Agents under study will be tested for their ability to activate PMNs in the absence of tumor promoters. 3) Agents which activate PMNs will be tested for the formation of HMdU and response of PMNs to 12-O-tetradecanoyl-phorbol-13- acetate (TPA). These experiments will be carried out on human PMNs (obtained by venipuncture from healthy volunteers) and on PMNs of unexposed rats. 5) Comparison will be made between the ability to form H2O2, HMdU and dTG by PMNs of rats exposed to these agents and by PMNs of unexposed rats.
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