Mechanistic studies of pulmonary toxicity of styrene

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Wide range effects of occupational styrene exposure have been reported to cause severe acute toxic effects. Inhaled styrene has been found to produce respiratory toxicity in human and animals. The overall objective of the research described in this proposal is to investigate the biochemical mechanism of acute respiratory toxicity induced by styrene. Our preliminary studies showed that para-substituted halogens "amplify" cytotoxicity of styrene. These styrene analogues are excellent model compounds for mechanistic studies of toxic action by comparing their toxicity potentials with their biochemical behaviors. Styrene toxicity has been suggested to be mediated by cytochrome P450 enzymes, specifically CYP2E1 and CYP2F2. Electrophilic styrene 7,8-epoxide has been proposed to be toxic metabolite responsible for styrene toxicity. We hypothesize that styrene toxicity is associated with cellular protein modification by epoxide metabolite of styrene. As initial steps for this project, we will (1) extend the structure-activity relationship study to determine the importance of the vinyl group (epoxide precursor) in styrene toxicity; (2) develop analytical approaches to determine protein modification by styrene and halogenated styrenes; (3) develop epoxide hydrolase transgenic cells to explore the role of epoxide metabolite in styrene toxicity; (4) identify reactive metabolites of halogenated styrene derivatives; and (5) to assess kinetics of styrene and halogenated styrenes. To probe the hypothesis, we will determine (1) association between protein modification and toxicity intensity induced by styrene and halogenated styrenes; (2) association beween protein modification and cellular glutathione content/glutathione S-transferase activity/epoxide hydrolase activity after exposure to styrene and halogenated styrenes. Our expectation is that protein modification is propotional to halogenated styrene toxicity potentials and that factors to increase reactivity of styrene derivatives and to make epoxide metabolites accumalted enhance protein modification and respiratory toxicity.