Polycyclic aromatic hydrocarbons (PAHs) represent a class of chemical compounds which have been well studied due to their ubiquitous contamination of the environment and because many are potent carcinogens. The binding of electrophilic PAH metabolites to DNA has been shown to be responsible for many of the mutagenic, carcinogenic and toxic effects produced by these biologically active compounds. Metabolic activation of PAHs has been shown to occur via the cytochrome P-450 monooxygenase pathway. Studies from our laboratory have demonstrated that PAHs also adversely affect the immune response, and that their effects can be observed both in vivo and when directly added to in vitro cultures. The overall goal of this project is to determine the molecular mechanism by which polycyclic aromatic hydrocarbons produce immunosuppression of the humoral immune response. As a result of our structure activity studies, in which we have identified PAHs which are immunosuppressive, as well as those which do not affect the humoral immune response, we now have the chemical probes necessary to dissect the molecular mechanism by which PAHs are immunotoxic. Our preliminary data suggest that DNA binding is not associated with the immunosuppression observed with these compounds and that the immunosuppressive selectivity of the different members of this chemical class is a function of the P-450 isozyme present in monocytes and lymphocytes of the spleen. The knowledge obtained from these studies will add to our understanding of the molecular mechanism by which PAHs and other environmentally relevant compounds produce immunosuppression.
Showing the most recent 10 out of 11 publications
