Polychlorinated dibenzo-p-dioxin (PCDD) and structurally related halogenated aromatic hydrocarbons, including the dibenzofurans and biphenyls, are widely distributed, highly toxic environmental contaminants that produce a similar and characteristic pattern of toxic and biochemical responses in animals. Structure/activity studies suggest that the toxic isomers of these chemicals act through a common receptor (the Ah receptor) which regulates the expression of a multitude of gene batteries. In all species studied, the toxic congeners produce thymic involution and suppression of the immune response, which also is mediated, at least in part, by the Ah receptor. However despite considerable investigation, the precise nature of the immune dysfunction and the target cells affected by these chemicals have not been determined. The cell membrane antigens and receptors displayed by lymphocyte/monocyte subsets phenotypically define the cells, and, with several markers, are associated with specific functions. Therefore, modulation of the expression of these cell-surface molecules by exposure to dioxin could be expected to have significant effects on cell behavior. Since the Ah receptor regulates the expression of multiple, and, as yet, not fully defined gene batteries, it is possible that activation of the Ah gene produces altered surface antigen or receptor expression which, in turn, alters the functional activity of the cell.
The specific aims of this proposal are: 1) to characterize lymphocyte/monocyte subpopulations in control and dioxin-treated mice in terms of cell-surface marker expression using multiparameter flow cytometry, 2) to characterize relative changes in lymphocyte/monocyte subpopulations following antigen challenge in control and dioxin-exposed mice by multiparameter flow cytometry, and 3) to determine if in vitro exposure of lymphocyte/monocyte subsets to dioxin produces similar alterations in surface antigen expression observed after in vivo exposure that may then be utilized for the study of dioxin-induced effects on the human immune system. Quantitative and qualitative surface marker expression of Ia, IgM, IgD, C3, Thy-1, Lyt-1, Lyt-2, L3T4 and I-J will be analyzed in response to exposure to 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, a major immunosuppressive contaminant of technical grade pentachlorophenol. Other dioxin isomers will be examined if positive results are found with HpCCD.
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