Results from the NIEHS-sponsored NTP at this institution have indicated immunosuppressive activity by subchronic exposure to the mutagen and hepatocarcinogen, N-Nitrosodimethylamine (DMN). This investigation will further characterize this suppression, initially regarding dose-response and time-course relationships. The models for these studies will be the in vitro antibody response of DMN-treated spleen cell suspensions to a number of mitogens/antigens including LPS (lipopolysaccharides) DNP-Ficoll, and SRBC (sheep erythrocytes) which were shown to be the most sensitive parameters for the suppression by DMN. The initial objective in this investigation will be to determine if the B-lymphocyte is a target for the immunosuppressive effects by DMN as suggested by the exquisite sensitivity of the in vitro antibody responses. This approach will be complemented by a parallel project at this institution investigating the effects of DMN on macrophages and T-lymphocytes. The second phase of this investigation will study the effects of direct exposure to DMN on spleen cell suspensions from untreated mice and the role of metabolism. The preliminary results suggest that the reactive metabolites which are thought to mediate the mutagenicity and carcinogenicity do not account for the immunotoxicity. An important component of this phase will be to correlate the effects of direct exposure to DMN on the antibody responses (i.e. or lack of effects) with genotoxic effects as measured by alkylation of macromolecules which should occur following generation of the reactive metabolites. Preliminary results have demonstrated immunosuppression by serum and liver homogenates from DMN-treated mice suggesting an indirect role by the liver which appears to be the primary target organ for DMN. The final objective of this investigation will be to characterize these immunosuppressive factors especially from the serum which has been more consistent and predictable in the initial experiments. The studies characterizing the serum and liver homogenates are significant since they suggest that DMN might be used as a probe to investigate a possible modulation of immunoresponsiveness by the liver.
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