The overall objective of this proposal is to study the etiology of B lymphoid malignancies. Using a rat model, these studies will further address the role of the gut-associated Peyer's patches (PP) in the chemical carcinogenesis of B lymphoid disorders. Based on the unique anatomical, functional and cellular characteristics of this lymphoid organ, we proposed that the lymphoid cells within the PP 1) may be exposed to greater amounts of a potential carcinogen which was orally introduced into the gastrointestinal tract and 2) subsequently have a greater probability of carcinogenesis of B- lymphocytes (the predominate cell type). Completed studies indicate that the PP are in fact very efficient in the adsorption of 3-methyl-cholanthrene (3-MC) from the lumenal content. Furthermore, a high incidence of B-lymphoid malignancies could be induced by localizing 3-MC within the PP. Our results also indicate that the dose of the 3-MC and treatment of the rats with pristane are important factors in the carcinogenesis of rat lymphoid malignancies. With high doses of 3-MC only thymic tumors were induced where a with low doses of 3-MC plus pristane priming the B lymphoid disorders were observed. Two general hypotheses are proposed to address the basis of these results. First, exposure of the PP to low versus high doses of 3-MC results in the generation of different 3-MC metabolites with different cellular specificities. And second, pristane acts as a promoter for B lymphocytes which have undergone an initiation event. There are five specific aims of these studies. First, metabolism of low and high doses of 3-MC in PP versus other lymphoid organs, as well as the reaction(s) of possible metabolites with lymphoid cells will be studied. Second, induction studies will be performed to determine if T versus B cell malignancies can be induced by different 3-MC metabolites. Third, the role of pristane in the induction of the B cell malignancies will be addressed. Fourth, the cellular aspects of tumorigenesis will be addressed using transplantation methods. Fifth, studies of the molecular mechanisms of chemical carcinogenesis of lymphoid malignancies will be conducted. These studies will provide insights into the role of the Peyer's patch in the initiation and promotion of lymphoid malignancies by chemicals which are orally introduced into the gastrointestinal tract.
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