Immunosuppressive disorders constitute a significant human health problem associated with increased individual susceptibility to infectious and neoplastic diseases. Human populations may be at risk for clinically significant immunosuppression following exposure to environmental metals, pesticides, or immunotoxic drugs. It is now known that induction of apoptosis in lymphoid cells is an important mediator of immunotoxicity following chemical exposure. However, lymphoid cell populations among and within individuals can vary extensively with respect to their sensitivity to undergo chemically induced apoptosis. Thus, differences in the mechanisms underlying the execution of pro- and anti-apoptotic pathways in resistant and susceptible cell populations need to be understood before the consequences of exposure to environmental contaminants can be fully appreciated. This study utilizes a unique panel of human B-lineage lymphocyte (BLL) cell lines that show large differences in their sensitivity to apoptosis induction by various chemicals to test the hypothesis that the differential activation of specific mitogen-activated protein (MAP) kinases is a critical factor in determining chemical sensitivity in BLLs. The activation of the three major MAP- kinase pathways, ERK1/2, JNK1/2, and -38 following exposure of the BLL-cell lines to the environmental pollutants arsenic and cadmium, and selected drugs that share with these metals the ability to perturb mitochondrial function will be examined. Specific chemical inhibitors and dominant negative strategies will be used to establish causality between activation of these kinases and induction of apoptosis in susceptible cell lines. In addition, the roles that these kinase pathways play in acquired sensitivity to apoptosis induction in resistant cell lines following low-level chemical exposure will also be studies. Experiments will also be performed to determine whether low-level chemical exposure can sensitize BLLs to the induction of apoptosis by engagement of the IgM receptor. IgM-induced apoptosis is an important mediator of negative selection of B- lymphocytes during development which, similar to chemically induced apoptosis, involves the activation of specific MAP kinase pathways. This research is expected to identify important mechanisms regulating differential lymphoid cell sensitivity to apoptosis induction and to contribute a novel model system for examining thresholds for adverse effects of environmental chemicals on B-lineage lymphoid cells.
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|Muscarella, Donna E; O'Brien, Kerry A; Lemley, Ann T et al. (2003) Reversal of Bcl-2-mediated resistance of the EW36 human B-cell lymphoma cell line to arsenite- and pesticide-induced apoptosis by PK11195, a ligand of the mitochondrial benzodiazepine receptor. Toxicol Sci 74:66-73|
|Muscarella, Donna E; Bloom, Stephen E (2002) Differential activation of the c-Jun N-terminal kinase pathway in arsenite-induced apoptosis and sensitization of chemically resistant compared to susceptible B-lymphoma cell lines. Toxicol Sci 68:82-92|