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Title:   Author  item
                                            VOGEL, CHRISTOPH FRANZ - UCD, ENVIRON.TOXICOL.item
                                            LI, WEN - UCD, ENVIRON. TOXICOL.item
                                            SCIULLO, ERIC - UCD, ENVIRON. TOXICOL.item
                                            Newman, Johnitem
                                            HAMMOCK, BRUCE - UCD, ENTOMOLOGYitem
                                            READER, RACHEAL - UCD, ENTOMOLOGYitem
                                            TUSCANO, JOSEPH - UCD, CANCER CNT. ONCOL.item
                                            MATSUMURA, FUMIO - UCD, ENVIRON, TOXICOL.
  Submitted to: American Journal of Pathology
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 6/29/2007
                                    Publication  Date: 11/1/2007
                                    Citation: Vogel, C., Li, W., Sciullo, E., Newman, J.W., Hammock, B., Reader, R.J., Tuscano, J., Matsumura, F. Pathogenesis of aryl hydrocarbon receptor-mediated development of lymphoma is associated with increased cyclooxygense-2 expression. 2007. American Journal of Pathology. Vol.171, No.5;1538-1548.Interpretive Summary: Lymphoma and leukemia can result from exposure to environmental pollutants. In this study, we have found that one such pollutant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in loss of programmed cell death (apoptosis) response in three different lymphoma cell lines.  The loss of apoptotic control plays a key role in the development of cancer, especially lymphoma and leukemkia. The TCDD-mediated defect is elicited through interactions with the nuclear receptor known as the aryl-hydrocarbon receptor (AhR). The AhR-mediated inhibition of apoptosis in vitro is associated with a clear increase of cyclooxygenase-2 (COX-2) and deregulation of genes of the B cell lymphoma-2 (Bcl-2) family involved in apoptosis including Bcl-xl and Mcl-1. Treatment with either a COX-2 inhibitor or an AhR antagonist abolished the TCDD-induced resistance of apoptosis in vitro. Furthermore, using micro positron emission tomography (PET) imaging in vivo demonstrated that exposure to TCDD promoted the development of lymphoma in superficial lymph nodes of C57BL/10J mice, which is associated with a marked increase of COX-2 expression (up to 20-fold) in the affected lymph nodes. These results indicate that activation of AhR and COX-2 over-expression likely represent a mechanism of resistance to apoptosis in lymphoma cell lines that might be relevant for the development of lymphoma in vivo.
                                Technical Abstract: Epidemiological studies indicate that exposure to environmental pollutants like pesticides and dioxins lead to the pathogenesis of lymphoma and leukemia. Here we show that activation of the Aryl-hydrocarbon-Receptor (AhR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in loss of programmed cell death (apoptosis) response in three different lymphoma cell lines, which plays a key role in the development of cancer especially lymphoma and leukemkia. The AhR-mediated inhibition of apoptosis in vitro is associated with a clear increase of cyclooxygenase-2 (COX-2) and deregulation of genes of the B cell lymphoma-2 (Bcl-2) family involved in apoptosis including Bcl-xl and Mcl-1 in several lymphoma cell lines. Treatment with the COX-2 inhibitor NS-398 and the AhR antagonist MNF abolished the TCDD-induced resistance of apoptosis in vitro. Furthermore, using micro positron emission tomography (PET) imaging in vivo findings demonstrate that exposure to TCDD promotes the development of lymphoma in superficial lymph nodes of C57BL/10J mice, which is associated with a marked increase of COX-2 expression (up to 20-fold) in the affected lymph nodes. The results indicate that activation of AhR and COX-2 over-expression likely represent a mechanism of resistance to apoptosis in lymphoma cell lines that might be relevant for the development of lymphoma in vivo.


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