2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most potent immunosuppressive agents known. Humans are exposed to low levels of this and related chemicals on a daily basis. Although the effects on the human immune system are not known, in experimental animals TCDD produces biological and toxic effects by binding to a gene regulatory protein, the Ah receptor (AhR), to inappropriately modulate gene expression, The exact mechanisms responsible for induced immunotoxicity are not known. A major obstacle has been the lack of understanding of the actual primary cell targets. It is hypothesized that stem and/or progenitor cells in the bone marrow and thymus are direct targets for TCDD, that developmental arrest contributes to elicited toxicity, and that TCDD, via the AhR, alters signaling events in these cells at critical stages of differentiation. Using flow cytometry, the hematopoietic developmental stage that is affected by TCDD in mice will be precisely determined. The presence and activity of the AhR with these cells will be determined at different stages of hematopoiesis. Analysis of cell cycle and proliferation rates will determine whether TCDD causes arrest development or programmed cell death. Using established culture systems, it will be determined whether TCDD can directly affect these cells under conditions in vitro. There are several candidate genes whose activities are critical at certain stages of stem/progenitor cell development. Once the precise cell targets in bone marrow and thymus have been determined, real time PCR and low-density array approaches will be used to define the gene targets modulated by TCDD and associated with the toxic endpoints elicited. Finally, recent data has suggested a role of the AhR in normal development of the immune system. Further studies examining phenotypic alterations and patterns of stem cell commitment in AhR null allele cells will further define a putative role of the AhR. ? ?
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