The chlorinated dibenzo-p-dioxins have received considerable attention as environmental containments due to numerous accidental poisonings to human and non-human animal populations, their extreme toxic potency in laboratory animals, and their carcinogenic potential. Furthermore, the recognition that these compounds act via the Ah receptor to modulate gene expression, cellular proliferation, and differentiation, has stimulated their use, especially of, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), as probes for our further understanding of cellular regulatory processes. The overall objective of the research described in this proposal is to better understand the molecular and cellular events that lead to the suppression of animals to TCDD. In contrast to most other species-specific signs of TCDD-elicited toxicity, thymic atrophy and immune suppression are consistently observed in a variety of mammalian species. Whereas TCDD exposure affects both cell-mediated and humoral immunity in the adult animal, cell-mediated processes appear to be more sensitive when exposure occurs during the perinatal period. The kinetics of thymocyte depletion will be defined in perinatal mice following a single maternal dose of TCDD. These studies combined with cross-fostering and genetic experiments will define the relative effects of TCDD exposure in utero vs. that from maternal milk and determine if the fetal-neonatal effects observed are due to direct maternal or fetal effects. Radioisotopes will be used to determine the accumulation and/or loss of TCDD by the thymus. By an examination of the content and expression of mRNA for the stem cell marker, terminal deoxynucleotidyl transferase, alterations in the thymocyte and bone marrow stem cell populations will be determined. Through a combination of in vitro and in vitro systems designed to examine the developmental pattern of pre-T and pre-B cells, we will determine if TCDD has a selective effect on specific classes of stem cells and if the effect may be on the stem cells or the bone marrow microenvironment. An analysis of specific cell surface antigens by the use of fluorescent antibodies and flow cytometry will be performed to determine if the distribution of thymocyte subpopulations is altered by TCDD exposure. The expression of genes which determine T-cell functionally will also be examined. The studies will focus on the T-cell Receptor (TcR) and the functionally linked molecule CD3.
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