The proposed research will assess the fetal hematopoietic toxicity of maternal exposure to the polyaromatic compounds beta- naphthoflavone (beta NF), 3-methylcholanthrene (MC), and 2, 3, 7, 8-tetrachloro-dibenzo-p-dioxin (TCDD). Experiments will evaluate the hypothesis that the fetotoxicity of this class of chemical is related to the induction of aryl hydrocarbon (AH) metabolism in fetal hematopoietic cells. The proposed research will study pregnant rats treated with fetotoxic doses of beta NF, MC, TCDD with the following objectives: 1) Determined whether feta blood has altered numbers of red cells, white cells and platelets, or hemoglobin content; Investigate whether nucleated fetal red blood cells in the placenta are AH induced and whether erythroid progenitor cells are detectable. 2) Evaluate whether there are reductions in the numbers of fetal hematopoietic commited stem cells by assay of the colony forming abilities of the committed erythroid (BFU-E and CFU-E) and granulocyte-macrophage (CFU-GM) stem cells in the fetal liver. 3) Determine whether there are alterations in the production of fetal hematopoietic growth factors, erythropoietin (EPO) and granulocyte-macrophage colony stimulating factor (GM-CSF); Investigate whether there are changes in responses of fetal hematopoietic stem cells to their respective growth factors. 4) Determine whether DNA adducts are formed in vivo in hematopoietic cells in the fetal liver. If so, do adducts persist and is there a relationship with alterations in numbers of hematopoietic stem cells. 5) Determine whether in utero exposure results in permanent changes in the hematopoietic system by assay of peripheral blood counts and hemoglobin levels, as well as bone marrow stem cell populations in 1 and 6 week old progeny; Evaluate the ability of the erythroid stem cell population to respond to a hemolytic stress in these offspring. These studies will serve to provide basic information on the interaction of polyaromatic compounds with the developing hematopoietic system which will define mechanisms for both immediate and longlasting manifestations of toxicity during pre- and postnatal life.
