The objectives of this project are twofold. The first is to identify and characterize those aspects of morphogenetic differentiation that modify the consequences of prenatal exposure to chemical carcinogens, especially in the nervous and genitourinary systems. The ultimate objective is to elucidate the control of expression of the neoplastic phenotype in transformed cells. The second objective is to devise and apply improved quantitative selective mutation systems to embryonal and fetal primary cells in culture from donors previously treated in utero with chemical carcinogens; to determine the time course of maximum sensitivity to induced gene mutation of cells from embryos or fetuses transplacentally exposed to carcinogens at different stages of gestation to determine quantitative dose curves for transplacentally induced gene mutation by selected carcinogens; to determine the sensitivity of various species to metabolism-independent transplacental chemical carcinogens and to determine inter- and intra-litter variations in response to chemical carcinogens; to determine the organ specificity in various species of gene mutations transplacentally induced by selected carcinogens; to apply in vitro transformation assays to cells isolated from embryos of different species treated transplacentally with chemical carcinogens; and to correlate the above quantitatively determined in vitro parameters with transplacental tumorigenesis data. A major achievement during this year has been to establish that epithelial differentiation in the mammalian permanent kidney is mediated by a soluble protein factor, and to make progress toward its purification and characterization.
