ONCOGENES AND TRANSPLACENTAL CARCINOGENESIS

胎儿组织对化学和物理的影响更敏感

Fetal tissues are more sensitive to the effects of chemical and physical carcinogens than are adult tissues. This suggests that the embryos and fetuses of pregnant women are at a greater risk of developing cancers from environmental exposures than is the adult population. It is thus important to gain further understanding of the mechanism(s) that help modulate the fetal organism's response to environmental toxicants, and to determine how the genetic background of the individual fetus can modulate its response to environmental carcinogens. The goal of this research will be to determine the molecular mechanisms governing the pathogenesis of lung tumors in mice differing in their susceptibility to polycyclic hydrocarbon-mediated tumor formation. Bioassays will determine the lung tumor yield following transplacental exposure to 3-methylcholanthrene in mice differing in their inducibility for CYPIA1, which will allow the tumor incidence to be correlated with the metabolic phenotype of the fetus. By analysis of oncogene RNA expression levels and examination of selected oncogenic loci for mutations by the highly sensitive polymerase chain reaction technique, particular patterns of oncogene over/under- expression and/or mutation can be established in the tumor models. It will be particularly interesting to determine whether differences in the metabolic capacity of the fetus toward 3-methylcholanthrene result in differences in the mutational spectrum at the molecular level, possibly as a result of damage occurring to different segments of the same gene or mutations occurring at different genetic loci . This project offers an unique opportunity to demonstrate the important role played by both genetic and environmental factors in determining the susceptibility of the individual to the induction of lung tumors. The data will show how the genetic make-up of the individual can influence susceptibility to cancer as a result of early in utero exposure to environmental chemicals.