The development of cancer is a complex multistage process that involves a series of genetic and epigenetic changes. Studies on gene-environment interactions have generally focused on events occurring after puberty. However, prenatal exposure to chemicals can result in structural or functional abnormalities that are evident at birth. There is now an increasing awareness that chemicals may also induce more subtle changes in utero that may not be manifest until adulthood. Changes in gene expression and/or mutations resulting from fetal and neonatal exposures may increase the mutational load and risk of adult cancer. Maternal transfer of genotoxic carcinogens such as 4-aminobiphenyl (4ABP) can result in fetal or neonatal DNA adducts in liver. The long-term effects of this exposure are unknown. The hypothesis to be tested is that fetal/neonatal exposure to 4ABP results in mutations in key genes that increase the risk of liver cancer after puberty. The proposed studies will utilize a mouse model.
The specific aims are: 1. to assess the persistence of hepatic 4ABP-DNA adducts; 2. to determine the role of p53 and p21 in hepatic responses to 4ABP-DNA damage; 3. to identify changes in hepatic expression of genes and proteins induced by a genotoxic dose of 4ABP; 4. to assess the ability of 4ABP to induce mutations; and 5. to evaluate pre- neoplastic changes in adult liver following fetal/neonatal exposure to 4ABP. Mice will be exposed pre and postnatally to 4ABP. Hepatic markers of apoptosis and cell proliferation will be determined. Levels of 4ABP- DNA adducts will be measured. Time dependent changes in expression of p53 and p21 will be determined in genetically engineered models. Expression of hepatic genes will be assessed by microarray analysis. Selected groups of genes functionally related to responses to DNA damage will be analyzed. In vivo mutations will be determined in transgenic mice. Adult mice exposed before or after birth to 4ABP will be given phenobarbital to promote initiated cells. Preneoplastic cells will be identified. The studies proposed in this application will provide insight into the genetic changes induced by exposure to the human carcinogen 4ABP before sexual maturity. Since tumors are characterized by an accumulation of genetic changes, increasing the mutational burden with exposures early in life has the potential to increase adult cancer risk. ? ? ?
