Risk Assessment for candidate environmental carcinogens is a complex, lengthy, expensive process. Testing of individual candidate carcinogens in rodent two year bioassays is a critical component of risk assessment. Often, however, this time consuming and expensive assay can produce equivocal results and the data obtained provide few clues into the mechanisms of enhanced carcinogen-induced tumorigenesis. The derivation of new rodent compounds is an imperative. Moreover, increased understanding of the mechanistic basis by which carcinogens induce tumors will provide important new information for consideration in risk assessment decisions. The primary goal of this proposal is to develop and characterize new mouse models to provide faster and more informative assay systems for those involved in screening and evaluating potential environmental carcinogens.
Three specific aims have been outlined: (1) to develop new models for measuring mitotic recombination in the somatic and tumor tissues of mice; (2) to further characterize and validate the p53 heterozygous mouse as a carcinogen testing model; and (3) to develop multiple lines of tissue- specific p53-deficient mice. Some of the hypotheses that will be addressed are: (1) the ability of a carcinogenic compound to induce to induce mitotic recombination as well as point mutations is a major component of the carcinogenic potential; (2) the genes p53, MSH2, and BRCA2 have, as a component of their tumor suppressor function, the ability to suppress mitotic recombination in somatic tissues and during tumorigenesis; and (3) the p53 heterozygous mouse is an effective model for testing genotoxic carcinogens because the carcinogens target the same genes is a wild type mice, and the resulting tumors arise sooner.
| Adams, Melissa M; Wang, Bin; Xia, Zhenfang et al. (2005) 53BP1 oligomerization is independent of its methylation by PRMT1. Cell Cycle 4:1854-61 |
