Activation of Ki-ras During Transplacental Carcinogenesis

EPA Grant Number: R829428
Title: Activation of Ki-ras During Transplacental Carcinogenesis
Investigators: Miller, Mark Steven
Current Investigators: Miller, Mark Steven , Cline, J. Mark , Kock, Nancy D. , Manderville, Richard A. , Ross, Jeffrey A. , Townsend, Alan J.
Institution: Wake Forest University School of Medicine, Winston-Salem, NC
Current Institution: Wake Forest University School of Medicine, Winston-Salem, NC , U. S. Environmental Protection Agency
EPA Project Officer: Deener, Kacee
Project Period: October 1, 2001 through September 30, 2004 (Extended to September 30, 2005)
Project Amount: $902,111
RFA: Children's Vulnerability to Toxic Substances in the Environment (2001) RFA Text |  Recipients Lists
Research Category: Children's Health , Health Effects , Human Health , Health

Description:

Our main hypothesis is that organ- and strain-specific differences in the levels of toxicant metabolism and/or DNA repair determine the relative susceptibility of the developing organism to genetic damage that leads to the initiation of cancer. Several studies have shown that the developing organism is very sensitive to chemical and physical carcinogens, suggesting that exposure of pregnant women to environmental toxicants may place the embryo and fetus at higher risk for the induction of cancer. Despite this higher sensitivity and increased vulnerability, few studies have examined the mechanisms of cancer causation and toxic responses to environmental chemicals during gestation. This application thus proposes to elucidate the biochemical and molecular mechanisms that determine oncogenic damage and modulate susceptibility to chemical carcinogens during the sensitive period of fetal development.

Approach:

We will first determine the levels of Phase I and Phase II enzyme activity in fetal tissues and their effects on the metabolism of MC in different strains of mice and F1 crosses between these mice. We will also assess DNA adducts levels and the rate of DNA repair to determine if differences in metabolism result in differences in adduct levels or whether the differences in mutational spectrum are the result of differences in DNA repair activity. Finally, the consequences of these differences in metabolism and/or DNA repair will be assessed in a carcinogenicity bioassay that will determine the types of mutations induced in the Ki-ras oncogene.

Expected Results:

We anticipate that our studies will demonstrate that a combination of alterations in the activation of MC by Phase I enzymes, detoxification of reactive MC metabolites by Phase II enzymes, and repair of DNA adducts by DNA repair enzymes will be important determinants of the amount and types of damage at the Ki-ras gene locus. We also expect that the observed strain- and organ-specific differences in the mutational spectrum of Ki-ras mutations will be related to the levels of drug metabolic enzymes and possibly to polymorphic variants of these enzymes in the two strains of mice to be examined. Identification of these differences in metabolism of MC, repair of DNA adducts, and the consequences for cancer initiation and mutations at Ki-ras can be used to assess how humans may respond to toxic chemicals with particular genetic complements of high or low activity forms of these enzymes.

Publications and Presentations:

Publications have been submitted on this project: View all 13 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 4 journal articles for this project

Supplemental Keywords:

carcinogen, fetus, vulnerability, susceptibility, metabolism, genetic predisposition, health effects., RFA, Health, Scientific Discipline, Toxicology, Genetics, Health Risk Assessment, Susceptibility/Sensitive Population/Genetic Susceptibility, Children's Health, genetic susceptability, Molecular Biology/Genetics, cancer risk, health effects, sensitive populations, Ki-ras , carcinogenesis, childhood cancer, exposure, genetic predisposition, lead, children, fetus, cancer risks, carcinogens, susceptibility, children's vulnerablity, susceptability, carcinogen, human susceptibility, transplacental carcinogenesis, pregnancy, oncogenes, Ki-ras, toxics, maternal exposure

Progress and Final Reports:

2002 Progress Report
2003 Progress Report
2004 Progress Report
Final Report