Grantee Research Project Results
2002 Progress Report: Activation of Ki-ras During Transplacental Carcinogenesis
EPA Grant Number: R829428Title: Activation of Ki-ras During Transplacental Carcinogenesis
Investigators: Miller, Mark Steven , Ross, Jeffrey A. , Manderville, Richard A. , Townsend, Alan J. , Cline, J. Mark
Current Investigators: Miller, Mark Steven , Cline, J. Mark , Manderville, Richard A. , Ross, Jeffrey A. , Townsend, Alan J. , Kock, Nancy D.
Institution: Wake Forest University School of Medicine
Current Institution: Wake Forest University School of Medicine , U. S. Environmental Protection Agency
EPA Project Officer: Aja, Hayley
Project Period: October 1, 2001 through September 30, 2004 (Extended to September 30, 2005)
Project Period Covered by this Report: October 1, 2001 through September 30, 2002
Project Amount: $902,111
RFA: Children's Vulnerability to Toxic Substances in the Environment (2001) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
Objective:
The overall objective of this research project is to elucidate the biochemical and molecular mechanisms that determine oncogenic damage and modulate susceptibility to chemical carcinogens during the sensitive period of fetal development. Organ- and strain-specific differences in the levels of toxicant metabolism and/or DNA repair may 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.
Progress Summary:
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 development of cancer because of their increased vulnerability. Our laboratory has shown that treatment of pregnant mice with 3-methylcholanthrene (MC) results in the formation of lung and liver tumors in the offspring 1 year after birth. The types of Ki-ras mutations induced in the lung tumors correlated with the histological stage of the tumors, suggesting that different Ki-ras mutations have different oncogenic potential. In addition, both strain- and organ-specific differences in the Ki-ras mutational spectrum were observed. We propose to elucidate the biochemical and molecular mechanisms that determine oncogenic damage and modulate susceptibility to chemical carcinogens during the sensitive period of fetal development. Because the observed differences in the Ki-ras mutational spectrum may be due to differences in the metabolic activation/detoxification of MC, our first specific objective is to determine the levels of CYP and glutathione S-transferases in fetal tissues and their effects on the metabolism of MC in strains of mice and F1 crosses that exhibit different mutational spectra at Ki-ras following in utero exposure to MC. Our second specific objective is to assess DNA adduct 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 Ki-ras in these strains of mice, F1 crosses between the two strains, and in an Ah receptor knockout mouse strain. These studies will provide critical information on the interaction between genetic and environmental factors in modulating susceptibility to tumor initiation in the developing organism following exposure to environmental carcinogens.
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 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.
Future Activities:
Future activities will continue to elucidate the biochemical and molecular mechanisms that determine oncogenic damage and modulate susceptibility to chemical carcinogens during the sensitive period of fetal development.
Journal Articles:
No journal articles submitted with this report: View all 13 publications for this projectSupplemental 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, Molecular Biology/Genetics, genetic susceptability, cancer risk, Ki-ras , health effects, sensitive populations, carcinogenesis, childhood cancer, lead, genetic predisposition, exposure, fetus, children, susceptibility, carcinogens, children's vulnerablity, cancer risks, carcinogen, transplacental carcinogenesis, susceptability, human susceptibility, Ki-ras, pregnancy, oncogenes, environmental hazard exposures, maternal exposureRelevant Websites:
http://www.wfubmc.edu/canbio/msmiller.htm Exit
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.