Grantee Research Project Results

2003 Progress Report: Activation of Ki-ras During Transplacental Carcinogenesis

EPA Grant Number: R829428
Title: 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
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, 2002 through September 30, 2003
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 main goal of this research 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. Several studies have shown that the developing organism is very sensitive to chemical and physical carcinogens, suggesting that the exposure of pregnant women to environmental toxicants may place the embryo and fetus at a 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. 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.

Progress Summary:

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. We identified both strain- and organ-specific differences in the Ki-ras mutational spectrum in lung and liver tumors induced by in utero exposure to MC. Thus, 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.

During the past project year, we compared the effects of in utero treatment with MC on lung tumor formation in the offspring of intermediately susceptible Balb/c (Bc) mice, resistant C57BL/6 (B6) mice, and reciprocal crosses between the two strains. Pregnant mice were treated with 45 mg/kg of MC on day 17 of gestation. Tumor incidence, multiplicity, and tumor size were determined in the offspring 14-18 months after birth. Bc, B6Bc, and BcB6 mice exhibited a 100-percent tumor incidence, whereas the resistant B6 mice had an incidence of 5.3 percent. B6 mice exhibited one small nodule 18 months after birth, whereas Bc mice rarely survived beyond 14 months, and BcB6 mice survived to approximately 16 months. Counting only discrete lesions, tumor multiplicities in Balb, B6Bc, BcB6, and B6 mice were 7.7±2.9, 5.5±3.3, 6.0±3.0, and less than 0.1, respectively. These results suggest that, similar to adults, crosses between susceptible and resistant strains result in a susceptible phenotype for lung cancer. Currently, we are examining differences in MC metabolism, DNA adduct levels and repair, and mutations in Ki-ras as possible mechanistic factors mediating strain susceptibility to lung carcinogens. These studies highlight the important interactions between genetic and environmental factors in determining individual susceptibility to environmental toxicants during development.

Future Activities:

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 an important determinant 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 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.

Journal Articles:

No journal articles submitted with this report: View all 13 publications for this project

Supplemental Keywords:

carcinogen, fetus, vulnerability, susceptibility, metabolism, genetic predisposition, health effects, embryo, Ki-ras, 3-methylcholanthrene, MC, toxicant, DNA., Health, RFA, Scientific Discipline, Susceptibility/Sensitive Population/Genetic Susceptibility, Health Risk Assessment, genetic susceptability, Molecular Biology/Genetics, Children's Health, Toxicology, cancer risk, Genetics, carcinogens, transplacental carcinogenesis, health effects, genetic predisposition, environmental hazard exposures, sensitive populations, carcinogen, fetus, maternal exposure, pregnancy, lead, susceptibility, carcinogenesis, cancer risks, childhood cancer, oncogenes, Ki-ras, children, exposure, children's vulnerablity, toxics, human susceptibility, Ki-ras

Relevant Websites:

http://www.wfubmc.edu/canbio/msmiller.htm Exit

Progress and Final Reports:

Original Abstract

2002 Progress Report

2004 Progress Report

Final Report