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Extramural Research

Mechanism of Non-genotoxic Occupational Carcinogens

EPA Grant Number: R828083
Title: Mechanism of Non-genotoxic Occupational Carcinogens
Investigators: Pereira, Michael A.
Institution: Medical College of Ohio
EPA Project Officer: Deener, Kacee
Project Period: April 20, 2000 through April 19, 2003
Project Amount: $834,714
RFA: Mechanistic-Based Cancer Risk Assessment Methods (1999)
Research Category: Health Effects , Human Health

Description:

Understanding the mechanism of carcinogens present in the workplace and the environment has become increasingly important because of the use of mechanism-based approaches to extrapolate results from laboratory animals to humans. There is great uncertainty in interspecies extrapolation because the dose levels used in animal studies are usually much greater than doses resulting from human exposure. High dose levels are required in animal carcinogenesis studies because of the low sensitivity of the bioassay. The uncertainty in the extrapolation is especially great for non-genotoxic carcinogens. This is because non-genotoxic carcinogens are likely to have dose-response curve that are not linear and that include a threshold. Furthermore, they could induce cancer in animals by a mechanism that is not applicable to humans. Knowledge of the mechanism of these carcinogens allows the development of molecular and biological markers for their activity. One of these biomarkers is the hypomethylation of DNA and protooncogenes. Biomarkers could be used to determine whether the mechanism applies to humans and to better define the dose-response relationship extending it to exposures/dose levels not applicable to carcinogenesis bioassay. Lung and mouse liver non-genotoxic carcinogens will be investigated, since the lung is a major site of occupational-related cancer and mouse liver is a major target organ in carcinogenesis bioassays.

The hypothesis to be tested is that non-genotoxic carcinogens induce cancer by increasing cell proliferation and then decreasing the methylation of the newly synthesized DNA, i.e. 5-methylcytosine (5-MeC). Increased cell proliferation is required to form the hemimethylated DNA requiring methylation. Furthermore, it is hypothesized that the 5-MeC content of DNA is decreased by either reducing the availability of S-adenosyl-l-methionine (SAM) for DNA methylation or by blocking DNA methyltransferase. Specific Aim 1 will evaluate mouse liver and lung non-genotoxic carcinogens including arsenic, chloroprene, dichloroacetic acid, methylene chloride, and tetrachloroethylene for the ability to decrease the methylation of protooncogenes. Specific Aim 2 will determine the mechanism for the decreased methylation of protooncogenes. Specific Aim 3 will demonstrate that an agent that prevents or reverses the hypomethylation of DNA prevents the induction of tumors supporting the importance of DNA hypomethylation to carcinogenic activity.

Approach:

The ability of arsenic, chloroprene, dichloroacetic acid, methylene chloride, and tetrachloroethylene to induce hypomethylation of the c-myc protooncogene will be determined in mouse liver and lung. Tetrachloroethylene and arsenic and its methylated metabolites will be administered by gavage, chloroprene and methylene chloride will be administered by inhalation and dichloroacetic acid will be administered in the drinking water and at times by gavage. The mice will be sacrificed and the methylation of the promoter region of the c-myc gene determined. Various dose levels including a non-active dose of the carcinogens will be evaluated. The effect of the carcinogens on the level of SAM and cell proliferation will also be determined in order to understand the mechanism for hypomethylation. In some studies methionine will be administered 30 minutes after the carcinogen to determine whether it prevents the hypomethylation. It is expected that methionine will prevent hypomethylation by increasing the concentration of SAM. Should methionine prevent the hypomethylation, we will determine whether it also prevents carcinogenic activity.

Expected Results:

The expected results of this project should better the understanding of the mechanism of non-genotoxic carcinogens, specifically the involvement of increased cell proliferation and decreased DNA methylation. Using the ability to induce DNA hypomethylation as a biomarker, the dose response relationship of the carcinogens will be determined and extended to dose levels below those applicable in carcinogenesis bioassays. This should decrease the uncertainty in the extrapolation of results from animal carcinogenesis bioassays using high dose levels to the carcinogenic efficacy of more environmentally relevant dose levels.

Publications and Presentations:

Publications have been submitted on this project: View all 5 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 3 journal articles for this project

Supplemental Keywords:

Arsenic, chloroprene, dichloroacetic acid, methylene chloride, tetrachloroethylene, mouse liver carcinogens, mouse lung carcinogens, DNA hypomethylation, cell proliferation and dose-response., RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Water, POLLUTANTS/TOXICS, HUMAN HEALTH, Environmental Chemistry, Health Risk Assessment, Exposure, Arsenic, Risk Assessments, Biochemistry, Physical Processes, Water Pollutants, cancer risk, risk factors, cell biology, dose response, occupational safety and health, carcinogens, arsenic exposure, bioassay data, cancer risk assessment, dietary exposure, molecular biology

Progress and Final Reports:
2000 Progress Report
2001 Progress Report
Final Report

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The 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.

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