ROLE OF CHROMOSOME ALTERATIONS IN ENVIRONMENTAL CARCINOGENESIS
Project Information
Funding Information
| Country | USA |
| Anticipated Total Funding | n/a |
| Annual Funding | n/a |
| Funding Source | USDA |
| Funding Mechanism | |
| Funding Sector | |
| Start Year | 2006 |
| Anticipated End Year | 2011 |
Abstract/Summary
NON-TECHNICAL SUMMARY: The widespread use of synthetic chemicals for both agricultural and industrial applications has created significant concern about the potential effects of these agents on human health and the environment. For the majority of these chemicals, relatively little information is available concerning the possible adverse effects associated with human exposure. The purpose of this project is to identify chromosome-damaging environmental and agricultural agents, and to determine the mechanisms underlying their genotoxic and cancer-inducing effects. This information will allow the human health risks associated with exposure to these agents to be more accurately evaluated. OBJECTIVES: The objective of this proposal is extend our research on chromosomal alterations induced by environmental and agricultural chemicals to detect and characterize genetic damage occurring in cells in vitro, in animal models and in exposed human populations. A series of studies will be conducted focusing on agents exerting damage through direct and indirect genotoxic mechanisms. 1) Initial studies will focus on the development and application of techniques to detect cellular and genetic alterations in human and animal cells. 2) The next phase of this research will be to apply these techniques to detect genetic damage induced by selected environmental and model agents, and to conduct mechanistic studies to understand the mechanisms responsible for the observed genotoxic effects. 3) In the last phase, we will continue and extend our efforts to apply these techniques to detect chromosomal alterations in cells obtained from humans exposed to environmental chemicals or individuals at elevated risk for developing cancer. APPROACH: A series of studies will be conducted using conventional and molecular cytogenetic approaches to identify genotoxic agents. The three phases are: 1) Initial studies will focus on the continued development and application of techniques to detect cellular and genetic alterations in human and animal cells. 2) The next phase of this research will be to apply these techniques to detect genetic damage induced by selected environmental and model agents, and to conduct mechanistic studies to understand the mechanisms responsible for the observed genotoxic effects. 3) In the last phase, we will continue and extend our efforts to apply these techniques to detect chromosomal alterations in cells obtained from humans exposed to environmental chemicals or individuals at elevated risk for developing cancer. We propose to extend our earlier studies to demonstrate the feasibility of utilizing fluorescence in situ hybridization and related techniques to detect chromosomal alterations in various rat and mouse tissues. We also plan to determine the feasibility measuring DNA damage-responding proteins within cells as a screen for detecting clastogenic and aneugenic agents. We proposed to build upon our in vitro work using proliferating human cells to explore the use this technique to detect chromosomal damage in resting (Go) cells in vitro, and in resting and dividing cells in rodents exposed to model and environmental agents in vivo. We propose to continue our in vitro and in vivo studies of benzene and o-phenylphenol (OPP), two widely used environmental carcinogens. We propose to perform these types of tests on other agents of current concern such as carbon nanotubes, propoxur metabolites, mosquito coil-releasing pesticides or related products. Studies specifically focusing on the mechanisms underlying the observed toxic and genotoxic effects will also be performed. For studies on benzene, we propose to continue our studies on the potential role of inhibition of topoisomerase II in the toxicity and clastogenicity of this agent. For OPP, we propose to investigate the role of a prostaglandin[H]synthase in the bioactivation of the OPP metabolite phenylhydroquinone in the rat bladder. We propose to continue our studies using FISH and conventional cytogenetic approaches to determine frequency of alterations in cells obtained from exposed human populations. These studies will be initiated as opportunities arise. Using the results from our previous studies, we propose to look for associations between polymorphisms in genes involved in xenobiotic metabolism and DNA repair and frequencies of chromosome breakage and aneuploidy. This should provide additional insights into individuals at risk for chromosomal damage as well as provide insights into the mechanisms underlying the genotoxic effects. As an extension of our biomonitoring studies, we also plan to continue our studies to determine if these FISH techniques can be used to identify individuals at elevated risk of developing cancer and improve cancer diagnosis. We believe that these more clinical studies will also provide mechanistic insights into the development of specific cancers.
