Fred Hutchinson Cancer Research Center, University of Washington join in national effort to study health impact of toxic substances

November 06, 2001

SEATTLE - The Fred Hutchinson Cancer Research Center, in collaboration with the University of Washington, has been selected to participate in a federally funded, $37 million research consortium to study how individual genetic makeup affects one's response to various environmental agents, from asbestos to tobacco smoke. Such research will help answer puzzling questions such as why some people who have never smoked a cigarette develop lung cancer, while others who have smoked heavily for years never show signs of the disease. The Hutchinson Center/UW Toxicogenomics Consortium, part of a research collective involving a handful of academic institutions nationwide, will receive more than $7 million in funding over five years from the National Institute of Environmental Health Sciences, or NIEHS, headquartered in Research Triangle Park, N.C.

Each member of the NIEHS Toxicogenomics Research Consortium brings its own area of expertise, but collectively the group will use the tools of genomics to obtain a fundamental understanding, on a genome-wide scale, of the mechanisms of environmentally induced disease processes. Researchers will attempt to better understand how disease occurs; how to identify potential environmental hazards; how to predict potential disease; how to identify exposed individuals; and how to prevent disease.

The long-range goal of the Hutchinson Center/UW partnership is to shed light on genetic differences that make some people more sensitive than others to various environmental exposures. The Seattle-based consortium will exploit the combined strengths of the Hutchinson Center and University of Washington in DNA-microarray technology - the use of so called "gene chips" to monitor the expression of thousands of genes at once - and the UW's long-standing expertise in toxicology and environmental-health sciences. The principal investigator of the Seattle consortium, an expert in both environmental sciences and DNA-array technology, is Helmut Zarbl, Ph.D., member of the Hutchinson Center's Human Biology and Public Health Sciences divisions. His work focuses on using DNA-array technology to determine whether particular genes are sensitive to the actions of chemical toxicants and how these genes are involved in cancer development. Genes that are sensitive to a particular toxic substance can be identified by an increase or decrease in their expression level after exposure.

"The ultimate goal is to predict an individual's risk of cancer based on their genetic profile and environmental exposures," said Zarbl, also an associate professor of pathology and toxicology at UW.

"If a person carries a combination of genes that puts them at higher risk with a particular environmental exposure, then we may be able to develop methods of intervention such as dietary modifications, chemopreventive agents or drugs to counter the effects of exposure," he said. "Or, among individuals we identify as highly susceptible, we may give them information on the types of occupations they should avoid, for example, or the types of exposures to which they may be particularly sensitive." Co-principal investigator of the consortium is David Eaton, Ph.D., director of the NIEHS-funded UW Center for Ecogenetics and Environmental Health.

"Many chronic diseases - such as most cancers, Parkinson's disease and Alzheimer's disease - are caused by complex interactions between genetics and the exposures to factors in our environment," said Eaton, a professor of environmental health and associate dean for research in the UW School of Public Health and Community Medicine.

"For example, recent research has shown that genetic factors alone account for only 20 to 40 percent of our risks for developing some form of cancer. Factors in our environment, such as diet, smoking and chemical pollutants, interact with our genetics to account for the other 60 to 80 percent of risk.

"The work of the Hutchinson Center/UW Toxicogenomics Consortium can help us better understand genetic differences that make some people more sensitive to environmental exposures." The consortium's four laboratory-based projects will focus on the effects of various toxic substances on breast-cancer development, how exposures to certain pesticides may affect behavior in children, environmental factors that may harm the developing nervous system, and the development of laboratory tests that can replace animal testing.

Below are brief descriptions of each project:

Project 1: Many environmental factors can harm the development of the nervous system in infants before and after birth. These factors can include exposure to metals such as methyl mercury, nutritional changes, and physical factors such as hyperthermia (exposure to excessive heat, which can occur if a pregnant woman experiences a high fever). Adverse neurodevelopmental effects of exposures can range from behavioral changes to major birth defects such as spina bifida. The goal of this project is to use genomic approaches to improve the understanding of how environmental factors can damage the developing nervous system and so improve our ability to identify and prevent birth defects. (Project leaders: Elaine Faustman, Ph.D., professor of environmental health, UW; Philip Mirkes, Ph.D., research professor of pediatrics, UW.)

Project 2: The goal of this project is to gain a better understanding of how exposures to certain pesticides can affect the behavior of children. The researchers are focusing on the HDL-associated plasma enzyme paraoxonase, which provides protection from the effects of exposures to some organophosphates, a group of chemicals that includes the pesticides chlorpyrifos and diazinon. Children produce very little paraoxonase enzyme until they are about a year old, and so are extremely vulnerable to these chemical exposures. (Project leaders: Clement Furlong, Ph.D., research professor of medical genetics, UW; Lucio Costa, Ph.D., professor of environmental health, UW.)

Project 3: This project aims to develop tests for toxic exposure and stress responses using liver cells cultured in the laboratory. Because the liver processes nearly all chemicals that enter the body, the expression of genes in liver cells could predict how a given exposure would affect one's health. To see if their cell-culture systems accurately model the toxic effects of chemical exposures, the researchers will compare the results of tests using cultured cells to those using rodents. One of their ultimate goals is to develop laboratory tests that can replace animal testing. (Project leader: Curtis Omiecinski, Ph.D., professor of environmental health, UW.)

Project 4: This project will use DNA-microarray technology to map and identify genes that influence susceptibility to environmental toxins that cause breast cancer. Relatively few women diagnosed with breast cancer - between 5 percent and 10 percent - carry BRCA1 and BRCA2, the so-called "breast-cancer genes" that have been linked to an inherited form of the disease. However, up to half of all women are believed to carry genetic mutations that may make them susceptible to various environmental exposures linked with breast-cancer growth. Researchers hope that by identifying such genes in rats - and ultimately, humans - they'll better understand how to identify sensitivity to environmental breast-cancer risk factors in the majority of women. (Project leader: Helmut Zarbl, Ph.D., member of the Hutchinson Center's Human Biology and Public Health Sciences divisions and principal investigator of the Hutchinson Center/UW Toxicogenomics Consortium.) Each research project is supported by an infrastructure of technology cores that will provide a range of materials and services. A tissue-acquisition core, directed by UW pathology professor Peter Rabinovitch, M.D., Ph.D., will provide access to genetically defined tissues and cell cultures. A DNA-expression array core, led by Zarbl, will compare the molecular fingerprints of cells exposed to different doses of environmental agents.

Another important strength of the consortium is the combined Hutchinson Center/UW expertise in bioinformatics and statistics, which will be key in analyzing data that ultimately will contribute to a national microarray gene-expression database. The consortium's bioinformatics core will be co-directed by Steven Self, Ph.D., member of the Hutchinson Center's Public Health Sciences Division; and Roger Bumgarner, Ph.D., director of the UW Center for Expression Arrays and research assistant professor in the Department of Microbiology.

A toxicology core, directed by Terry Kavanagh, Ph.D., associate professor of environmental health at UW, will coordinate the development of standardized methodologies in expression-array analysis to be used across the national consortium's participating universities as well as the NIEHS.

Other academic institutions participating in the NIEHS Toxicogenomics Research Consortium are the University of North Carolina at Chapel Hill; Oregon Health and Science University in Portland; Duke University in Durham, N.C.; and the Massachusetts Institute of Technology in Cambridge.

"We know that we can stretch the research dollar by having scientists at NIEHS and grantees at universities work in concert," said Kenneth Olden, Ph.D., director of NIEHS. "But perhaps more important, we know that bringing ideas together in science increases the advances we achieve."
-end-
Editor's note: For more information about the NIEHS Toxicogenomics Research Consortium and the National Center for Toxicogenomics, please contact Tom Hawkins at (919) 541-1402 or visit the NIEHS Web site at http://www.niehs.nih.gov/oc/news/home.htm

ABOUT THE FRED HUTCHINSON CANCER RESEARCH CENTER

The Fred Hutchinson Cancer Research Center, home of two Nobel Prize laureates, is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Recognized internationally for its pioneering work in bone-marrow transplantation, the Center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. The Hutchinson Center is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest. For more information, visit the Hutchinson Center's Web site at www.fhcrc.org. Advancing Knowledge, Saving Lives

ABOUT THE UNIVERSITY OF WASHINGTON

The University of Washington's faculty includes five Nobel Prize winners, five MacArthur Fellows and 40 members of the prestigious National Academy of Sciences. Since 1975, the UW has been the nation's top public university in receipt of federal research funds, and since 1992 it has been second among all U.S. universities, public and private. For more information, visit the University's Web site at www.washington.edu.

Fred Hutchinson Cancer Research Center

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