CIIT Spearheads Microarray Use In Toxicology

For scientists searching for new drugs, it offers an approach to screening many chemicals quickly to detect potential beneficial effects. For toxicologists it offers the opportunity to identify chemicals with potential for adverse effects and a greater understanding of how chemicals cause toxicity. For research budget directors it means saving time and money by avoiding repetitive assays for effects on individual genes.

In a microarray, copies of DNA, each from a separate gene, are printed on "platforms" which can be glass slides, silicon chips or nylon membranes. After exposure to a chemical, gene expression is assessed in a tissue sample by measuring the messenger RNA binding to the microarray. The messenger RNA has been tagged with fluorescent or radioactive components so it can be easily detected using specialized machines. Computer software is then used to analyze the huge data set.

The importance of the microarray as an analytical tool is immense. It not only speeds understanding of how chemicals alter the structure and function of the cell, but has been used to map mutations in genes involved in cancer and other diseases. This technique will be used extensively to map the difference in genetic makeup across the population as part of the Human Genome Project at the National Institute of Environmental Health Sciences (NIEHS). This may help in identifying sub-populations that are either susceptible or resistant to the effects of some chemicals.

Short-cuts for Toxicology

Microarrays can be used to develop a data base containing the "fingerprints" of chemicals with known toxic responses. If this data base is large enough, fingerprints of new chemicals could be compared to the data base and quickly categorized as to their effects. For researchers that would mean a major shortcut around the extensive battery of tests required to characterize the effects of a chemical.

Cooperation and Collaborations

CIIT is cooperating with others in exploring microarray uses. Dr. J. Christopher Corton, who uses microarrays to study the effects of chemicals on the liver, has provided leadership for launching the Triangle Microarray Users Group (TAUG) in the Research Triangle Park area. The Users Group provides a setting for exchanging ideas and experiences on using microarray techniques for different purposes. It includes scientists in disciplines from molecular biology to pathology to information science and statistics. Members include researchers from the U.S. EPA, NIEHS, Duke University, University of North Carolina at Chapel Hill, North Carolina State University, and a variety of private labs. Also, CIIT will be collaborating with NIEHS to build a microarray of 8700 mouse cDNAs on glass slides. The microarrays will be used in a number of collaborations, including studies to assess the value of the mouse liver tumor as a predictor of human cancer.

Innovative Analysis

"It's relatively easy to generate large amounts of data. The problem is trying to make sense of it all," says Corton about the microarrays.

CIIT is using innovative ways to extract important information from these data sets. Dr. Julia Kimbell of CIIT takes a researcher's data and creates a three-dimensional dynamic computer model that depicts changes as steep mountains in a colorful geography where the hotter hues indicate more intense gene expression.

"This way it's easy to see variations; they're spatially oriented, and I can plot many different kinds of variations," says Kimbell. In most cases she can have a visual rendering back to the researcher in just a couple of hours.

Although there's tremendous excitement and optimism about the use of microarrays in toxicological research, Corton cautions that much research needs to be done before the data can be used in human risk assessment.

"We just don't know what the relationships are between gene expression and either beneficial or toxic outcomes after chemical exposure. If the experiments aren't performed correctly and properly interpreted, we may get fooled."

Corton advocates carefully performed experiments in which gene expression changes can be tracked with both beneficial and toxic effects over a wide range of doses and exposure times for many chemicals. It will be especially important to use this new technique to obtain data on chemicals whose effects are well-known before moving to studies on new chemicals.

While many have been kept out of the microarray arena by the relative expense, more researchers are getting on the bandwagon every week by developing collaborative relationships with other scientists. The long-term dollar savings from microarrays are in the speed and volume that allow researchers to screen a wide range of genes and cut directly to the best options for further investigation.

For more information, visit CIIT's microarray page on the web at http://www.ciit.org/TOXICOGENOMICS/homepage.html. CIIT is a scientifically independent, not-for-profit research institute supported primarily by the chemical industry. Its peer-reviewed research is published in critical scientific journals.