Initial efforts will focus on known toxinssuch as known carcinogens or mutagensto build a database showing the typical genetic changes that these known compounds produce. With these "signature" profiles, they will evaluate other chemicals for potential harm by comparing the gene changes they produce with those made by the known toxins. A match between an expression signature produced by an unknown compound and that from an established toxic compound would indicate a potential danger in the test compound.
Schematic diagram comparing a test chemical to three known toxicants and "matching" key gene patterns.
NIEHS director Olden said, "There are thousands of both natural and man-made chemicals in human use and commerce that have never been adequately tested. We are developing a technology that will greatly aid in their evaluation and identification. The idea is simple: If ToxChip screening shows that a test chemical changes key gene expressions in the same way as a known toxin does, there's a strong likelihood the test chemical may be harmful too."
NIEHS is planning on helping other organizations establish microarray capabilities, including its 20 university-based environmental health centers. Grant support for such an effort in the form of administrative supplements will be offered. (See the NIEHS web site for details.)
Start-up costs for a microarray facility can run up to $500,000, while traditional screening tests done on rodents can take up to two years and cost as much as $2.5 million per substance. As a result, only about 10 commonly used chemicals are screened each year by the National Toxicology Program, which is also headquartered at NIEHS' facilities in Research Triangle Park.
NIEHS Microarray Center co-director Cynthia Afshari said that before mass chemical screening is carried out, the work promises to unlock some of the secrets of how our environment changes our genes. "From a public health standpoint, knowing how the environment changes our genes may be as important as knowing the functions of the genes themselves," Afshari said, "because we often can do something effective to change the environment or substitute one chemical for another in industry, whereas in most cases we cannot alter our genetic or cellular response to these agents."
The ToxChip was developed by NIEHS scientific director J. Carl Barrett, Afshari, and postdoctoral fellow Emile F. Nuwaysir at NIEHS in Research Triangle Park. Jeff Trent and Michael Bittner, pioneers in microarray studies at the National Human Genome Research Institute in Bethesda, MD, helped NIEHS develop its toxicology-focused center.
The ToxChip also has potential to accelerate drug testing for safety before using them in clinical trials. The original ToxChip contains human genes, but additional microarrays using cloned genes from common test animalsmice, rats, frog (xenopus), and yeasthave been constructed. "We are making profiles of known toxins using several or all of these species' genes," center co-director Richard S. Paules said.
For more information: Cindy Afshari, Director of Basic Research Applications, NIEHS cDNA Microarray Center, P.O. Box 12233, Research Triangle Park, NC 27709. Tel: 919-541-1310. Email: firstname.lastname@example.org.