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NIEHS Conference Explores Omics Technologies

By Eddy Ball
January 2007

Rick Paules, Ph.D.
In his presentation on day two of the conference, Paules reported on research into a genetic screen for toxicity. (Photo courtesy of Steve McCaw)

Jennifer Fostel
Fostel took her audience through sample searches using the CEBS Knowledgebase. (Photo courtesy of Steve McCaw)

NIEHS held its Empowering Environmental Health Sciences Research with New Technologies conference December 4-6 at the Friday Center in Chapel Hill. Attendees included NIEHS DIR and DERT scientists associated with the former National Center for Toxicogenomics (NCT) along with grantees working at the five centers that make up the Toxicogenomics Research Consortium and in other research initiatives nationwide.

NIEHS described the event as "A Conference on Omics Applications in the Environmental Health Sciences." Along with a half-day Symposium in Recognition of the Contributions of Ramond Tennant and the National Center for Toxicogenomics (see related Spotlight story), sessions included reports from participants in the Toxicogenomics Research Consortium (TRC), Functional Proteomics Initiative, and Metabolomics Application Initiative. In addition to 34 presentations, the conference also featured a poster session on the second day that included 27 abstracts.

Several of the presenters focused on the technical aspects of omics approaches. For example, NIEHS Laboratory of Respiratory Biology Staff Scientists Scott Alper, Ph.D., and Ivana Yang reported on the "Genetics of Innate Immunity" in a study utilizing two high-throughput RNA-interference assays developed in their laboratory. UNC Environmental Health Physician-Scientist Ivan Rusyn, M.D., Ph.D., presented the "TRC Standardization Experiment #3 Report," which focused on the application of microarray analysis to study hepatotoxicity induced by acetaminophen using the power of a prospective multi-laboratory investigation.

Two presenters, Cynthia Afshari, Ph.D., who had helped to develop toxicogenomic assessments for NIEHS before joining the biomedical company Amgen, and Weida Tong, Ph.D., of the Food and Drug Administration (FDA), spoke on the translational applications of toxicogenomic research in drug development and regulation. Of primary concern to Afshari is the pharmaceutical industry's ability to predict toxicological response early in the clinical trial process in order to expedite drug development and minimize expense. Tong's regulation efforts are often hampered by data variability between FDA and other testing sites, and he has worked to achieve platform standardization.

A number of speakers explored mechanisms of disease and the body's response to toxicity. UNC Lineberger Cancer Center Fellow Katherine A. Hoadley, Ph.D., for example, reported on her findings in "EGFR Signaling Pathways in Breast Cancer." Peter Spencer, Ph.D., of Oregon Health and Science University, explored the actions of organic solvent neurotoxicity employing proteomic and genomic applications. University of California at Davis Entomologist Bruce Hammock, Ph.D., spoke on "Metabolomic Approach to Pulmonary Inflammation Resulting from Air Pollution" and the insights gained from metabolomic analysis of effects on the arachidonic cascade in exposed subjects.

A smaller number of presenters spoke on translational aspects of their research in the clinical setting. One of these was NIEHS Laboratory of Molecular Toxicology Senior Scientist Rick Paules, Ph.D., who reported on his work "Linking Phenotype Endpoints with Genomics to Identify Signatures Predictive of Adverse Health Effects." His work addressed the poor performance of clinical chemistry in predicting outcomes of acetaminophen (APAP) overdose and the need of health care providers for accurate indicators of exposure in surrogate tissue to discriminate between mild, moderate and severe injury.

Paules compared blood gene expression data from rats exposed to APAP with blood expression levels of orthologs of the rat discriminatory genes in human blood samples. He was able to use analysis of a small group of human samples to separate APAP-intoxicated patients from controls, demonstrating a potentially useful clinical tool for traumatic injury health care providers. Improving predictive ability will help providers reduce the number of deaths and serious injuries among the more than 50,000 patients who seek emergency room treatment for APAP overdose each year.

CEBS Scientific Administrator Jennifer Fostel, Ph.D., reported on her collaboration with NCT Assistant Director for Database Development Mike Waters, Ph.D., to create an integrated toxicogenomic database. The two recently completed version 2.0.8 of the Chemical Effects in Biological Systems (CEBS) Knowledgebase. CEBS contains enormous amounts of both private and public data, including toxicity findings, microarray data and proteomics images and spectra that can be downloaded from CEBS.

Omics Applications in Toxicogenomics

Omics applications are distinguished by their unbiased and global analyses of specimens for specific categories of analytes. They include proteomics (proteins), metabolomics (products of metabolism), and genomics (transcription of individual genes), performed with a high throughput technology. The most common technologies for proteomics and metabolomics are Gas-Liquid Chromatography and Liquid Chromatography-Mass Spectrometry, which produce peaks from analytes identified in an extract. Genomics studies utilize DNA Microarray, which measures the transcription of thousands of genes simultaneously and produces a color-coded printout of results.

Theoretically, the number of analytes measured in an omics approach is limited only by the sophistication of available technology. In the words of presenter Bruce Hammock, Ph.D., "This approach allows one to both test and generate hypotheses regarding mechanism of action of toxins or therapies in a high throughput fashion." Thus, the approach is global and largely discovery-oriented, rather than strictly hypothesis-driven. "The most valuable approach," Hammock maintains, "is one using an integrated database of results from the genomic, transcriptomic, proteomic and metabolomic levels."

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