Environmental Factor

June 2011

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Taking the pulse of toxicogenomics at GEMS

By Ernie Hood
June 2011

GEMS President-elect Nagu Keshava, Ph.D., with EPA

GEMS President-elect Keshava introduced the day's proceedings, titled “Application of Genomics Data to Understand Chemical Mechanisms of Action.” (Photo courtesy of Steve McCaw)

GEMS President Stephen Little, with EPA

Little pointed to the potential impact of toxicogenomics on public health - “speeding up getting information about the large number of chemicals that are out there that the public is worried about and we don't have a lot of information on.” (Photo courtesy of Steve McCaw)

ILS, Inc., Michael Waters, Ph.D.

Waters illustrated a point in his GEMS presentation on the use of existing toxicogenomics databases to understand chemical modes of action and pre-disease genomic signatures. (Photo courtesy of Steve McCaw)

NIEHS/NTP Director Linda Birnbaum, Ph.D.

Birnbaum found herself back on familiar turf, as she revisited EPA, where she worked for many years, to present to the GEMS attendees. (Photo courtesy of Steve McCaw)

At its annual spring meeting held May 2 at the U.S. Environmental Protection Agency (EPA) campus in Research Triangle Park, the Genetics and Environmental Mutagenesis Society (GEMS) welcomed a series of speakers with ties to NIEHS and EPA working in the emerging field of toxicogenomics in recent years.

The meeting was organized by GEMS President-elect Nagu Keshava, Ph.D., and President Stephen Little, both of the EPA, around the theme of “Application of Genomics Data to Understand Chemical Mechanisms of Action.” As Keshava explained, “The original idea was to see how far we have come in terms of toxicogenomics or any genomics or systems biology data for using in risk assessment.”

Little agreed, and noted that the program emphasized the importance of new tools for gaining knowledge about chemicals' mechanisms of action. “They can help you assess the likelihood that a chemical is going to contribute to a toxicological endpoint,” he said.

Resources linked to NIEHS

In the initial presentation, Michael Waters, Ph.D., chief scientific officer of ILS, Inc., and a longtime researcher at both EPA and NIEHS, set the tone for the day's proceedings, with his talk on “Utilizing Available Toxicogenomics Datasets to Understand Chemical Mode of Action.” He showed that recent advances in the field allow more robust queries of existing toxicogenomics datasets (see text box).

NIEHS grantee Ivan Rusyn, M.D., Ph.D.(http://www.sph.unc.edu/?option=com_profiles&profileAction=ProfDetail&pid=702665970) Exit NIEHS, of the University of North Carolina at Chapel Hill Gillings School of Public Health briefed GEMS attendees on his group's work in population-based discovery of toxicogenomic biomarkers for hepatotoxicity. Using dozens of thoroughly genotyped inbred mouse strains as models for human genetic diversity, Rusyn and his team have made important strides in understanding the genotoxic and epigenotoxic effects of toxicants.

Following the scientific presentations, NIEHS/NTP Director Linda Birnbaum, Ph.D.(https://www.niehs.nih.gov/about/od/director/index.cfm), provided the GEMS members a comprehensive overview of NIEHS and NTP genetics, epigenetics, genomics and epigenomics-related research. She delineated both intramural and extramural activities, as well as multi-agency and trans-NIH programs such as the Genes, Environment and Health Initiative and the Environmental Genome Project, outlining the Institute's extensive endeavors in the field, both currently and over the past 45 years.

EPA initiatives

Vincent Cogliano, Ph.D., head of the EPA Integrated Risk Information System (IRIS)(https://www.epa.gov/IRIS/) Exit NIEHS, reported on “The Use of Mechanistic Data to Classify Carcinogens - An IARC [International Agency for Research on Cancer] Classification.” He noted that mechanistic studies had been pivotal in more than 60 of IARC's cancer classifications - assessments in which the mechanistic data had actually changed the classifications from what they would have been based upon epidemiological or animal bioassay data alone. Moving forward, he said, IARC guidelines now recognize that chemicals can be classified as carcinogenic based solely on mechanistic data.

EPA scientist Stephen Edwards, Ph.D., of the National Health and Environmental Effects Research Laboratory (NHEERL), described a systems biology-based approach to understanding gene-environment interactions and developing disease-centric predictive toxicology, in conjunction with working with the EPA National Center for Computational Toxicology. The idea of the disease-centric approach is to treat chemical exposures as one of many potential perturbations to a system, and to seek better comprehension of how the system responds and adapts to such perturbations as it seeks to maintain homeostasis.

EPA researcher Lyle Burgoon, Ph.D., also of NHEERL, provided an update on “Use of Genomics and Systems Biology Data in Risk Assessment - The NexGen Project(https://www.epa.gov/risk/nexgen/) Exit NIEHS.” Burgoon discussed the need for EPA to begin to incorporate so-called next generation data being spawned by toxicogenomics, metabolomics and similar approaches from molecular systems biology into its risk assessment decision-making processes in the interagency Advancing the Next Generation of Risk Assessment (NexGen) program.

(Ernie Hood is a contract writer for the NIEHS Office of Communications and Public Liaison.)

EPA scientist Stephen Edwards, Ph.D.

Edwards described the potential to improve risk assessment through systems biology by developing a predictive model incorporating a wide variety of factors to generate useful risk estimates. (Photo courtesy of Steve McCaw)

EPA researcher Lyle Burgoon, Ph.D.

Burgoon updated GEMS attendees on the NexGen program, EPA's collaborative initiative with other Federal and state partners, including NIEHS/NTP, to incorporate systems biology and omics data into risk assessment decision-making. (Photo courtesy of Steve McCaw)

left to right, NIEHS/NTP scientists Barbara Shane, Ph.D., Ruth Lunn, Ph.D., and Errol Zeiger, Ph.D., J.D.

A significant number of NIEHS/NTP scientists are members of GEMS. Shown above, left to right, are former NTP scientist Barbara Shane, Ph.D., NTP scientist Ruth Lunn, Ph.D., and former NIEHS scientist Errol Zeiger, Ph.D., J.D. (Photo courtesy of Steve McCaw)

EPA biochemist Jeff Ross, Ph.D.

Among the many EPA scientists at the meeting was biochemist Jeff Ross, Ph.D., above, who served as GEMS president-elect in 2008 and president in 2009. (Photo courtesy of Steve McCaw)

Waters running deep

In his GEMS presentation on the use of available toxicogenomics databases to understand chemical modes of action, Waters reported that he was particularly excited about the NTP's 2010 acquisition of the commercial DrugMatrix database and the recent public release of a Japanese toxicogenomics database called TG-GATEs. “These two databases actually have about 82 chemicals in common that could be looked at to verify that the technology is giving you the same information in two different parts of the world,” Waters said. He also noted the largely untapped resource represented by the NTP's extensive archive of formalin-fixed, paraffin-embedded (FFPE) two-year carcinogenicity bioassay materials. 

By applying the new tools such as microarray technology and NexGen sequencing to early, acute-phase toxicity studies such as those found in DrugMatrix and TG-GATEs and to longer-term studies, such as the NTP 2-year bioassays, it should be possible to characterize both chemicals' modes of actions and associated gene expression signatures pertinent to the disease process. “We would use that ‘pre-disease' signature to describe what we think are the markers that would indicate the disease that is going to occur in two years, or sometimes between 90 days and two years,” Waters explained. “The technologies and the data are now available to do this,” he added. “We have an opportunity that we didn't have before, and I think we really should exercise that opportunity.” 

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