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Environmental Factor, April 2015

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Variety of rodent models explored in NIEHS symposium

By Robin Arnette and Kelly Lenox

“Many recently published proof-of-principle studies, showing the diverse utility of these population-based rodent models in the environmental health sciences and toxicology fields, were highlighted during the meeting,” said McAllister, pointing to the Ebola and benzene studies.

“Many recently published proof-of-principle studies, showing the diverse utility of these population-based rodent models in the environmental health sciences and toxicology fields, were highlighted during the meeting,” said McAllister, pointing to the Ebola and benzene studies. (Photo courtesy of Steve McCaw)

Linda Brinbaum, Ph.D. Director of the National Institute of Environmental Health Sciences

"When we don’t see anything in our animal models, it may not mean nothing is happening — it may mean we haven’t used a sensitive model,” said Birnbaum, summing up one of the take-away messages of the meeting. (Photo courtesy of steve McCaw)

From left to right, Terrance Kavanagh, Ph.D., University of Washington; Rick Paules, Ph.D., acting chief of the NIEHS Biomolecular Screening Branch; and Nigel Walker, Ph.D., NTP deputy division director for science.

From left to right, Terrance Kavanagh, Ph.D., University of Washington; Rick Paules, Ph.D., acting chief of the NIEHS Biomolecular Screening Branch; and Nigel Walker, Ph.D., NTP deputy division director for science, were among the large audience at the symposium. (Photo courtesy of Steve McCaw)

An NIEHS symposium, Population-Based Rodent Resources for Environmental Health Sciences, featured scientists from around the country addressing ways that traditional and newer strains, or models, of laboratory mice can accurately reflect human disease. Besides traditional inbred strains, or strains that are essentially clones, researchers are using diverse, or outbred, populations, which are thought to reflect population-wide exposures in humans.

Besides presentations, panel discussions, and a poster session, planners of the March 18-19 symposium took advantage of the gathered experts and scheduled breakout sessions for the second day. “We wanted to use all the expertise to brainstorm experimental designs for these new population-based rodent resources,” said lead organizer Kim McAllister, Ph.D., health scientist administrator in the NIEHS Division of Extramural Research and Training. “That gives NTP [National Toxicology Program] and the EPA [U.S. Environmental Protection Agency] more information on the challenges and opportunities these new models provide.”

Mouse strains that model human genetic variability

David Threadgill, Ph.D., from Texas A&M University, set the stage with a discussion of Collaborative Cross (CC), a mouse strain developed to mimic the variable genetic backgrounds in the human population. When tested with Ebola, for instance, the distribution of responses in the CC mice was much closer to that seen in humans than was found in tests on traditional strains.

The growing variety of strains helped Ivan Rusyn, M.D., Ph.D., also from Texas A&M, study why a few clinical trial participants taking acetaminophen developed signs of liver injury. With one hybrid mouse and 36 inbred strains, he and his team performed genetic analysis, which told them the liver was failing due to an inflammatory response and because 26 genes were triggering the cell death process.

Mouse models may also be used to reduce the cost of developing medicines, which is increased when synthesized drugs fail during clinical trials, according to Alison Harrill, Ph.D., from the University of Arkansas for Medical Sciences. "Since these preclinical mouse models do a good job of replicating human illness, they will help us narrow the focus to making compounds that work in people," she said.

Computational analysis

The importance of computational analysis was underlined by Daniel Pomp, Ph.D., from the University of North Carolina at Chapel Hill. “No matter how good your model is, and no matter how nicely you design your experiment, what you get out is mostly dependent on the computational and statistical tools available to analyze the data.”

Mouse strains with diverse genetic material call for new approaches to data analysis, which can generate new insights. Eleazar Eskin, Ph.D., from the University of California, Los Angeles, and his team developed analytical methods to examine gene-environment interactions. “Our approach … does not require prior knowledge about environmental variables to look for potential genes involved in the effects,” he explained. “This gives us a great opportunity to move forward,” Eskin said.

Applying to disease and moving forward

Several speakers addressed the study of particular diseases. Elissa Chesler, Ph.D., from the Jackson Laboratory, has used the Diversity Outbred mouse to more precisely identify the loci involved in notoriously variable behavioral traits, which have been traditionally mapped to larger regions of the genome. “We now have the level of precision we need to identify molecular networks that are associated with these behavioral traits,” she said.

After the talks, participants broke into four groups to discuss experimental designs and test cases. Reports from the break-out sessions addressed pros and cons of different models, study proposals, and how the use of diverse models affects the concept of reproducibility.

“It’s been a fabulous meeting,” said Linda Birnbaum, Ph.D., director of NIEHS and the National Toxicology Program. “The Collaborative Cross and Diversity Outbred mouse offer tremendous opportunities for screening chemicals,” she said.

A full meeting agenda, including abstracts of all talks and posters, is available on the meeting Web page. Organizers will also post a summary of the symposium, once it is completed.


  • Fred Tyson, Ph.D. listening to Amelia Baud, Ph.D.
    1/6

    Fred Tyson, Ph.D., NIEHS health scientist administrator, listened as Amelie Baud, Ph.D., a postdoctoral fellow at the European Bioinformatics Institute, describes her research on the effects that the genetic makeup of cage-mates has on important clinical traits. (Photo courtesy of Steve McCaw)

  • Linda Brinbaum, Ph.D., David Balshaw, Ph.D., and McAllister
    2/6

    From right to left, Birnbaum; meeting co-organizer David Balshaw, Ph.D.; and McAllister had front row seats during the syposium. Balshaw, chief of the Exposure, Response, and Technology Branch in the NIEHS Division of Extramural Research and Training, moderated the first day’s morning session. (Photo courtesy of Steve McCaw)

  • David Threadgill, Ph.D.
    3/6

    Speaking of the eight founding strains of the Collaborative Cross mouse, Threadgill said, “They seeded the population with a much higher level of genetic polymorphisms [variations] than we would have had if we had just used standard laboratory strains." (Photo courtesy of Steve McCaw)

  • Kavanagh and Witt speaking to each other
    4/6

    Kavanagh, left, listens as NTP toxicologist Kristine Witt, center, discusses her work with Diversity Outbred mice during her poster presentation. (Photo courtesy of Steve McCaw)

  • Gary Churchill, Ph.D.
    5/6

    Gary Churchill, Ph.D., and others from The Jackson Laboratory, developed the Diversity Outbred mouse to test responses to benzene exposure. "Genetically diverse mice provide a reproducible response to benzene exposure variation that reflects the range of responses that can be expected in the human population," he said. (Photo courtesy of Steve McCaw)

  • Weihsueh Chiu, Ph.D.
    6/6

    Weihsueh Chiu, Ph.D., of Texas A&M University, spoke on risk assessment, citing the power of population-based resources. “When you add population variability, the power goes beyond genes and helps identify pathways involved in susceptibility or resistance to environmental factors,” he said. (Photo courtesy of Steve McCaw)



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