Academic journal article Environmental Health Perspectives

Diversity Outbred: A New Generation of Mouse Model

Academic journal article Environmental Health Perspectives

Diversity Outbred: A New Generation of Mouse Model

Article excerpt

The use of genetically identical mice in toxicology studies can make it tricky to extrapolate findings to people. A new mouse model known as the Diversity Outbred better reflects the genetic diversity of the human population, offering intriguing possibilities for safety assessment. [C] Roy Scott

Most of the mice used for testing the toxic effects of chemicals and drugs are genetically inbred with a long history in the laboratory. (1) But toxicologists are increasingly turning to newer mouse models that more accurately mimic the genetic diversity of the human population. Investigators with the National Toxicology Program (NTP) at the National Institute of Environmental Health Sciences have now reported that one such model--the Diversity Outbred (DO) mouse model--varies widely in its susceptibly to benzene, a known cause of human leukemia. (2) The results demonstrate the model's improved capacity for identifying subtle chemical effects and lend further credibility to the use of DO mice in toxicology research and safety assessment, according to lead author John E. French, a toxicologist specializing in toxicogenetics formerly with NTP and now an adjunct professor in the Center for Pharmacogenomics and Individualized Therapy at the University of North Carolina at Chapel Hill.

Proof of Concept

Because toxicity depends in part on how chemicals and genes interact, genetically inbred mice--generated by breeding siblings--tend to respond similarly to the agents tested in a given study. That has certain advantages; for instance, it limits the number of animals needed to detect statistically significant differences in chemical effects. But among other disadvantages, it's possible that inbred mice might exhibit strain-specific responses with little relevance to the genetically diverse human population, says Kristine Witt, a toxicologist with the NTP. (3)

It's not unusual for toxicologists to work with outbred mouse strains derived from unrelated pairings. These strains have more varied reactions to chemicals and drugs, but they also vary unpredictably with respect to their own "outbredness." By contrast, the DO model is maintained under strict randomized breeding conditions designed to ensure that only unrelated mice mate. (4,5) Thus, every DO mouse is genetically unique. Moreover, the eight "founders"--the original parental strains of mice from which all subsequent DO generations derive--were fully sequenced, (6,7) "and so we can reconstruct the genome of any single DO mouse with a high degree of precision," says Gary Churchill, a professor at Jackson Laboratories in Bar Harbor, Maine. That ability, Churchill says, facilitates genomewide association studies that aim to pinpoint the genes or alleles that govern a particular trait.

For the new proof-of-concept study, (2) NTP investigators and their collaborators exposed two independent cohorts of 300 male DO mice each to benzene. This chemical was chosen because its metabolism in vivo is well characterized and known to be similar in mice and humans. "The possibility of finding distinct gene associations in the response to benzene exposure, based on the diversity of the metabolic pathways involved, seemed high," says Witt, a coauthor.

Groups of 75 mice each were exposed to benzene in air at 0, 1, 10, or 100 ppmv for 28 days. Then the investigators looked at peripheral blood and bone marrow samples for evidence of micronuclei (MN). MN arise from chromosomal fragments or whole chromosomes that fail to incorporate into daughter nuclei during cell division, and their numbers are known to increase dose-dependently with benzene exposure.

MN counts in peripheral blood were significantly different in mice with the highest exposure compared with unexposed animals, but were similar to unexposed mice for those animals with lower exposures. MN counts in bone marrow, however, differed from non-exposed controls at every dose level. …

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