New Mouse Model Mimics Human Genetic Diversity

Most mouse models used for testing chemicals and drugs in toxicity studies are inbred and therefore genetically identical. These mice respond similarly to chemical exposure, whereas humans may respond differently, depending on their own genetic susceptibility.

Now investigators are reporting that a new outbred mouse model with high genetic diversity exhibits wide-ranging responses to benzene, a known cause of human leukemia. Known as the Diversity Outbred (DO) model, it was developed over 5 years of successive crossbreeding at Jackson Laboratories in Bar Harbor, ME.

The proof-of-concept findings from a recent study confirm that genetically diverse mice respond uniquely to toxic chemicals, and “therefore more accurately predict the range of potential human responses to pollutants and experimental drugs, including those used in treating cancer,” says senior author Gary Churchill, PhD, a statistical geneticist and professor at Jackson Laboratories.

Four groups of mice were exposed to benzene in air at different levels—0, 1, 10, or 100 parts per million (ppm) for 28 days. Then the investigators looked for evidence of micronuclei in peripheral blood samples. These chromosomal fragments fail to incorporate properly into daughter nuclei during cell division, and their numbers are known to increase dose-dependently with benzene exposure. The number of micronuclei per thousand cells diverged widely at the highest dose level, from a low of 2.29 in the most resistant animal to a high of 92.7 in the mouse that was most susceptible to benzene toxicity.

Based on the dose-response curve, the investigators set a safe exposure limit for benzene that was an order of magnitude lower in the DO mice than that established in prior studies with inbred mouse strains.

Finally, by performing linkage mapping analysis, the investigators identified a region on chromosome 10 that contained genes associated with resistance to benzene-induced chromosomal damage. “This shows that we can use DO mice to identify a mechanism for further evaluation,” Churchill says.

Samir Kelada, PhD, an assistant professor in genetics at the University of North Carolina, Chapel Hill, who was not involved in the study, says the results are promising. “We need a model that mimics the genetic diversity we see in humans,” he says, “and that is what the DO model does best. It models heterozygosity at most loci in the genome.”

Policymakers at the NIH are now debating how to use DO mice in studies that will set safety standards for human chemical exposure. In addition, researchers are using DO mice for basic research in cancer. Kent Hunter, PhD, a senior investigator in the Laboratory of Cancer Biology and Genetics at the NCI, breeds DO females with transgenic males designed to spawn mammary tumors. Then he looks for genes that drive cancer progression and metastasis in the offspring, which also develop tumors at a young age.

“Many of the cancer genes we identify in the mice have analogues in human patients,” he says. “We couldn't do this type of work with inbred strains.”