Mouse Translational Studies
Experimental animal studies are an important tool for biomedical research, chemical safety evaluation, and risk assessment. Recent scientific advances, however, provide new opportunities to enhance the use of whole-animal testing. Gene-editing technologies, for example, have led to the creation of transgenic rodents that can be used to investigate specific questions, such as those related to susceptibility or GxE interactions.
Estimation of inter-individual variability is necessary to determine the human health hazard posed by environmental chemcials. Several genetically-diverse experimental model systems are available to address this challenge. Though not high-throughput, the mouse is an in vivo model fo which genetic resources and genetic maps across dozens of strains are available. Mouse populations, such as the Collaborative Cross, provide an excellent testing system for evaluation of complexities in toxicokinetics and toxicodynamics.
Our group has demonstrated convincingly that genetic diversity in the mouse can be used to identify sensitive populations, leading us to propose a "mouse model of the human population." The Collaborative Cross and other population-wide mouse resources will be utilized by TiCER and will serve as an important in vivo validation strategy for studies in humans and in vitro.
Check out these examples of how the mouse translation studies area of the IHFSC has been used by TiCER scientists below.
First example is a bedside-to-bench-to-population translation study of acetaminophen (APAP)-induced liver injury (Figure 4B). In that study, Drs. Rusyn, Threadgill, and collaborators modelled inter-individual variability in APAP-induced liver injury observed in a human clinical cohort in a population of ~40 inbred mouse strains, mapped the susceptibility loci, validated several of the candidates in the human cohort, and then demonstrated that inflammation, not metabolism of APAP to a reactive thiol, is the most important mechanism for the variability in adverse outcomes in humans.