Abstract
The antineoplastic drug bleomycin leads to the side effect of pulmonary fibrosis in both humans and mice. We challenged genetically diverse inbred lines of mice from the Collaborative Cross with bleomycin to determine the heritability of this phenotype. Sibling pairs of mice from 40 lines were treated with bleomycin. Lung disease was assessed by scoring lung pathology and by measuring soluble collagen levels in lavage fluid. Serum micro ribonucleic acids (miRNAs) were also measured. Inbred sibling pairs of animals demonstrated high coinheritance of the phenotypes of disease susceptibility or disease resistance. The plasma levels of one miRNA were clearly correlated in sibling mice. The results showed that, as in humans, the lines that comprise the Collaborative Cross exhibited wide genetic variation in response to this drug. This finding suggests that the genetically diverse Collaborative Cross animals may reveal drug effects that might be missed if a study were based on a conventional mouse strain.
Acknowledgements
The authors thank Christine Bhirdo, Lisa Branstetter, Pat Hunsicker, William Parkhurst, Jason Spence, Ginger Shaw, and Sarah Shinpock at the Oak Ridge National Laboratory for the production, treatment, and dissection of the Collaborative Cross mice. We also thank our colleague at Battelle: Connie Essman-Wood, at the Ohio State University: Melissa Piper, and colleagues at the Institute for Systems Biology: David Baxter and Ji-Hoon Cho. The authors wish to acknowledge support from the Pulmonary Systems Biology Initiative from the Battelle Memorial Institute (to Oak Ridge National Laboratory and Institute for Systems Biology), from the University of Luxembourg and the Luxembourg Centre for Systems Biomedicine (to the Institute for Systems Biology), and the Systems Biology Center Grant (NIH-GM 076547) to the Institute for Systems Biology. The Collaborative Cross was initiated with the generous support of The Ellison Medical Foundation.
Disclosure
The authors report no conflicts of interest in this work.