Exposure to the ambient air pollutant ozone (O₃) is associated with adverse respiratory health outcomes. Rodent models have been used to identify mechanisms of response to O₃ but their utility has been questioned owing to species differences in physiologic response, most notably exposure-induced hypothermia, which renders rodents relatively resistant to O₃ compared to humans.

First, to test whether a recombinant inbred mouse strain from the Collaborative Cross population, CC002/Unc, provides a sensitive model of ozone response by benchmarking it to the most commonly used inbred strain, C57BL/6J. Second, to identify the genetic basis of CC002/Unc’s sensitivity.

We examined the responses of CC002/Unc and C57BL/6J mice to either acute (0.4 or 0.8 ppm O₃ x 4 hours) or repeated (0.8 ppm O₃ x 4 hours/day x 3 or 9 weekdays) O₃ exposure. Then, we mapped quantitative trait loci (QTL) for responses to 9 days of O₃ in a CC002/Unc x CC005/TauUnc (O₃-resistant) backcross population.

CC002/Unc was far more responsive to acute O₃ than C57BL/6J, exhibiting significant inflammation following a single 0.4 ppm O₃ exposure and greater inflammation and injury after 0.8 ppm O₃. Enhanced sensitivity of CC002/Unc mice was associated with decreased breathing frequency and diminished hypothermic responses. Following repeated exposure, C57BL/6J lungs appeared normal, while CC002/Unc lungs had eosinophilic inflammation and centriacinar fibrosis. We identified five QTLs for airway eosinophilia, including a large-effect QTL on chromosome 11 that accounted for 18% of phenotypic variation and contains genes with plausible links to aberrant immune responses.

The CC002/Unc strain provides an improved model to study the effects of acute and repeated O₃ exposure due to its enhanced sensitivity vs. C57BL/6J and more human-like thermoregulatory response. Further genetic analysis to pinpoint causal genes underlying CC002/Unc’s susceptibility will provide new insights into mechanisms of O₃-induced lung disease. https://doi.org/10.1289/EHP15745