Further investigation of this contrast indicated that baseline gene expression differences likely contribute to their divergent post-O 3 exposure transcriptional responses. We identified many genes that were altered by O 3 exposure across all strains, and examination of genes whose expression was influenced by strain-by-treatment interactions revealed prominent differences in response between the CC017/Unc and CC003/Unc strains, which were low- and high-responders, respectively (as measured by cellular inflammation and injury). Animals exposed to O 3 developed airway neutrophilia and lung injury, with varying degrees of severity. Additionally, we collected airway macrophages and performed RNA-seq analysis to investigate influences of strain, treatment, and strain-by-treatment interactions on gene expression as well as transcriptional correlates of lung phenotypes. Here, we exposed adult, female and male mice from 6 strains, including 5 Collaborative Cross (CC) strains, to filtered air (FA) or 2 ppm O 3 for 3 hours, and measured several inflammatory and injury parameters 21 hours later. However, molecular determinants of response, including biomarkers that distinguish which individuals will develop more severe injury and inflammation (i.e., high responders), are poorly characterized. In summary, we have shown that O 3 -induced lung injury is modulated by genetic variation and demonstrated the value of the CC for uncovering and dissecting gene-environment interactions.Īcute ozone (O 3 ) exposure is associated with multiple adverse cardiorespiratory outcomes, the severity of which varies across human populations and rodent models from diverse genetic backgrounds.
Using a weight of evidence approach that incorporated candidate variant analysis, functional annotations, and publicly available lung gene expression data, we nominated three candidate genes (Oxr1, Rspo2, and Angpt1).
15 QTL to a ~2 Mb region containing 21 genes (10 protein coding). Using additional statistical analysis and high-density SNP data, we delimited the Chr. 15 locus, C57BL/6J and CAST/EiJ founder haplotypes were associated with higher protein responses compared to all other CC founder strain haplotypes. The protein response phenotype was heritable, and QTL mapping revealed two novel loci on Chromosomes 10 (peak: 26.2 Mb 80% CI: 24.6-43.6 Mb) and 15 (peak: 47.1 Mb 80% CI: 40.2-54.9 Mb), the latter surpassing the 95% significance threshold. Because animals were exposed in sex- and batch-matched pairs, we defined a protein response phenotype as the difference in lavage protein between the O 3 - and FA-exposed animal within a pair. We evaluated hallmark O 3 -induced respiratory phenotypes in 56 CC strains after exposure to filtered air or 2 ppm O 3, and performed focused genetic analysis of variation in lung injury as measured by the total bronchoalveolar lavage protein concentration. We sought to expand our understanding of the genetic architecture of O 3 responsiveness using the Collaborative Cross (CC) recombinant inbred mouse panel, which contains more genetic diversity than previous inbred strain panels. Though previous studies genetic mapping studies using classical inbred strains have identified several quantitative trait locus (QTL) and candidate genes underlying responses to O 3 exposure, precise mechanisms of susceptibility remain incompletely described. Respiratory toxicity caused by the common urban air pollutant ozone (O 3 ) varies considerably within the human population and across inbred mouse strains, suggestive of gene-environment interactions (G圎).
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