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Genetic analysis of ozone-induced acute lung injury in sensitive and resistant strains of mice

Nature Genetics volume 17, pages 471–474 (1997)Cite this article

Abstract

Epidemiological studies have found air pollution to be associated with excessive mortality, particularly death from respiratory and cardiovascular causes1,2. Interpretation of these findings is controversial, however, because toxicological mechanisms controlling mortality are uncertain. Susceptibility to many air pollutants entails an oxidative stress response3,4. Accordingly, the best-characterized oxidant air pollutant is ozone5, which causes direct oxidative damage of lung biomolecules6. An underlying characteristic derived from clinical and epidemiological studies of healthy and asthmatic individuals of all ages is marked variability in the respiratory effects of ozone7–11. This susceptibility difference among humans suggests that genetic determinants may control predisposition to the harmful effects of ozone12. Mice also vary considerably in their response to ozone13"15. Moreover, ozone-induced differences in strain responses16 indicate that susceptibility in mice can be genetically determined. Therefore, we used inbred mice to investigate the genetic determinants of acute lung injury. Recombinant inbred (Rl) strains derived from A/J (A) mice (sensitive) and C57BL/6J (B) mice (resistant) showed a continuous phenotypic pattern, suggesting a multigenic trait. Quantitative trait locus and Rl analyses suggested three major loci linked to ozone susceptibility. Differences in phenotype ratios among the reciprocal back-crosses were consistent with parental imprinting. These findings implicate various genetic and epigenetic factors in individual susceptibility to air pollution.

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Authors and Affiliations

  1. Departments of Environmental Health, Molecular & Cellular Physiology and Medicine, University of Cincinnati, Cincinnati, Ohio, 45267-0056, USA

    Daniel R. Prows, Howard G. Shertzer & George D. Leikauf

  2. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts, 02142, USA

    Mark J. Daly

  3. Department of Molecular Genetics, Biochemistry & Microbiology, University of Cincinnati Medical Center, Cincinnati, Ohio, 45267-0524

    Charles L. Sidman

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  1. Daniel R. Prows
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  2. Howard G. Shertzer
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  5. George D. Leikauf
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Prows, D., Shertzer, H., Daly, M. et al. Genetic analysis of ozone-induced acute lung injury in sensitive and resistant strains of mice. Nat Genet 17, 471–474 (1997). https://doi.org/10.1038/ng1297-471

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