Genetic analysis of ozone-induced acute lung injury in sensitive and resistant strains of mice.
Epidemiological studies have found air pollution to be associated with excessive mortality, particularly death from respiratory and cardiovascular causes. Interpretation of these findings is controversial, however, because toxicological mechanisms controlling mortality are uncertain. Susceptibility to many air pollutants entails an oxidative stress response. Accordingly, the best-characterized oxidant air pollutant is ozone, which causes direct oxidative damage of lung biomolecules. 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 ozone. This susceptibility difference among humans suggests that genetic determinants may control predisposition to the harmful effects of ozone. Mice also vary considerably in their response to ozone. Moreover, ozone-induced differences in strain responses 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 (RI) 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 RI 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.
Prows
D R
DR
Department of Environmental Health, University of Cincinnati, Ohio 45267-0056, USA.
Shertzer
H G
HG
Daly
M J
MJ
Sidman
C L
CL
Leikauf
G D
GD
D000818:Animals; D003433:Crosses, Genetic; D004198:Disease Susceptibility; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D005838:Genotype; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D018895:Microsatellite Repeats; D010126:Ozone / Q000633:toxicity*; D019655:Quantitative Trait, Heritable; D012130:Respiratory Hypersensitivity / Q000139:chemically induced* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis
D005819:Genetic Markers; D010126:Ozone