Genetic susceptibility to toxicologic lung responses among inbred mouse strains following exposure to carbon nanotubes and profiling of underlying gene networks.
The risk of human exposure to fiber nanoparticles has risen in recent years due to increases in the manufacture and utilization of carbon nanotubes (CNTs). CNTs are present as airborne particulates in occupational settings and their hazard potential has been demonstrated in experimental lung exposure studies using inbred mouse strains. However, it is not known whether different inbred strains differ in lung responses to CNTs by virtue of their genetics. In this work, common inbred strains (BALB/c, C57Bl/6, DBA/2, and C3H/He) were exposed to CNTs via oropharyngeal aspiration and lung histology and bronchoalveolar lavage (BAL) samples were evaluated over 28days with the objective of evaluating sensitivity/resistance among strains. C57Bl/6 mice developed significantly more extensive type II pneumocyte (T2P) hyperplasia and alveolar infiltrate compared to DBA/2 mice, which were resistant. Surprisingly, DBA/2 but not C57Bl/6 mice were extremely sensitive to increases in leukocytes recovered in BAL fluid. Underlying global gene expression patterns in the two strains were compared using mRNA sequencing to investigate regulatory networks associated with the different effects. The impact of exposure on gene networks regulating various aspects of immune response and cell survival was limited in DBA/2 mice compared to C57Bl/6. Investigation of B6D2F1 (C57Bl/6×DBA/2 hybrid) mice demonstrated inheritance of sensitivity to CNT exposures in regard to toxicologic lung pathology and BAL leukocyte accumulations. These findings demonstrate a genetic basis of susceptibility to CNT particle exposures and both inform the use of inbred mouse models and suggest the likelihood of differences in genetic susceptibility among humans.
['Frank|Evan A|EA|', 'Carreira|Vinicius S|VS|', 'Shanmukhappa|Kumar|K|', 'Medvedovic|Mario|M|', 'Prows|Daniel R|DR|', 'Yadav|Jagjit S|JS|']
D000818:Animals D001992:Bronchoalveolar Lavage Fluid D015870:Gene Expression D020869:Gene Expression Profiling D053263:Gene Regulatory Networks D020022:Genetic Predisposition to Disease D007958:Leukocyte Count D008168:Lung D008171:Lung Diseases D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D008809:Mice, Inbred C3H D008810:Mice, Inbred C57BL D008811:Mice, Inbred DBA D008815:Mice, Inbred Strains D037742:Nanotubes, Carbon D011650:Pulmonary Alveoli D012333:RNA, Messenger D013045:Species Specificity
Genetic susceptibility Carbon nanotubes Nanoparticles Inbred strains Mouse models Toxicologic pathology