Toxicogenomic analysis of susceptibility to inhaled urban particulate matter in mice with chronic lung inflammation.
BACKGROUND
Individuals with chronic lung disease are at increased risk of adverse health effects from airborne particulate matter. Characterization of underlying pollutant-phenotype interactions may require comprehensive strategies. Here, a toxicogenomic approach was used to investigate how inflammation modifies the pulmonary response to urban particulate matter.


RESULTS
Transgenic mice with constitutive pulmonary overexpression of tumour necrosis factor (TNF)-alpha under the control of the surfactant protein C promoter and wildtype littermates (C57BL/6 background) were exposed by inhalation for 4 h to particulate matter (0 or 42 mg/m3 EHC-6802) and euthanized 0 or 24 h post-exposure. The low alveolar dose of particles (16 mug) did not provoke an inflammatory response in the lungs of wildtype mice, nor exacerbate the chronic inflammation in TNF animals. Real-time PCR confirmed particle-dependent increases of CYP1A1 (30-100%), endothelin-1 (20-40%), and metallothionein-II (20-40%) mRNA in wildtype and TNF mice (p < 0.05), validating delivery of a biologically-effective dose. Despite detection of striking genotype-related differences, including activation of immune and inflammatory pathways consistent with the TNF-induced pathology, and time-related effects attributable to stress from nose-only exposure, microarray analysis failed to identify effects of the inhaled particles. Remarkably, the presence of chronic inflammation did not measurably amplify the transcriptional response to particulate matter.


CONCLUSIONS
Our data support the hypothesis that health effects of acute exposure to urban particles are dominated by activation of specific physiological response cascades rather than widespread changes in gene expression.
Thomson
Errol M
EM
Environment and Occupational Toxicology Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, Canada. renaud_vincent@hc-sc.gc.ca.
Williams
Andrew
A
Yauk
Carole L
CL
Vincent
Renaud
R