Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of mouse SP-C/TNF-Ia mice and their wildtype littermates to investigate the acute effects of particulate matter (EHC-93) inhalation in mice with chronic lung inflammation

ABSTRACT: We examined the impact of chronic lung inflammation on the pulmonary transcriptional response to inhaled urban particles. Transcript levels were measured using high density microarrays in total RNA isolated from whole lungs of wildtype and TNF-Î± overexpressing mice exposed by inhalation to particulate matter and euthanized immediately or 24 h post-exposure. Experiment Overall Design: Transgenic SP-C/TNF-Î± mice and their wildtype littermates were exposed by inhalation to particulate matter (0, 42 mg/m3 EHC-93) for 4 h and euthanized immediately or 24 h post-exposure (n=5 per treatment per time point, 40 animals total). Agilent 22K oligonucleotide microarrays were used to examine transcript levels in whole lung RNA. Stratagene Universal Mouse RNA was used as a reference.

ORGANISM(S): Mus musculus

SUBMITTER: Andrew Williams

PROVIDER: E-GEOD-11037 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure. Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer F344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m3 (0.03, 0.06, 0.11, and 0.44 mg Ni/m3) for one and four weeks (6 hours per day, 5 days per week). Results: Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1 week to up-regulation at 4 weeks. Conclusions: These results support a mode of action for Ni3S2 carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026 mg Ni/m3, for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64 M-BM-5g Ni/g lung, for immune/inflammatory signaling. Implications: These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni3S2 toxicity and carcinogenicity. Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer F344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m3 (0.03, 0.06, 0.11, and 0.44 mg Ni/m3) for one and four weeks (6 hours per day, 5 days per week).

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Transcription profiling of mouse SP-C/TNF-Ia mice and their wildtype littermates to investigate the acute effects of particulate matter (EHC-93) inhalation in mice with chronic lung inflammation

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