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Concordance in Genomic Changes Between Mouse Lungs and Human Airway Epithelial Cells Exposed to Diesel Exhaust Particles
Citation:
STEVENS, T., W. Reed, S. D. HESTER, J. M. SAMET, AND M. I. GILMOUR. Concordance in Genomic Changes Between Mouse Lungs and Human Airway Epithelial Cells Exposed to Diesel Exhaust Particles. Presented at Society of Toxicology Annual Meeting, Seattle, WA, March 16 - 20, 2008.
Impact/Purpose:
This information provides validation for the use of experimental animals in predicting human health effects for respiratory toxicants, while examination of cellular pathways that are altered with various forms of DEP will extend biological understanding of DEP-induced toxicity.
Description:
Human and animal toxicity studies have shown that exposure to diesel exhaust particles (DEP) or their constituents affect multiple biological processes including immune and inflammatory pathways, mutagenesis and in some cases carcinogenesis. This study compared genomic changes by three DEPs with varying extractable organic content in a mouse in vivo lung model and a human airway epithelial cell culture system (HAEC). The three DEPs used were from a forklift (NIST SRM 2975 [N-DEP]), a compressor (C-DEP), and an automobile (A-DEP). BALB/c mice were instilled intranasally with saline or 150 ug of DEP on days 0 and 13 and necropsied 18 hrs later. HAECs were exposed to saline or 100 ug/ml of DEP for 4hrs. RNA was isolated from the lungs or cells, labeled, and hybridized to Affymetrix Mouse 430A GeneChips. Gene expression was normalized using Robust Multichip Average Analysis (RMA) and analyzed by Gene Set Enrichment Analysis (GSEA) followed by Ingenuity Pathway Analysis (IPA). Exposure to all the DEP samples caused alterations in genes associated with hypoxia signaling, regulation of peroxisome proliferators, and anti-apoptosis pathways in both mouse lung tissue and HAEC. C-DEP and A-DEP also induced alterations in the Aryl hydrocarbon pathway. Several other pathways related to acute phase proteins, cell cycling, NFkB activation and oxidative stress were also significant in mouse lung tissue exposed to all DEP samples. In conclusion DEPs elicited several toxicologic responses in common to both in vitro and in vivo exposure systems and demonstrated strong concordance between species, while additional effects in whole organ systems were complicated by more cell types.