ToxSci Advance Access published online on May 21, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn097
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Genomic Signatures and Dose Dependent Transitions in Nasal Epithelial Responses to Inhaled Formaldehyde in the Rat
The Hamner Institutes for Health Sciences, Six Davis Drive PO Box 12137, Research Triangle Park, NC 27709-2137
Corresponding author: Melvin E. Andersen, Ph.D., DABT, CIH, FATS, Computational Biology Division, The Hamner Institutes for Health Sciences, Six Davis Drive PO Box 12137, Research Triangle Park, NC 27709-2137. Tel: 919-558-1205 Fax: 919-558-1300. MAndersen{at}Thehamner.org
Received January 4, 2008; revision received April 22, 2008; accepted May 10, 2008
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Abstract |
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Repeated and acute exposure studies assessed time and concentration-dependencies of nasal responses to formaldehyde. Exposures were to 0, 0.7, 2 and 6 ppm for 6 hr/day, 5 days/week for up to three weeks. Neither cell proliferation nor histopathology was observed at 0.7 ppm. At 6 ppm, cell proliferation increased at the end of the first week (Day5), but not at the end of week three (Day15). Squamous metaplasia occurred at Day5; epithelial hyperplasia occurred at both Day5 and Day15. In microarray studies, no genes were altered at 0.7 ppm. At 2 ppm, 15 genes were changed on Day5; only half of them were changed at 6 ppm. No genes were changed significantly at 2 ppm at Day15. The pattern of gene changes at 2 and 6 ppm, with transient squamous metaplasia at Day5, indicated tissue adaptation and reduced tissue sensitivity by Day15. The acute study included an additional concentration (15 ppm) and an instillation group (40µl, 400 mM per nostril). Three-times more genes were affected by instillation than inhalation. U-shaped dose responses were noted in the acute study for many genes that were also altered at 2 ppm on Day5. On the basis of cellular component gene ontology Benchmark Dose Analysis (BMD), the most sensitive changes were for genes were associated with extracellular components and plasma membrane. With formaldehyde, there are temporal and concentration-dependent transitions in epithelial responses and genomic signatures between 0.7 and 6 ppm. Low concentrations primarily affect extracellular matrix or external plasma membrane portions of the epithelium.
Key Words: genomics; mode of action; formaldehyde; epithelial cell responses; progression; phenotypic anchoring; dose-dependent transitions.
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