ToxSci Advance Access originally published online on May 21, 2008
Toxicological Sciences 2008 105(2):368-383; 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, Research Triangle Park, North Carolina 27709-2137
1 To whom correspondence should be addressed at Computational Biology Division, The Hamner Institutes for Health Sciences, Six Davis Drive, PO Box 12137, Research Triangle Park, NC 27709-2137. Fax: (919) 558-1300. E-mail: MAndersen{at}Thehamner.org.
Received January 4, 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 h/day, 5 days/week for up to 3 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 (day 5), but not at the end of week 3 (day 15). Squamous metaplasia occurred at day 5; epithelial hyperplasia occurred at both day 5 and day 15. In microarray studies, no genes were altered at 0.7 ppm. At 2 ppm, 15 genes were changed on day 5; only half of them were changed at 6 ppm. No genes were changed significantly at 2 ppm at day 15. The pattern of gene changes at 2 and 6 ppm, with transient squamous metaplasia at day 5, indicated tissue adaptation and reduced tissue sensitivity by day 15. The acute study included an additional concentration (15 ppm) and an instillation group (40 µl, 400mM 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 day 5. On the basis of cellular component gene ontology benchmark dose analysis, 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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