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DIFFERENTIATING THE TOXICITY OF CARCINOGENIC ALDEHYDES FROM NONCARCINOGENIC ALDEHYDES IN THE RAT NOSE USING CDNA ARRAYS
Citation:
Hester, S D. AND D C. Wolf. DIFFERENTIATING THE TOXICITY OF CARCINOGENIC ALDEHYDES FROM NONCARCINOGENIC ALDEHYDES IN THE RAT NOSE USING CDNA ARRAYS. Presented at Oncogenomics 2002: Dissecting Cancer Through Genome Research, Dublin, Ireland, May 1-5, 2002.
Description:
Differentiating the Toxicity of Carcinogenic Aldehydes from Noncarcinogenic Aldehydes in the Rat Nose Using cDNA Arrays.
Formaldehyde is a widely used aldehyde in many industrial settings, the tanning process, household products, and is a contaminant in cigarette smoke. Humans have a significant
exposure to glutaraldehyde as it is used extensively in hospitals for cold sterilization, radiograph processing, and as a constituent of embalming solution. Humans are exposed to these and other aldehydes by inhalation as environmental or occupational contaminants. Therefore, it is
important to identify potential adverse health outcomes from inhaled aldehyde exposure. In addition, to better assess the relative risk of these contaminants, it is important to be able to differentiate carcinogenic aldehydes from those that are merely surface irritants. Inhaled
formaldehyde induces hyperplasia, inflammation, and squamous metaplasia leading to squamous cell carcinoma in rodent nasal respiratory epithelium. In contrast, inhaled glutaraldehyde produces a similar cytotoxic tissue response to formaldehyde but does not result in a neoplastic response. To identify the transcriptional alterations which may account for these two different biologic responses we utilized gene expression analysis. Three groups of male F344 rats received either 40 ul of distilled water, 400mM formaldehyde, or 20 mM glutaraldehyde by intranasal instillation into each nostril. After 24 hours they were euthanized, and the nostrils were infused with 200 ul TrizolTM Reagent, followed by a 10 minute in situ incubation was utilized to dislodge respiratory cells lining the rostral nose. Repeated flushing by syringe attached tubing was used to remove the cell TrizolTM mixture and RNA was isolated from the cell suspension. cDNA probe generated from total RNA was used to hybridize ClontechTM Rat Toxicology II macroarrays. Global analyses revealed expression levels of twenty one genes (4.5%) were significantly (p=0.05) altered across 3 treatment groups. Functional categories most altered included cell cycle, DNA synthesis and repair, proliferation, apoptosis, metabolizing enzymes, and oncogene regulating genes Variability within each treatment group was greatest in the control animals with a tendency toward less variability of expression as follows; glutaraldehyde < formaldehyde < control. Parametric analysis (p=0.05) of the formaldehyde to glutaraldehyde comparison showed 10 genes with significantly changed expression levels including inhibitor of DNA binding, DNA repair protein RAD 51, MAP/ERK kinase 3, polymerase (P ARP), matrix metalloproteinase 11, CCAAT/enhancer binding protein, endothelin precursor, heat shock protein, aryl hydrocarbon receptor, and retinoic acid binding protein. These results show that multiple pathways are dysregulated at an early time point and that 2 critical processes, cell proliferation and DNA synthesis/repair, sustain unbalanced changes. Differential gene expression profiles derived may provide clues that could be used to define a carcinogenic versus a toxic biologic outcome in nasal epithelium.
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