Transcriptomic analysis of F344 rat nasal epithelium suggests that the lack of carcinogenic response to glutaraldehyde is due to its greater toxicity compared to formaldehyde.
Formaldehyde is cytotoxic and carcinogenic to the rat nasal respiratory epithelium inducing tumors after 12 months. Glutaraldehyde is also cytotoxic but is not carcinogenic to nasal epithelium even after 24 months. Both aldehydes induce similar acute and subchronic histopathology that is characterized by inflammation, hyperplasia, and squamous metaplasia. Because early aldehyde-induced lesions are microscopically similar, we investigated whether transcriptional patterns using cDNA technology could explain the different cancer outcomes. Treatments included 1-, 5-, or 28-day exposure by nasal instillation of formaldehyde solution (400 mM) or glutaraldehyde solution (20 mM). Animals were euthanized and the nasal respiratory epithelium removed for gene expression analysis and a subset of rats treated for 28 days was processed for microscopic examination. RNA was isolated and processed for expression assessment using Clontech Atlas Toxicology II Arrays. Both aldehydes induced hyperplasia, squamous metaplasia, and inflammatory infiltrates with scattered apoptotic bodies in the epithelium covering luminal surfaces of the nasoturbinate, maxilloturbinate, and nasal septum. A subset of 80 genes that were the most variant between the treated and control included the functional categories of DNA repair and apoptosis. Hierarchical clustering discriminated chemical treatment effects after 5 days of exposure, with 6 clusters of genes distinguishing formaldehyde from glutaraldehyde. These data suggest that although both aldehydes induced similar short-term cellular phenotypes, gene expression could distinguish glutaraldehyde from formaldehyde. The gene expression patterns suggest that glutaraldehyde's lack of carcinogenicity may be due to its greater toxicity from lack of DNA-repair, greater mitochondrial damage, and increased apoptosis.
Hester
S D
SD
Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27709, USA. hester.susan@epa.gov
Barry
W T
WT
Zou
F
F
Wolf
D C
DC
D000281:Administration, Intranasal; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000145:classification / Q000633:toxicity*; D016000:Cluster Analysis; D005557:Formaldehyde / Q000145:classification / Q000633:toxicity*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D005976:Glutaral / Q000145:classification / Q000633:toxicity*; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D012333:RNA, Messenger; D005557:Formaldehyde; D005976:Glutaral