title: Identification of early molecular pathways affected by paraquat in rat lung.
abstract: We have used global gene expression profiling, combined with pathway analysis tools, to identify in rats the molecular events associated with paraquat toxicity in the lung. Early (2, 8 and 18h) gene expression changes induced following intraperitoneal (i.p.) exposure to paraquat were measured in the caudal lobe of lungs using Affymetrix rat genome GeneChips (31,042 probe sets). A single high dose of paraquat dichloride (20mg/kg) was used that has been shown previously to cause in rats extensive lung fibrosis after 10 days. Hierarchical clustering of 543 paraquat-responsive genes (false discovery rate<0.05) revealed that under these conditions of exposure paraquat induces a staged transcriptional response in the rat lung that precedes the appearance of lung damage. We report here that many of the transcriptional responses to paraquat were rapid (being maximal at 2h post-dose), and that the predominant molecular functions and biological processes associated with these genes include membrane transport, oxidative stress, lung development, epithelial cell differentiation and transforming growth factor beta (TGF-beta) signalling. These data provide novel insights into the molecular pathways that lead to toxicity after exposure of the rat lung to paraquat.
authors.affiliation: Syngenta CTL, Alderley Park, Cheshire SK10 4TJ, United Kingdom. Guy.Mainwaring@syngenta.com
authors.forename: Guy
authors.initials: G
authors.lastname: Mainwaring
authors.forename: Fei Ling
authors.initials: FL
authors.lastname: Lim
authors.forename: Kate
authors.initials: K
authors.lastname: Antrobus
authors.forename: Cindy
authors.initials: C
authors.lastname: Swain
authors.forename: Mike
authors.initials: M
authors.lastname: Clapp
authors.forename: Ian
authors.initials: I
authors.lastname: Kimber
authors.forename: George
authors.initials: G
authors.lastname: Orphanides
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Moggs
mesh_terms: D000818:Animals; D005355:Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006540:Herbicides / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010269:Paraquat / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D006540:Herbicides; D012333:RNA, Messenger; D010269:Paraquat