title: Oral administration of pentachlorophenol induces interferon signaling mRNAs in C57BL/6 male mouse liver.
abstract: Pentachlorophenol (PCP) was monitored for transcriptome responses in adult mouse liver at 2, 4, 8 and 24 hr after a single oral administration at four dose levels, 0, 10, 30 and 100 mg/kg. The expression data obtained using Affymetrix GeneChip MOE430 2.0 were absolutized by the Percellome method and expressed as three dimensional (3D) surface graphs with axes of time, dose and copy numbers of mRNA per cell. We developed the programs RSort, for comprehensive screening of the 3D surface data and PercellomeExploror for cross-referencing and confirmed the significant responses by visual inspection. In the first 8 hr, approximately 100 probe sets (PSs) related to PXR/SXR and Cyp2a4 and other metabolic enzymes were induced whereas Fos and JunB were suppressed. At 24 hr, about 1,200 PSs were strongly induced. We cross-referenced the Percellome database consisting of 111 chemicals on the liver transcriptome and found that about half of the PSs belonged to the metabolic pathways including Nrf2-mediated oxidative stress response networks shared with some of the 111 chemicals. The other half of the induced genes were interferon signaling network genes (ISG) and their induction was unique to PCP. Toll like receptors and other pattern recognition receptors, interferon regulatory factors and interferon alpha itself were included but inflammatory cytokines were not induced. In summary, these data indicated that functional symptoms of PCP treatment, such as hyperthermia and profuse sweating might be mediated by the ISG rather than the previously documented mitochondrial uncoupling mechanism. PCP might become a hint for developing low molecular weight orally available interferon mimetic drugs following imiquimod and RO4948191 as agonists of toll-like receptor and interferon receptor.
authors.affiliation: Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences, Japan. kanno@nihs.go.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Kanno
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Aisaki
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Igarashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kitajima
authors.forename: Nae
authors.initials: N
authors.lastname: Matsuda
authors.forename: Koichi
authors.initials: K
authors.lastname: Morita
authors.forename: Masaki
authors.initials: M
authors.lastname: Tsuji
authors.forename: Noriko
authors.initials: N
authors.lastname: Moriyama
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Furukawa
authors.forename: Maki
authors.initials: M
authors.lastname: Otsuka
authors.forename: Erika
authors.initials: E
authors.lastname: Tachihara
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nakatsu
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kodama
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D007306:Insecticides / Q000008:administration & dosage* / Q000633:toxicity*; D007372:Interferons / Q000502:physiology*; D008099:Liver; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D010416:Pentachlorophenol / Q000008:administration & dosage* / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D013997:Time Factors; D043922:Toxicogenetics / Q000379:methods*; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D007306:Insecticides; D012333:RNA, Messenger; D007372:Interferons; D010416:Pentachlorophenol