title: Gene expression of mesothelioma in vinylidene chloride-exposed F344/N rats reveal immune dysfunction, tissue damage, and inflammation pathways.
abstract: A majority (∼80%) of human malignant mesotheliomas are asbestos-related. However, non-asbestos risk factors (radiation, chemicals, and genetic factors) account for up to 30% of cases. A recent 2-year National Toxicology Program carcinogenicity bioassay showed that male F344/N rats exposed to the industrial toxicant vinylidene chloride (VDC) resulted in a marked increase in malignant mesothelioma. Global gene expression profiles of these tumors were compared to spontaneous mesotheliomas and the F344/N rat mesothelial cell line (Fred-PE) in order to characterize the molecular features and chemical-specific profiles of mesothelioma in VDC-exposed rats. As expected, mesotheliomas from control and VDC-exposed rats shared pathways associated with tumorigenesis, including cellular and tissue development, organismal injury, embryonic development, inflammatory response, cell cycle regulation, and cellular growth and proliferation, while mesotheliomas from VDC-exposed rats alone showed overrepresentation of pathways associated with pro-inflammatory pathways and immune dysfunction such as the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway, interleukin (IL)-8 and IL-12 signaling, interleukin responses, Fc receptor signaling, and natural killer and dendritic cells signaling, as well as overrepresentation of DNA damage and repair. These data suggest that a chronic, pro-inflammatory environment associated with VDC exposure may exacerbate disturbances in oncogene, growth factor, and cell cycle regulation, resulting in an increased incidence of mesothelioma.
authors: Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA Integrated Laboratory Systems, Inc., Research Triangle Park, North Carolina, USA.
authors: Pamela E
authors: PE
authors: Blackshear
authors: Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA Experimental Pathology Laboratories, Inc., Research Triangle Park, North Carolina, USA.
authors: Arun R
authors: AR
authors: Pandiri
authors: Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors: Hiroaki
authors: H
authors: Nagai
authors: Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors: Sachin
authors: S
authors: Bhusari
authors: Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors: Hue-Hua
authors: HH
authors: Hong
authors: Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors: Thai-Vu T
authors: TV
authors: Ton
authors: Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors: Natasha P
authors: NP
authors: Clayton
authors: Experimental Toxicology Group, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors: Michael
authors: M
authors: Wyde
authors: Biostatistics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors: Keith R
authors: KR
authors: Shockley
authors: Biostatistics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors: Shyamal D
authors: SD
authors: Peddada
authors: Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors: Kevin E
authors: KE
authors: Gerrish
authors: Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors: Robert C
authors: RC
authors: Sills
authors: Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA hoenerho@med.umich.edu.
authors: Mark J
authors: MJ
authors: Hoenerhoff
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004249:DNA Damage; D004000:Dichloroethylenes / Q000633:toxicity*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018816:Genes, cdc / Q000187:drug effects; D007154:Immune System Diseases / Q000139:chemically induced* / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced* / Q000503:physiopathology; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D008654:Mesothelioma / Q000139:chemically induced* / Q000235:genetics*; D000086002:Mesothelioma, Malignant; D046228:Microarray Analysis; D010534:Peritoneal Neoplasms / Q000139:chemically induced / Q000473:pathology; D012334:RNA, Neoplasm / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects; D013736:Testicular Neoplasms / Q000139:chemically induced / Q000473:pathology
chemical_list: D004000:Dichloroethylenes; D012334:RNA, Neoplasm; C029297:vinylidene chloride
keywords: F344/N rat; Fred-PE cells; National Toxicology Program; gene expression; mesothelial cell; mesothelioma; microarray; vinylidene chloride