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Toxicol Pathol. 2015 Feb;43(2):171-85. doi: 10.1177/0192623314537885. Epub 2014 Jun 23.

Gene expression of mesothelioma in vinylidene chloride-exposed F344/N rats reveal immune dysfunction, tissue damage, and inflammation pathways.

Author information

1
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.
2
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.
3
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
4
Experimental Toxicology Group, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
5
Biostatistics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
6
Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
7
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA hoenerho@med.umich.edu.

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.

KEYWORDS:

F344/N rat; Fred-PE cells; National Toxicology Program; gene expression; mesothelial cell; mesothelioma; microarray; vinylidene chloride

PMID:
24958746
PMCID:
PMC4275413
DOI:
10.1177/0192623314537885
[Indexed for MEDLINE]
Free PMC Article

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