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

Our plain-English summary of Gene expression of mesothelioma in vinylidene chloride-exposed F344/N rats reveal immune dysfunction, tissue damage, and inflammation pathways, by P.E. Blackshear, A.R. Pandiri, H. Nagai, et al (Toxicologic Pathology, 2015).

The study

• Authors: P.E. Blackshear, A.R. Pandiri, H. Nagai, S. Bhusari, H.H. Hong, T.V. Ton, N.P. Clayton, M. Wyde, K.R. Shockley, S.D. Peddada, K.E. Gerrish, R.C. Sills, M.J. Hoenerhoff
• Journal: Toxicologic Pathology
• Published: 2015;43(2):171-85
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2014 by The Author(s).

In plain English

This animal study examined mesotheliomas in male F344/N rats exposed to vinylidene chloride (VDC), an industrial chemical, in a 2-year National Toxicology Program bioassay. It did not study asbestos. The authors collected tumors from 9 VDC-exposed rats (6 at 100 ppm, 2 at 50 ppm, 1 at 25 ppm). One sample was excluded because of a smudged array, leaving 8 VDC-related tumors for analysis. The authors compared these with 5 mesotheliomas that arose spontaneously in control rats and with a normal rat mesothelial cell line. Under the microscope the two tumor groups looked alike, and both shared gene pathways linked to tumor growth and inflammation. However, particular pro-inflammatory and immune dysfunction pathways, and DNA replication, recombination and repair, were significantly overrepresented only in the VDC-related tumors. A marker of DNA double-strand breaks was slightly higher in the VDC-related tumors. The authors found no statistically significant association between testicular interstitial cell tumors or testis size and mesothelioma. They concluded that VDC exposure may lead to cytotoxicity and DNA damage, which, together with inflammation and immune dysregulation, may increase susceptibility to mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal study: gene expression (microarray) profiling of rat mesotheliomas, with immunohistochemistry and qPCR, plus an analysis of testicular tumor size and mesothelioma incidence
• Who was studied: Mesotheliomas from 9 VDC-exposed male F344/N rats in an NTP 2-year bioassay (5 from the testes capsule, 2 from mesentery, 2 from peritoneum). One VDC sample was removed for a smudged array image, leaving 8. These were compared with 5 spontaneous mesotheliomas from control rats in other NTP studies (codeine, riddelliine, cobalt metal; 3 of them came from one cobalt-study animal) and with a non-transformed rat mesothelial cell line (Fred-PE), giving 19 samples in total.
• Exposure: Vinylidene chloride at 100 ppm (6 animals), 50 ppm (2 animals) or 25 ppm (1 animal) in the 2-year NTP bioassay; no asbestos exposure was studied
• Main results:
  • Mesotheliomas in VDC-exposed rats looked like spontaneous rat mesotheliomas under the microscope and were classified as epitheliomatous
  • Of 31,099 probe sets on the array, 14,136 were differentially expressed in mesotheliomas from VDC-exposed rats compared with Fred-PE cells
  • 10,372 probe sets were shared between spontaneous and VDC-related mesotheliomas, 3,764 were unique to the VDC-related tumors and 3,612 were unique to spontaneous tumors. The probe sets unique to VDC were largely associated with skeletal muscle biology, which the authors considered not relevant to mesothelioma development.
  • Mesotheliomas from both control and VDC-exposed rats shared pathways associated with tumorigenesis, including inflammatory response
  • Several canonical pathways associated with inflammation and immune response were significantly overrepresented in mesotheliomas from VDC-exposed rats, compared with Fred-PE cells, but not in spontaneous tumors. These included NF-κB, IL-8 and IL-12 signaling, Fc receptor signaling, and natural killer and dendritic cell signaling.
  • DNA replication, recombination and repair was a statistically significantly overrepresented biologic function only in mesotheliomas from VDC-exposed rats
  • Quantitative real-time PCR of selected genes agreed in direction with the microarray results in all cases
  • Gamma H2AX, a marker of DNA double-strand breaks, was slightly increased in mesotheliomas of VDC-exposed rats compared with spontaneous mesotheliomas. TP53 protein was not detected in either tumor group.
  • Among vehicle control (32) and VDC-exposed (97) rats with testicular interstitial cell adenomas, there was no statistically significant association between interstitial cell tumor incidence, tumor size or testis size and the presence of mesothelioma
• The authors' conclusion: The authors concluded that gene expression profiling distinguished VDC-related mesotheliomas from spontaneous ones despite identical appearance. They suggested that VDC exposure may cause cytotoxicity and DNA damage leading to regenerative hyperplasia and genomic instability. Together with a pro-inflammatory phenotype and immune dysregulation, these may increase susceptibility to mesothelioma in these rats.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Inflammation, Mesothelial Cells, Carcinogenesis.

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