Susceptibility of p53-deficient mice to induction of mesothelioma by crocidolite asbestos fibers

Our plain-English summary of Susceptibility of p53-deficient mice to induction of mesothelioma by crocidolite asbestos fibers, by J.M. Marsella, B.L. Liu, C.A. Vaslet, et al (Environmental Health Perspectives, 1997).

The study

• Authors: J.M. Marsella, B.L. Liu, C.A. Vaslet, A.B. Kane
• Journal: Environmental Health Perspectives
• Published: 1997;105 Suppl 5(Suppl 5):1069-72
• Cited by: 35 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Exposure of mesothelial cells to asbestos fibers in vitro has been shown to induce DNA damage mediated by oxidants. An early cellular response to DNA damage is increased expression of the p53 protein. This protein induces transcription of genes that activate cell cycle checkpoints or induce apoptosis. A murine mesothelial cell line that spontaneously acquired a point mutation in the p53 gene shows increased sensitivity to DNA damage induced by crocidolite asbestos fibers. It is hypothesized that p53-deficient mice will show increased sensitivity to the genotoxic effects of asbestos and accelerated development of malignant mesotheliomas.

In plain English

In this laboratory study, the authors tested whether mice lacking working p53 genes, which help cells respond to DNA damage, develop mesothelioma more readily after asbestos exposure. Groups of 10 to 30 young mice with no working p53 copy, one copy, or normal genes were scheduled to receive weekly abdominal (intraperitoneal) injections of UICC crocidolite asbestos for 35 weeks. Mesotheliomas developed in 1 of 8 mice with no working copy (12.5%) after 22 weekly injections, and the rest died with thymic lymphomas or hemangiosarcomas. They developed in 13 of 17 mice with one copy (76%), after a mean of 44 weeks, and in 9 of 28 normal mice (32%), after a mean of 67 weeks. Tumor rates were linked to genotype (p = 0.003), and the one-copy versus normal latency difference was statistically significant (p = 0.002). In culture, mesothelial cells lacking p53 doubled faster, had more chromosomes (mean 72 versus 41), and resisted apoptosis (programmed cell death) induced by crocidolite or the drug camptothecin. The authors proposed that loss of p53 function would speed later stages of asbestos-induced 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 experiment in genetically engineered mice, plus laboratory (in vitro) experiments on mouse mesothelial cells
• Who was studied: Mice of the 129/Sv strain from Jackson Laboratories. The groups were homozygous p53-deficient (no working copy), heterozygous (one copy) and wild-type (normal). Groups of 10 to 30 mice were used, aged 6 to 8 weeks at the start. Table 1 lists 8, 17 and 28 mice respectively. Peritoneal mesothelial cells from wild-type and homozygous p53-deficient mice were also studied in culture.
• Exposure: Weekly intraperitoneal injections of UICC crocidolite asbestos in saline on a 35-week schedule. Mice were sacrificed as they developed ascites or weight loss, so not all completed the schedule. The printed dose is garbled by scanning. In culture, cells were exposed to crocidolite asbestos or the drug camptothecin for 24 hours.
• Main results:
  • In homozygous p53-deficient mice, 1 of 8 (12.5%) developed mesotheliomas after 22 weekly injections.
  • The remaining homozygous p53-deficient mice died with thymic lymphomas or hemangiosarcomas.
  • Mesotheliomas developed in 13 of 17 heterozygous mice (76%) after a mean latency of 44 weeks (plus or minus 2). They developed in 9 of 28 wild-type mice (32%) after a mean latency of 67 weeks (plus or minus 1).
  • Tumor incidence was not independent of genotype (p = 0.003, Fisher's exact test).
  • The difference in mean latency between heterozygous and wild-type mice was statistically significant (p = 0.002).
  • In culture, wild-type mesothelial cells doubled in about 24 hours. Homozygous p53-deficient cells doubled in about 12 hours.
  • Wild-type cells were nearly diploid, with a mean of 41 chromosomes (plus or minus 7). Homozygous p53-deficient cells were nearly tetraploid, with a mean of 72 chromosomes (plus or minus 6).
  • Wild-type cells treated with crocidolite or camptothecin showed apoptosis (programmed cell death). Homozygous p53-deficient cells were resistant to induction of apoptosis.
• The authors' conclusion: The authors proposed, as a hypothesis, that functional inactivation of p53 or other parts of the G1 cell cycle checkpoint would accelerate later stages in the development and progression of malignant mesotheliomas induced by asbestos fibers.
• Limitations the authors state:
  • The authors had not yet tested whether p53-deficient mesothelial cells resist apoptosis in living animals; those experiments were still in progress.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Crocidolite, Mesothelial Cells, Apoptosis.

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• Possible role of lipid peroxidation in the induction of NF-kappa B and AP-1 in RFL-6 cells by crocidolite asbestos: evidence following protection by vitamin E — S.P. Faux, P.J. Howden (1997)
• Dose-dependent mesothelioma induction by intraperitoneal administration of multi-wall carbon nanotubes in p53 heterozygous mice — A. Takagi, A. Hirose, et al. (2012)
• Synchrotron X-ray microscopy reveals early calcium and iron interaction with crocidolite fibers in the lung of exposed mice — L. Pascolo, G. Zabucchi, et al. (2016)
• Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice — S. Funahashi, Y. Okazaki, et al. (2018)

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