Zeolites ameliorate asbestos toxicity in a transgenic model of malignant mesothelioma

Our plain-English summary of Zeolites ameliorate asbestos toxicity in a transgenic model of malignant mesothelioma, by X. Fan, C. McLaughlin, C. Robinson, et al (FASEB bioAdvances, 2019).

The study

• Authors: X. Fan, C. McLaughlin, C. Robinson, J. Ravasini, K. Schelch, T. Johnson, N. van Zandwijk, G. Reid, A.M. George
• Journal: FASEB bioAdvances
• Published: 2019;1(9):550-560
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is an almost invariably fatal cancer caused by asbestos exposure. The toxicity of asbestos fibers is related to their physicochemical properties and the generation of free radicals. We set up a pilot study to investigate the potential of the zeolite clinoptilolite to counteract the asbestos carcinogenesis by preventing the generation of reactive nitrogen and oxygen radicals. In cell culture experiments, clinoptilolite prevented asbestos-induced cell death, reactive oxygen species production, DNA degradation, and overexpression of genes known to be up-regulated by asbestos. In an asbestos-induced transgenic mouse model of MM, mice were injected intraperitoneal injections with blue asbestos, with or without clinoptilolite, and monitored for 30 weeks. By the end of the trial all 13 mice injected with asbestos alone had reached humane end points, whereas only 7 of 29 mice receiving crocidolite and clinoptilolite reached a similar stage of disease. Post-mortem examination revealed pinpoint mesothelioma-like tumors in affected mice, and the absence of tumor formation in surviving mice. Interestingly, the macrophage clearance system, which was largely suppressed in asbestos-treated mice, exhibited evidence of increased phagocytosis in mice treated with asbestos and clinoptilolite. Our study suggests that inhibiting the asbestos-induced generation of reactive oxygen species and stimulating the macrophage system may represent a pathway to amelioration of asbestos-induced toxicity. Additional studies are warranted to explore the underlying mechanisms responsible for our observations.

© 2019 The Authors.

In plain English

This was a pilot laboratory and animal study testing whether clinoptilolite, a zeolite mineral, could reduce the harmful effects of asbestos. In human lung (A549) and mesothelial (MeT-5A) cell lines, fewer than 10% of cells survived exposure to chrysotile or crocidolite. More than 60% survived when natural or synthetic clinoptilolite or synthetic mordenite was added. The zeolites also prevented the rise in reactive oxygen species. Natural clinoptilolite left DNA largely intact and kept two asbestos-responsive genes, which asbestos raised five- to 20-fold, nearer control levels. In transgenic MexTAg299 mice given crocidolite injections into the abdomen, all 13 mice given crocidolite alone developed abdominal tumors. Among mice also given clinoptilolite injections, 5 of 18 given it weekly and 3 of 11 given it only early or only late developed tumors by week 30. In sampled liver and spleen sections from mice given both, more fibers had been taken up by cells. The authors called the data preliminary. They concluded that the findings point toward a potential means to reduce asbestos-induced carcinogenesis, but that it is too early to speculate on clinical use.

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: Pilot study combining cell culture experiments and an animal experiment in transgenic mice
• Who was studied: Human lung adenocarcinoma (A549) and mesothelial (MeT-5A) cell lines; mixed-sex MexTAg299 transgenic mice aged 17 to 19 weeks. These mice express the SV40 large T antigen in mesothelial cells.
• Exposure: In cells: chrysotile or crocidolite at 5 µg/cm2, with or without natural clinoptilolite, synthetic clinoptilolite or synthetic mordenite at 10 µg/cm2. In mice: crocidolite (120 mg/kg, about 3 mg per injection) injected into the abdomen in weeks 1 and 4. Some mice also received natural clinoptilolite at 30 or 90 mg/kg weekly, either throughout the trial, until week 10, or from week 10.
• Main results:
  • In cell culture, survival was under 10% after chrysotile or crocidolite exposure. It was over 60% when a zeolite was added (P < .0001).
  • The increase in reactive oxygen species after asbestos exposure in both cell lines was prevented when zeolites were present at the same time.
  • Genomic DNA was heavily degraded in cells exposed to chrysotile or crocidolite, but largely intact with asbestos plus natural clinoptilolite.
  • The genes EGR1 and IL-8 were overexpressed five to 20-fold in A549 cells exposed to chrysotile or crocidolite.
  • When natural clinoptilolite was also present, expression of EGR1 and IL-8 stayed nearer control levels.
  • All 13 mice injected with crocidolite alone developed tumors in the abdominal cavity.
  • 5 of 18 mice given crocidolite plus weekly natural clinoptilolite developed tumors by the end of the trial at week 30.
  • In the early and late clinoptilolite subgroups, 1 and 2 mice respectively developed tumors, out of 11 mice in total.
  • No mesothelioma tumors occurred in the saline or clinoptilolite-only control subgroups (three mice each).
  • Ascites fluid was present in all asbestos-treated mice but not in the zeolite group.
  • In sampled sections from asbestos-only mice, 42 free and 7 phagocytosed (taken up by cells) crocidolite fibers were counted.
  • In spleen and liver sections from asbestos plus clinoptilolite mice, 12 free and 107 phagocytosed fibers were counted.
  • Asbestos-only mice had 65 SV40-positive mesothelial cells and 38 SV40-negative Kupffer cells. Asbestos plus clinoptilolite mice had 29 and 152 respectively.
• The authors' conclusion: The authors concluded that the effects of zeolites shown here point toward a potential means to reduce asbestos-induced carcinogenesis.
• Limitations the authors state:
  • The authors acknowledged that the data are preliminary and that the mechanisms are not yet understood.
  • The control group in Trial 1 had only three mice, below the six per subgroup used for the power calculation.
  • Reactive oxygen species were measured only as general oxidative stress. More selective measures were considered beyond the study's scope.
  • The authors stated that toxicology studies and trials with more mice are needed before any clinical studies.
  • The authors stated it is too early to speculate on clinical application of the findings.

Topics

Medical terms in this study, explained in our Lexicon: Zeolite, Malignant Mesothelioma, Asbestos Exposure, Carcinogenesis, Reactive Oxygen Species (ROS), Crocidolite, Autopsy, Mesothelioma.

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