Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma

Our plain-English summary of Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma, by A. Napolitano, L. Pellegrini, A. Dey, et al (Oncogene, 2016).

The study

• Authors: A. Napolitano, L. Pellegrini, A. Dey, D. Larson, M. Tanji, E.G. Flores, B. Kendrick, D. Lapid, A. Powers, S. Kanodia, S. Pastorino, H.I. Pass, V. Dixit, H. Yang, M. Carbone
• Journal: Oncogene
• Published: 2016;35(15):1996-2002
• Cited by: 139 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated with professional exposure to asbestos. However, to date, we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after minimal exposure. Using a BAP1(+/-) mouse model, we found that, compared with their wild-type littermates, BAP1(+/-) mice exposed to low-dose asbestos fibers showed significant alterations of the peritoneal inflammatory response, including significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1(+/-) mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, doses that rarely induced mesothelioma in wild-type mice. Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response.

In plain English

This short communication reported animal experiments. The authors compared mice with a germline change in one copy of the BAP1 gene (BAP1+/− mice), which made about half the normal BAP1 protein, with their normal (wild-type) littermates. Mice received weekly injections of crocidolite asbestos or inert glass beads into the abdominal (peritoneal) cavity. In a 5-week experiment, the overall inflammatory cell response to asbestos was largely similar in both genotypes. Asbestos-exposed BAP1+/− mice, however, had a higher share of M2 macrophages, which the authors called pro-tumorigenic, and lower levels of several signaling molecules such as MCP-1. In a 10-week experiment with 13 months of follow-up, mesothelioma developed at the low dose (0.5 mg total) in 9 of 25 (36.0%) BAP1+/− mice versus 5 of 50 (10.0%) wild-type mice. At the standard dose (5 mg total) it developed in 15 of 25 (60.0%) versus 14 of 50 (28.0%). Glass-bead groups developed no tumors. At both asbestos doses, BAP1+/− mice also had shorter life spans than wild-type mice. The authors concluded that their findings supported their hypothesis that BAP1 heterozygosity increases susceptibility to low asbestos doses. They noted that the mouse doses cannot be directly compared with human environmental exposure.

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 (short communication) comparing germline BAP1 heterozygous mice with wild-type littermates
• Who was studied: BAP1+/− mice (C57BL/6 background) and BAP1+/+ (wild-type) littermates, 10–12 weeks old, of either sex. The short-term experiment used 7 BAP1+/− and 9 wild-type mice per group. The long-term experiment used 25 BAP1+/− and 50 wild-type mice per group. Experiments were approved by the University of Hawaii animal care committee.
• Exposure: Intraperitoneal injections of crocidolite asbestos (UICC crocidolite), with inert glass beads as the control. The short-term experiment used 0.05 mg weekly for 5 weeks (0.25 mg total). The long-term experiment used 10 weekly injections of either 0.05 mg ('low-dose', 0.5 mg total) or 0.5 mg ('standard-dose', 5 mg total).
• Main results:
  • In the short-term experiment, the cellular inflammatory response to low-dose crocidolite largely overlapped between the two genotypes. In both genotypes, total leukocytes and the percentage of neutrophils increased.
  • Among asbestos-exposed mice, M2 macrophages made up 3.8% (2.1–6.8) of total macrophages in BAP1+/− mice versus 1.2% (0.5–3.6) in wild-type littermates (p less than 0.05). M1 macrophages made up 43.2% versus 67.3%.
  • In asbestos-exposed mice, MCP-1 in peritoneal lavage was lower in BAP1+/− mice than in wild-type littermates: 52.4 pg/ml (4.7–113.4) versus 178.5 pg/ml (102.9–373.2), p less than 0.05. Leukemia inhibitory factor and keratinocyte-derived chemokine were also significantly lower. The IL-6 difference did not reach significance (P = 0.08), and the eotaxin difference after asbestos was non-significant (P = 0.28).
  • Low-dose group (0.5 mg total): pathologically confirmed mesothelioma in 9/25 (36.0%) BAP1+/− mice versus 5/50 (10.0%) wild-type mice (P = 0.010).
  • Standard-dose group (5 mg total): mesothelioma in 15/25 (60.0%) BAP1+/− mice versus 14/50 (28.0%) wild-type mice (P=0.011).
  • No mesothelioma or other tumor was seen in the glass-bead control groups during 13 months of follow-up. In asbestos-exposed mice, mesothelioma was the only malignancy observed.
  • BAP1 nuclear staining was absent in all mesotheliomas analyzed from BAP1+/− mice and in 66.7% of those from wild-type mice.
  • All mesotheliomas in both genotypes showed, totally or partially, sarcomatoid features.
  • Among asbestos-exposed mice, BAP1+/− mice had significantly shorter survival (life span) than wild-type mice in both the low-dose group (p less than 0.01) and the standard-dose group (p less than 0.001).
• The authors' conclusion: The authors concluded that their findings support their hypothesis that germline BAP1 heterozygosity increases susceptibility to the carcinogenic effects of low doses of asbestos, possibly via alterations of the inflammatory response.
• Limitations the authors state:
  • The low-dose exposure in mice cannot be directly compared with indoor or outdoor environmental exposure in humans.
  • Survival from diagnosis could not be evaluated, because mice were killed at the first clinical evidence of disease.
  • The mouse tumors showed sarcomatoid features, unlike the epithelioid mesotheliomas the authors observed in human BAP1 mutation carriers. The authors attributed this likely to interspecies differences.

Topics

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

Medical terms in this study, explained in our Lexicon: Asbestos Exposure, BAP1, Mesothelioma, BAP1 Tumor Predisposition Syndrome, Malignant Mesothelioma, Carcinogenesis, Macrophage, Cytokine.

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• Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma — A. Bononi, K. Goto, et al. (2020)
• BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos — F. Novelli, A. Bononi, et al. (2021)
• Germline BAP1 mutations induce a Warburg effect — A. Bononi, H. Yang, et al. (2017)
• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)
• Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma — J. Xu, Y. Kadariya, et al. (2014)

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