asbestos--crocidolite and Peritonitis

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.

Topics: Animals; Asbestos, Crocidolite; Ascitic Fluid; Chemokines; Cytokines; Dose-Response Relationship, Drug; Female; Genetic Predisposition to Disease; Germ-Line Mutation; Heterozygote; Leukocytes; Macrophages, Peritoneal; Male; Mesothelioma; Mice; Mice, Inbred C57BL; Mineral Fibers; Peritoneal Neoplasms; Peritonitis; Random Allocation; Tumor Suppressor Proteins; Ubiquitin Thiolesterase

Experiments were carried out to assess the effect of intraperitoneal injection of the mineral dusts, titanium dioxide, quartz, or asbestos, on splenic lymphocyte antibody forming cells in immunised mice. Titanium dioxide and quartz caused similar, about one third, reductions in plaque forming cells; asbestos caused substantial reduction to about a quarter of the number found in control spleens. The inhibition of antibody forming cells in the spleen found with chrysotile was dose dependent and both chrysotile and crocidolite asbestos were similar in activity. Systemic immunomodulation after local deposition of mineral dust may be important to the development of disease.

Topics: Animals; Antibody-Producing Cells; Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; Dose-Response Relationship, Immunologic; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Peritonitis; Quartz; Silicon Dioxide; Spleen; Titanium