Dose-dependent mesothelioma induction by intraperitoneal administration of multi-wall carbon nanotubes in p53 heterozygous mice.
Bottom Line: Right beneath was a mononuclear cell accumulation consisting of CD45- or CD3-positive lymphocytes and CD45/CD3-negative F4/80 faintly positive macrophages; some of the macrophages contained singular MWCNT in their cytoplasm.The lesions were devoid of epithelioid cell granuloma and fibrosis.These findings were in favor of the widely proposed mode of action of fiber carcinogenesis, that is, frustrated phagocytosis where the mesotheliomagenic microenvironment on the peritoneal surface is neither qualitatively altered by the density of the fibers per area nor by the formation of granulomas against agglomerates.
Affiliation: Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan.Show MeSH
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Mentions: Peritoneal mesotheliomas were induced in a dose-dependent manner shown by an increase in the cumulative incidence of the tumors (Fig. 1). In the high-dose group, 14/20 mice had single or multiple lethal mesotheliomas up to 2 × 2 cm in size located within the peritoneal cavity, invading adjacent organs and structures with or without peritoneal dissemination. The remaining mice died of ileus due to severe peritoneal adhesion and fibrosis, and among them five had small incidental (non-lethal) mesotheliomas. The total incidence of mesothelioma was 19/20 (95%) among the animals. These lesions were qualitatively identical to our previous study.2 In the middle-dose group, 17/20 (85%) mice had lethal mesothelioma. Three mice without lethal mesothelioma died or became moribund due to other reasons including leukemia. In the low-dose group, 4/20 mice had lethal mesothelioma (Fig. 2) and 1/20 had a non-lethal mesothelioma (found at the terminal kill on day 365), which makes the overall incidence of mesothelioma 5/20 (25%). The other 15 mice that survived until the terminal kill showed focal mesothelial atypical hyperplasia.13 These lesions, up to 0.5 mm in diameter, consisted of a single layer of mesothelium characterized by cuboidal or hobnail appearance with slight to moderate nuclear atypia. Right beneath the atypical mesothelium was a lentiform accumulation of mononuclear inflammatory cells up to 0.1 mm in thickness (Fig. 3). The accumulation is a combination of ill-demarcated zones of CD45-positive lymphocytes, CD3-positive lymphocytes and CD45/CD3-negative F4/80-negative or CD45/CD3-negative F4/80 weakly positive macrophage-like cells (Fig. 4). Single MWCNT fiber was often found in the cytoplasm of the macrophage-like cells. These lesions were devoid of epithelioid cell granuloma and fibrous scars.
Affiliation: Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan.