title: Diameter and rigidity of multiwalled carbon nanotubes are critical factors in mesothelial injury and carcinogenesis.
abstract: Multiwalled carbon nanotubes (MWCNTs) have the potential for widespread applications in engineering and materials science. However, because of their needle-like shape and high durability, concerns have been raised that MWCNTs may induce asbestos-like pathogenicity. Although recent studies have demonstrated that MWCNTs induce various types of reactivities, the physicochemical features of MWCNTs that determine their cytotoxicity and carcinogenicity in mesothelial cells remain unclear. Here, we showed that the deleterious effects of nonfunctionalized MWCNTs on human mesothelial cells were associated with their diameter-dependent piercing of the cell membrane. Thin MWCNTs (diameter ∼ 50 nm) with high crystallinity showed mesothelial cell membrane piercing and cytotoxicity in vitro and subsequent inflammogenicity and mesotheliomagenicity in vivo. In contrast, thick (diameter ∼ 150 nm) or tangled (diameter ∼ 2-20 nm) MWCNTs were less toxic, inflammogenic, and carcinogenic. Thin and thick MWCNTs similarly affected macrophages. Mesotheliomas induced by MWCNTs shared homozygous deletion of Cdkn2a/2b tumor suppressor genes, similar to mesotheliomas induced by asbestos. Thus, we propose that different degrees of direct mesothelial injury by thin and thick MWCNTs are responsible for the extent of inflammogenicity and carcinogenicity. This work suggests that control of the diameter of MWCNTs could reduce the potential hazard to human health.
authors.affiliation: Department of Pathology and Biological Responses,  Nagoya University Graduate School of Medicine, Nagoya 466-8550,  Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Nagai
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Shan Hwu
authors.initials: SH
authors.lastname: Chew
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Misawa
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Shinya
authors.initials: S
authors.lastname: Akatsuka
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ishihara
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yamashita
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshikawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasui
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohara
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Gaku
authors.initials: G
authors.lastname: Ichihara
authors.forename: Kostas
authors.initials: K
authors.lastname: Kostarelos
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Miyata
authors.forename: Hisanori
authors.initials: H
authors.lastname: Shinohara
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D055028:Comparative Genomic Hybridization; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D004848:Epithelium / Q000293:injuries / Q000648:ultrastructure; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008654:Mesothelioma / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D037742:Nanotubes, Carbon / Q000506:poisoning* / Q000648:ultrastructure; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016207:Cytokines; D037742:Nanotubes, Carbon
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