Table 2.
CNT-induced pathologic effects in rodent mesothelial tissues
| Effect | CNT (length, diameter) | Animal model (exposure) | Pathologic phenotype | References |
|---|---|---|---|---|
| Inflammation and fibrosis | MWCNT (variable dimensions) | C57BL/6 mice, female (i.p., once, 50 ug for 24 h or 7 d) | Long (10–20 um or >20 um), but not short/tangled (<5 um), MWCNT caused peritoneal inflammation at 24 h and granulomas at 7 d post-exposure | Poland et al. 2008 |
| MWCNT (0.7 μm, 11.3nm) | Wistar rats (i.p., once, 2 or 20 mg for 24 m) | Moderate peritoneal inflammation and granulomas by MWCNT | Muller et al. 2009 | |
| MWCNT (variable dimensions) | C57BL/6 mice, female (i.p.i., once, 5 μm, up to 24 w) | Deposition, acute inflammation, and fibrosis in the parietal pleura by long MWCNT (NTlong2, 84% >15 μm) | Murphy et al. 2011 | |
| MWCNT (12.4 μm, 60 nm) | C57BL/6J mice (i.p., once, 50 ug for 24 h or 7 d) | Peritoneal inflammation and fibrosis by pristine fibers; reduced inflammation and fibrosis by less durable MWCNT | Osmond-McLeod et al. 2011 | |
| MWCNT-N; MWCNT-M (MWNT-7) | F344 rats (t.i.p.s., 5 times in 9 d; 250 μm each) | MWCNT translocated to the pleural cavity; visceral pleural inflammation and mesothelial proliferation | Xu et al. 2012 | |
| MWCNT (tangled CNTs, 15 nm) | F344-Brown Norway F1 hybrids (i.p., once, 10 mg for 3 y) | Absence of mesothelioma or granuloma in the peritoneal cavity | Nagai et al. 2013 | |
| MWCNT-L (8 μm, 150 nm); MWCNT-S (3 μm, 15 nm) | F344 rats (t.i.p.s., once every 2 w, 13 times over 24 w, 125 μm each time) | MWCNT-L translocated to the pleural cavity, deposited in parietal pleura, and induced fibrosis and mesothelial proliferation; MWCNT-S induced stronger inflammation in the lung than MWCNT-L | Xu et al. 2014 | |
| SWCNT (3.83 nm or 4.3 nm) | Wistar rats (i.p., once, 0.1, 0.3, 1, 3, 10 mg for 4 w) | No remarkable peritoneal inflammation or other lesions | Toyokuni et al. 2015 | |
| MWNT-7 [1.81 μm (0.12–21.5)]; SWCNT [0.5 μm (0.05–8.14)] | Wistar rats (i.t.i., once, 0.15 or 1.5mg/kg b.w., 90 d) | Persistent pulmonary inflammation by SWCNT, but greater levels of pleural inflammation by MWNT-7 | Fujita et al. 2016 | |
| CNT-1 (MWNT-7); CNT-2 (MWCNT) | C57BL/6 mice, IL1α/β double KO (i.p.i., once, 50 or 100 μg, 28 d) | Pleural mesothelial hyperplasia, inflammation, and fibrosis; CNT-1 induced stronger response than CNT-2; IL1α/β double KO mice showed ↓ lesions | Arnoldussen et al. 2018 | |
| Malignancy | MWNT-7 (1-<5 μm, 72.5%; 100 nm) | p53+/− mice, male (i.p., once; 3mg, up to 180 d) | Peritoneal fibrous scars and granulomas; atypical hyperplasia; typical mesothelioma; mortality from metastasis and peritoneal adhesion | Takagi et al. 2008 |
| MWNT-7 (same as in Takagi et al. 2008) | F344 rats (i.s., once; 1 mg/kg b.w., up to 52 w) | High incidence of peritoneal mesothelial hyperplasia, ascites, mesothelioma, metastasis, and mortality | Sakamoto et al. 2009 | |
| MWNT-7 (4 μm, 50 nm); MWCNTs (varied dimensions and rigidity) | F344-Brown Norway F1 hybrids (i.p., twice with 1 w interval; total of 1 or 10 mg for 1 y) | MWNT-7 induced frequent and early mesothelioma, and granulomas, fibrosis, iron deposition, mesothelial hyperplasia, and Cdkn2a/2b deletions | Nagai et al. 2011 | |
| MWNT-7 (2 μm, 90 nm) | p53+/− mice, male (i.p., once; 3, 30, or 300 mg for 1 y) | Concentration-dependent inflammation, granuloma, monocytes, hyperplasia, mesothelioma | Takagi et al. 2012 | |
| MWCNT (varied dimensions) | Wistar rats (i.p., once; two doses for each MWCNTs for up to 2 y) | Peritoneal mesothelioma with frequencies inversely correlated with MWCNT curvature; granuloma | Rittinghausen et al. 2014 | |
| MWNT-7 (7.1 μm or 2.8 μm) | Wistar rats (i.p., once; 6 mg for 12 m; 2mg for 30 d) | Long and short MWNT-7 induced mesothelioma, promoted by an early and sustained accumulation of immunosuppressive monocytes | Huaux et al. 2016 | |
| MWCNT-N (51% 1–4 μm, 47% 5–20 μm, 30–100 nm) | F344/Crj rats (t.i.p.s., 8 times over 2 w, 125 mg each time; up to 109 w) | Both pleural mesothelioma and lung tumors induced by MWCNT-N sieve fractions; MWCNT-N deposited in granulomas and macrophages | Suzui et al. 2016 | |
| Long MWCNT (>15 μm, 165 nm); short MWCNT (<15 μm, 125 nm) | C57BL/6 mice, female (i.p.i., variable dose and duration) | Mesothelioma with sustained inflammation and increased proliferation by long MWCNT correlated with epigenetic silencing of the tumor suppressor gene Cdkn2a | Chernova et al. 2017 |
References are listed chronologically. Abbreviations used: b.w.: body weight; CNT: carbon nanotube; d: day; h: hour; i.p.: intraperitoneal injection; i.p.i.: intrapleural injection; i.s.: intrascrotal injection; i.t.i.: intratracheal instillation; KO: knockout; m: month; MWCNT: multi-walled CNT; MWNT-7: Mitsui MWNT-7; SWCNT: single-walled CNT; t.b.i.: total body inhalation; t.i.p.s.: transtracheal intrapulmonary spraying; w: week; y: year.