A rat model of
mesothelioma development by peritoneal injection of multiwalled
carbon nanotube (MWCNT) has been established and found to be useful to understand the mechanisms underlying fibrous particles-associated
carcinogenesis. Its detailed histological sequence, however, remains largely obscure. We therefore aimed to assess the time-course of
mesothelioma development by MWCNT and evaluate a set of
lipoprotein-related molecules as potential mechanism-based
biomarkers for the phenomenon. Male Fischer 344 rats were injected intraperitoneally (ip) with MWCNT (MWNT-7) at 1 mg/kg
body weight, and necropsied at 8, 16, 24, 32, or 42 wk after injection. For biochemical analyses of the
lipoprotein-related molecules, more samples, including severe
mesothelioma cases, were obtained from 2 other carcinogenicity tests. Histologically, in association with chronic
inflammation, mesothelial proliferative lesions appeared at c. Wk-24. Before and at the beginning of the
tumor development, a prominent infiltration of CD163-positive cells was seen near mesothelial cells. The histological pattern of early
mesothelioma was not a papillary structure, but was a characteristic structure with a spherical appearance, composed of the
mesothelioma cells in the surface area that were underlain by connective tissue-like cells. Along with the progression,
mesotheliomas started to show versatile histological subtypes. Serum levels of
apolipoprotein A-I and A-IV, and a ratio of
HDL cholesterol to total
cholesterol were inversely correlated with
mesothelioma severity. Overall, the detailed histological sequence of mesotheliomagenesis by MWCNT is demonstrated, and indicated that the altered profile of
apolipoproteins may be involved in its underlying mechanisms.