Recent progress and perspectives on the mechanisms underlying Asbestos toxicity

Abstract

Most cases of mesothelioma are known to result from exposure to asbestos fibers in the environment or occupational ambient air. The following questions regarding asbestos toxicity remain partially unanswered: (i) why asbestos entering the alveoli during respiration exerts toxicity in the pleura; and (ii) how asbestos causes mesothelioma, even though human mesothelial cells are easily killed upon exposure to asbestos. As for the latter question, it is now thought that the frustrated phagocytosis of asbestos fibers by macrophages prolongs inflammatory responses and gives rise to a "mutagenic microenvironment" around mesothelial cells, resulting in their malignant transformation. Based on epidemiological and genetic studies, a carcinogenic model has been proposed in which BRCA1-associated protein 1 mutations are able to suppress cell death in mesothelial cells and increase genomic instability in the mutagenic microenvironment. This leads to additional mutations, such as CDKN2A [p16], NF2, TP53, LATS2, and SETD2, which are associated with mesothelioma carcinogenesis. Regarding the former question, the receptors involved in the intracellular uptake of asbestos and the mechanism of transfer of inhaled asbestos from the alveoli to the pleura are yet to be elucidated. Further studies using live-cell imaging techniques will be critical to fully understanding the mechanisms underlying asbestos toxicity.

Keywords: Asbestos; BAP1; Carcinogenesis; Live-cell imaging; Mesothelioma; Mutagenic microenvironment; Toxicity.

Fig. 1

Electron micrograph of asbestos. Amosite, obtained from the Japan Association for Working Environment Measurement (Tokyo, Japan), was observed by field emission scanning electron microscopy (Ultra Plus, Carl Zeiss)

Fig. 2

Frustrated phagocytosis. Fluorescently labeled asbestos (red) was phagocytosed by RAW264.7 cells. The actin cytoskeletons and nuclei were stained with Actin Green™ 488 (green) and 4′,6-diamidino-2-phenylindole (blue), respectively. This image was taken using a confocal laser scanning microscope [81]. Scale bar = 10 μm. This figure has been reproduced from the open-access article [81]

Fig. 3

A model of the carcinogenesis of mesothelioma in an asbestos-induced mutagenic microenvironment. Phagocytosed asbestos induces a mutagenic microenvironment rich in Fe (II), IL-1ß, ROS, and HMGB1 [, , , , , –52]. The BAP1 mutation contributes to the suppression of mesothelial cell death and the accumulation of additional mutations associated with mesothelioma carcinogenesis [69]. Abbreviations: IL-1ß: Interleukin-1ß; ROS, reactive oxygen species; HMGB1, high mobility group box-1 protein; BAP1, BRCA1-associated protein 1

Fig. 4

Transport of asbestos fibers from the alveoli to the pleura