Project: Cancer risk associated with low dose silica exposure
In a recent risk assessment of silica exposure it was found that occupational exposure limits are too high in Sweden and in EU. It was also found that increased risk of lung cancer could be detected at the same low levels as silicosis could be detected.
This observation challenges the contention that silica-induced cancer is a sequel of silicosis induced by high doses of silica. Another finding was that available data on silica-induced mutagenicity and its dependency on activated inflammatory cells were outdated. We thus want to investigate the relationship between inflammation and DNA damage and we focus on events occurring in respiratory epithelial cells as these are the origin of cancer.
The overall aim of this project is to characterize mechanisms for silica-induced inflammation and silica-induced DNA damage at low doses.
- Specific Aim 1: recent literature data indicate that epithelial cells have machinery for activating inflammation and ROS (reactive oxygen species) production in response to particles, and we wanted to explore the sensitivity of this system in response to silica particles and its capacity to induce DNA damage.
- Specific Aim 2: silica is known to activate autoimmunity and we wanted to explore the role of silica-induced DNA damage in activating the innate immunity system.
In cell studies we find that silica particles induce inflammation and DNA damage (double strand breaks) in lower doses then previously employed. The finding that this occurs in epithelial cells suggests that this may have a direct bearing on silica-related lung cancer. Our data challenge the mode of action for silica carcinogenesis suggested by IARC, and suggest that cancer should be seen not as a sequel of silicosis but rather as process that develops in parallel with silicosis. We have also observed that silica particles induce nuclear blebs with DNA leaving the nucleus. The role of this extranuclear DNA in silica induced immunity is under investigation. In collaboration with Lars Alfresson, IMM KI, we will also approach the question whether our inflammatory markers can be used as biomarker for harmful silica exposure.
Crystalline silica particles cause rapid NLRP3-dependent mitochondrial depolarization and DNA damage in airway epithelial cells.
Wu R, Högberg J, Adner M, Ramos-Ramírez P, Stenius U, Zheng H
Part Fibre Toxicol 2020 08;17(1):39
ATM-activated autotaxin (ATX) propagates inflammation and DNA damage in lung epithelial cells: a new mode of action for silica-induced DNA damage?
Zheng H, Högberg J, Stenius U
Carcinogenesis 2017 12;38(12):1196-1206
Antal fall av lungcancer i Sverige orsakade av yrkesmässig exponering för kvarts.
Underlagsrapport (Bilaga 2) till rapport till AFA för projektet (Dnr 110220)