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finding was that available data on silica-induced mutagenicity and its dependency on activated inflammatory cells were outdated.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.
In cell studies we find that silica particles induce inflammation and DNA damage in lower doses than 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 challenges the mode of action for silica carcinogenesis suggested by IARC and suggests that cancer should be seen not as a sequel of silicosis but rather as process that develops in parallel with silicosis. In this project, an alternative type of DNA damage mechanism will be studied; quartz particles can cause double strand breaks and micronuclei through activation of endonuclease G. The mechanism will be further characterized in experimental models and its relevance to cancer development investigated. The project may lead to a simplified risk assessment of quartz and perhaps also to a lowering of occupational exposure limits.
ATX-LPA-Dependent Nuclear Translocation of Endonuclease G in Respiratory Epithelial Cells: A New Mode Action for DNA Damage Induced by Crystalline Silica Particles.
Zheng H, Stenius U, Högberg J
Cancers (Basel) 2023 Jan;15(3):
Approaches for the setting of occupational exposure limits (OELs) for carcinogens.
Högberg J, Järnberg J
Crit Rev Toxicol 2023 Jun;():1-37
Crystalline silica particles induce DNA damage in respiratory epithelium by ATX secretion and Rac1 activation.
Wu R, Högberg J, Adner M, Stenius U, Zheng H
Biochem Biophys Res Commun 2021 Apr;548():91-97
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)