ROLE OF DNA REPAIR IN PARTICLE- AND FIBER-INDUCED LUNG INJURY

Abstract

Lung injury after particle exposure is associated with the generation of reactive oxygen species (ROS), leading to increased levels of oxidative DNA damage. Furthermore, both stable and unstable DNA lesions may arise after metabolization of polycyclic aromatic hydrocarbons (PAH) frequently bound to particles. Oxidative DNA damage is predominantly removed by base excision repair (BER), which is usually comparatively fast and efficient. Nevertheless, even without exogenous exposure a measurable steady-state level of oxidative DNA lesions exists due to oxygen metabolism, and repair capacities may be exceeded upon particle exposure. Stable DNA adducts induced by PAHs are eliminated by nucleotide excision repair (NER), which is unequally distributed in the genome and incomplete in transcriptionally inactive DNA regions. Thus, even low adduct levels due to environmental exposure lead to persistent lesions in the human lung. Other factors that need to be considered are potential repair inhibitions by associated metal compounds and interindividual differences in repair capacities. Taken together, the extent of DNA repair is an important determinant in particle-induced genotoxicity and carcinogenicity.