Formation of the Nitrative DNA Lesion 8‐Nitroguanine is Associated with Asbestos Contents in Human Lung Tissues: A Pilot Study

Abstract

Formation of the Nitrative DNA Lesion 8‐Nitroguanine is Associated with Asbestos Contents in Human Lung Tissues: A Pilot Study: Yusuke HIRAKU, et al. Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine— Objectives Asbestos causes lung cancer and malignant mesothelioma, and chronic inflammation is considered to participate in carcinogenesis. However, biomarkers to evaluate its carcinogenic risk have not been established. Reactive oxygen/nitrogen species are generated in biological systems under inflammatory conditions and may contribute to carcinogenesis by causing DNA damage. In this study, we examined the relationship between the formation of 8nitroguanine (8‐nitroG), a mutagenic DNA lesion formed during inflammation, and asbestos contents in human lung tissues. Methods We obtained non‐tumor lung tissues from patients with (n=15) and without mesothelioma (n=21). The expression of 8‐nitroG and related molecules was examined by immunohistochemistry, and their staining intensities were semiquantitatively evaluated. Asbestos contents in lung tissues were analyzed by analytical transmission electron microscopy. Results In subjects without mesothelioma, staining intensities of 8‐nitroG and apurinic/apyrimidinic endonuclease 1 (APE1) were significantly correlated with total asbestos and amphibole contents (p<0.05), but not with chrysotile content. In mesothelioma patients, their staining intensities were not correlated with asbestos contents. The double immunofluorescence technique revealed that APE1 was expressed in 8‐nitroGpositive cells, suggesting that abasic sites were formed possibly due to the removal of 8‐nitroG. The staining intensities of 8‐oxo‐7,8‐dihydro‐2’‐deoxyguanosine, an oxidative DNA lesion, and its repair enzyme 8‐oxoguanine DNA‐glycosylase were correlated with age (p<0.05), but not with asbestos contents in subjects without mesothelioma. Conclusions This is the first study to demonstrate that 8‐nitroG formation is associated with asbestos contents in human lung tissues. This finding raises a possibility that 8‐nitroG serves as a biomarker that can be used to evaluate asbestos exposure and carcinogenic risk.

Crosstalk between DNA Damage and Inflammation in the Multiple Steps of Carcinogenesis

“…Inhalation of particulate matters, including diesel engine exhaust and nanomaterials, causes chronic inflammation in respiratory systems, that may lead to chronic obstructive pulmonary disease and cancer [ 36 , 37 , 38 , 39 , 40 ]. We reported that nitrative DNA damage was strongly formed at related cancer sites by particulate matters such as asbestos [ 41 , 42 ].…”

“…In asbestos-exposed mice, 8-nitroguanine was formed in the nucleus of bronchial epithelial cells, whereas 8-nitroguanine formation was not significantly observed in control mice [ 41 ]. In humans, 8-nitroguanine formation was associated with asbestos contents in lung tissues [ 42 ]. The precise mechanisms of asbestos-induced carcinogenesis have not well been understood, but appear to involve the following molecular events: (a) irritation of the tissues; (b) severing and/or piercing the mitotic spindle, resulting in disruption of mitosis and chromosomal damage including aneuploidy; (c) ROS generation catalyzed by iron to cause DNA damage [ 44 ].…”

Catechin Attenuates the Effect of Combined Arsenic and Deltamethrin Toxicity by Abrogation of Oxidative Stress and Inflammation in Wistar Rats

“…Several studies have shown that either toxicant can induce the expression of proinflammatory cytokines [7,47]. 8-NO 2 -Gua is a product of the interaction of the highly reactive peroxynitrite, formed when nitric oxide synthase reacts with superoxide, and guanine, during inflammation [48]. Elevated plasma 8-NO 2 -Gua level in the rats further corroborates the inducement of inflammation by co-administration of As and DM.…”

Oxidative Stress and Its Significant Roles in Neurodegenerative Diseases and Cancer

“…Therefore, the formation of nitrative DNA damage could be one of the mechanisms responsible for the difference in carcinogenic potential between crocidolite and chrysotile. Our recent study demonstrated that 8-nitroguanine formation is associated with asbestos content in human lung tissues, suggesting that 8-nitroguanine serves as a biomarker that can be used to evaluate asbestos exposure and risk [ 109 ]. OLP is a chronic inflammatory mucosal disease [ 110 ] and a risk factor for oral squamous cell carcinoma (OSCC) [ 111 ].…”