Abstract
Indium compounds have been widely used in manufacturing displays of mobile phones, computers and televisions. However, inhalation exposure to indium compounds causes interstitial pneumonia in exposed workers and lung cancer in experimental animals. 8-Nitroguanine (8-nitroG) is a mutagenic DNA lesion formed under inflammatory conditions and may participate in indium-induced carcinogenesis. In this study, we examined 8-nitroG formation in A549 cultured human lung epithelial cells treated with indium compounds, including nanoparticles of indium oxide (In2O3) and indium-tin oxide (ITO), and indium chloride (InCl3). We performed fluorescent immunocytochemistry to examine 8-nitroG formation in indium-exposed A549 cells. All indium compounds significantly increased 8-nitroG formation in A549 cells at 5 ng/ml after 4 h incubation. 8-NitroG formation was largely reduced by 1400 W, methyl-β-cyclodextrin (MBCD) and monodansylcadaverine (MDC), suggesting the involvement of nitric oxide synthase and endocytosis. 8-NitroG formation in A549 cells was also largely suppressed by small interfering RNA (siRNA) for high-mobility group box-1 (HMGB1), receptor for advanced glycation and end products (AGER, RAGE) and Toll-like receptor 9 (TLR9). These results suggest that indium compounds induce inflammation-mediated DNA damage in lung epithelial cells via the HMGB1-RAGE-TLR9 pathway. This mechanism may contribute to indium-induced genotoxicity in the respiratory system.
Highlights
Indium compounds have been widely used in manufacturing displays of mobile phones, computers and televisions
high-mobility group box-1 (HMGB1) forms a complex with DNA, and the HMGB1-DNA complex binds to receptor for advanced glycation end products (RAGE), which is a multi-ligand receptor on cell membrane involved in cancer, sepsis and other diseases[24]
In2O3 and indium-tin oxide (ITO) nanoparticles were suspended in Dulbecco’s Modified Eagles Medium (DMEM) containing fetal bovine serum (FBS) and kanamycin, and agglomerates were dispersed with an ultrasonic homogenizer
Summary
Indium compounds have been widely used in manufacturing displays of mobile phones, computers and televisions. 8-NitroG formation in A549 cells was largely suppressed by small interfering RNA (siRNA) for high-mobility group box-1 (HMGB1), receptor for advanced glycation and end products (AGER, RAGE) and Toll-like receptor 9 (TLR9) These results suggest that indium compounds induce inflammation-mediated DNA damage in lung epithelial cells via the HMGB1-RAGE-TLR9 pathway. Our recent study has demonstrated that the HMGB1-RAGE-TLR9 signaling pathway was involved in nitrative DNA damage in human lung epithelial cells treated with multi-walled carbon nanotube (MWCNT)[27]. To clarify whether this pathway is involved in indium-induced DNA damage, we examined inhibitory effects of small interfering RNA (siRNA) for these molecules on 8-nitroG formation
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