Respiratory Exposure to Copper Oxide Particles Causes Multiple Organ Injuries via Oxidative Stress in a Rat Model

Abstract

Introduction The wide application of copper oxide nanoparticles (CuO NPs) in industry, agriculture, environmental remediation, and biomedicine has increased the risk of human exposure to CuO NPs. Recent studies suggested that CuO NPs have genotoxic and cytotoxic effects on various cells. However, little is known about the toxicity of CuO NPs on major peripheral organs after respiratory exposure. Materials and Methods We investigated the toxicities of CuO NPs on human bronchial epithelial (BEAS-2B) and human cardiomyocytes (AC16) cells in vitro, and on the lungs, liver, kidneys, and heart of spontaneously hypertensive rats (SHRs) at 24 and 72 h after intrabronchial instillation in vivo. Results CuO NPs induced concentration-dependent toxicities in both BEAS-2B and AC16 cells mainly through hierarchical oxidative stress mechanisms, involving generation of reactive oxygen species (ROS), upregulation of heme oxygenase-1 (HO-1), mitochondrial dysfunction, and secretion of proinflammatory and profibrogenic cytokines. Respiratory exposure to CuO NPs induced acute multiple organ injuries in SHRs manifesting through inflammation and fibrosis. However, cardiac injury was relatively less severe than injuries in the lungs, liver, and kidneys. Upregulation of serum C-reaction protein (CRP), tumor necrosis factor α (TNF-α), intercellular adhesion molecule 1 (ICAM-1), endothelin-1 (ET-1), angiotensin converting enzyme (ACE), and von Willebrand factor (vWF) after exposure to CuO NPs indicated systematic inflammation, endothelial injury, and potential prothrombosis. Conclusion Respiratory exposure to CuO NPs induced acute injuries in main peripheral organs, including the lungs, liver, kidneys, and heart. Individuals with existing cardiovascular diseases were susceptible to exposure to CuO NPs. This study provides a warning about the extensive toxic effects of CuO NPs, especially in the susceptible population.

A comparative in vitro and in vivo analysis of the impact of copper substitution on the cytocompatibility, osteogenic, and angiogenic properties of a borosilicate bioactive glass

“…Wang et al discovered that exposure to CuO nanoparticles induced the expression of EDN1 in human bronchial epithelial cells 77 . Furthermore, as previously discussed, by creating hypoxia‐like conditions, Cu could also positively impact EDN1 secretion 69,70,77 . This is in line with observations from our study, overall suggesting a positive influence of Cu‐BGs on EDN1 secretion.…”

“…[66][67][68] Apart from its ability to create a hypoxia-mimicking environment by the formation of reactive oxygen species, 69,70 there was increased expression of PlGF-transcription factors MTF-1 and NF-κB reported under the exposure of Cu. 77 Furthermore, as previously discussed, by creating hypoxia-like conditions, Cu could also positively impact EDN1 secretion. 69,70,77 80 Therefore, different Cu-concentrations seem to play an important role regarding their impact on osteogenesis in vivo.…”

“…77 Furthermore, as previously discussed, by creating hypoxia-like conditions, Cu could also positively impact EDN1 secretion. 69,70,77 80 Therefore, different Cu-concentrations seem to play an important role regarding their impact on osteogenesis in vivo. Furthermore, Bi and co-workers observed the effect of Cu to be dependent on the microstructure of the scaffold, whereas Cu seemed to enhance osteoconduction only in scaffolds of fibrous microstructure.…”

“…To date, there is very limited data available regarding the influence of Cu or Cu‐containing BGs on EDN1 secretion. Wang et al discovered that exposure to CuO nanoparticles induced the expression of EDN1 in human bronchial epithelial cells 77 . Furthermore, as previously discussed, by creating hypoxia‐like conditions, Cu could also positively impact EDN1 secretion 69,70,77 .…”

Non-ROS-Mediated Cytotoxicity of ZnO and CuO in ML-1 and CA77 Thyroid Cancer Cell Lines

“…Pcd1l2g is another inflammatory gene upregulated in CA77 cells after treatment ( Figure 11 ). It is clear that CuO MONPs cause increased inflammation as reported many times in the recent literature [ 41 , 42 , 43 ]. Given that CuO MONPs can bind to cell death ligands to induce non-ROS-mediated apoptosis [ 44 ], our RNAseq studies further confirm non-ROS-mediated apoptosis through increased inflammation pathways.…”