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

Int J Nanomedicine. 2022 Sep 24:17:4481-4496. doi: 10.2147/IJN.S378727. eCollection 2022.

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.

Keywords: CuO nanoparticle; hierarchical oxidative stress response; intratracheal instillation; nanotoxicology; spontaneously hypertensive rat.

MeSH terms

  • Animals
  • Copper / toxicity
  • Endothelin-1
  • Heme Oxygenase-1
  • Humans
  • Inflammation
  • Intercellular Adhesion Molecule-1
  • Metal Nanoparticles* / toxicity
  • Nanoparticles*
  • Oxidative Stress
  • Oxides
  • Peptidyl-Dipeptidase A
  • Rats
  • Rats, Inbred SHR
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • von Willebrand Factor

Substances

  • Endothelin-1
  • Oxides
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • von Willebrand Factor
  • Intercellular Adhesion Molecule-1
  • Copper
  • Heme Oxygenase-1
  • Peptidyl-Dipeptidase A
  • cuprous oxide
  • cupric oxide