The protective mechanism of antioxidants in cadmium-induced ototoxicity in vitro and in vivo

Environ Health Perspect. 2008 Jul;116(7):854-62. doi: 10.1289/ehp.10467.


Background: Several heavy metals have been shown to have toxic effects on the peripheral and central auditory system. Cadmium (Cd2+) is an environmental contaminant showing a variety of adverse effects. Given the current rate of release into the environment, the amount of Cd2+ present in the human body and the incidence of Cd2+-related diseases are expected to increase.

Objective: The overall aim of this study was to gain further insights into the mechanism of Cd2+-induced ototoxicity.

Methods: Cell viability, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), cytochrome c (cyt c), phosphorylated extracellular signal-regulated protein kinase (p-ERK), caspases, morphologic change, and functional changes in HEI-OC1 cells, rat cochlear explants, and mouse cochlea after Cd2+ exposure were measured by flow cytometry, immunohistochemical staining, Western blot analysis, and auditory brainstem response (ABR) recording. Mechanisms underlying Cd2+ototoxicity were studied using inhibitors of different signaling pathways, caspases, and antioxidants.

Results: Cd2+ exposure caused cell death, ROS generation, MMP loss, cyt c release, activation of caspases, ERK activation, apoptosis, and finally auditory threshold shift. Cd2+ toxicity interfered with inhibitors of cellular signaling pathways, such as ERK and c-jun N-terminal kinase, and with caspase inhibitors, especially inhibitors of caspase-9 and caspase-3. The antioxidants N-acetyl-l-cysteine and ebselen showed a significant protective effect on the Cd2+ toxicity.

Conclusions: Cd2+ is ototoxic with a complex underlying mechanism. However, ROS generation may be the cause of the toxicity, and application of antioxidants can prevent the toxic effect.

Keywords: ERK; auditory cells; cadmium; caspase-3; caspase-9; extracellular signal-regulated protein kinase; organ of Corti; reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology*
  • Animals
  • Antioxidants / pharmacology*
  • Apoptosis / drug effects
  • Cadmium / toxicity*
  • Caspases / metabolism
  • Cell Line
  • Cell Survival / drug effects
  • Cochlear Diseases / chemically induced*
  • Cochlear Diseases / pathology
  • Cochlear Diseases / physiopathology
  • Environmental Pollutants / toxicity*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Organ of Corti / drug effects
  • Organ of Corti / pathology
  • Oxidative Stress / drug effects*
  • Reactive Oxygen Species / metabolism


  • Antioxidants
  • Environmental Pollutants
  • Reactive Oxygen Species
  • Cadmium
  • Caspases
  • Acetylcysteine