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

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), cytochronic 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, immunohisto-chemical staining, Western blot analysis, and auditory brainstem response (ABR) recording. Mechanisnis 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.