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$({\rm Cd}^{2+})$is an environmental contaminant showing a variety of adverse effects. Given the current rate of release into the environment, the amount of${\rm Cd}^{2+}$present in the human body and the incidence of${\rm Cd}^{2+}\text{-related}$diseases are expected to increase. Objective: The overall aim of this study was to gain further insights into the mechanism of${\rm Cd}^{2+}\text{-induced}$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${\rm Cd}^{2+}$exposure were measured by flow cytometry, immunohistochemical staining, Western blot analysis, and auditory brainstem response (ABR) recording. Mechanisms underlying${\rm Cd}^{2+}$ototoxicity were studied using inhibitors of different signaling pathways, caspases, and antioxidants. Results:${\rm Cd}^{2+}$exposure caused cell death, ROS generation, MMP loss, cyt c release, activation of caspases, ERK activation, apoptosis, and finally auditory threshold shift.${\rm Cd}^{2+}$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${\rm Cd}^{2+}$toxicity. Conclusions:${\rm Cd}^{2+}$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.