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

• Published in: Environmental health perspectives 2008-07, Vol.116 (7), p.854-862
• Main Authors: Kim, Su-Jin, Jeong, Hyun-Ja, Myung, Noh-Yil, Kim, Min-chol, Lee, Jeong-Han, So, Hong-seob, Park, Rae-Kil, Kim, Hyung-Min, Um, Jae-Young, Hong, Seung-Heon
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Animals; Antioxidants; Antioxidants - pharmacology; Apoptosis - drug effects; Cadmium; Cadmium - toxicity; Care and treatment; Caspases - metabolism; Cell Line; Cell Survival - drug effects; Cellular signal transduction; Cochlear Diseases - chemically induced; Cochlear Diseases - pathology; Cochlear Diseases - physiopathology; Environmental Pollutants - toxicity; Health aspects; Hearing disorders; Humans; Male; Mice; Mice, Inbred C57BL; Organ of Corti - drug effects; Organ of Corti - pathology; Oxidative Stress - drug effects; Physiological aspects; Reactive Oxygen Species - metabolism; Risk factors
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/ehp.10467

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