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Su-Jin Kim,^1,2 Hyun-Ja Jeong,^1,2 Noh-Yil Myung,^1,2 Min-chol Kim,² Jeong-Han Lee,² Hong-seob So,² Rae-Kil Park,² Hyung-Min Kim,¹ Jae-Young Um,¹ and Seung-Heon Hong²

¹College of Oriental Medicine, Kyung Hee University, Hoegi-Dong, Dongdaemun-Gu, Seoul, Republic of Korea; ²Vestibulocochlear Research Center of Wonkwang University, Iksan, Jeonbuk, Republic of Korea

Abstract
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-junN-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.

Key words: auditory cells, cadmium, caspase-3, caspase-9, ERK, extracellular signal-regulated protein kinase, organ of Corti, reactive oxygen species. Environ Health Perspect 116:854–862 (2008) . doi:10.1289/ehp.10467 available via http://dx.doi.org/ [Online 26 February 2008]

Address correspondence to S.H. Hong, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea. Telephone: 82 2 850 6805. Fax: 82 2 843 3421. E-mail: jooklim@wonkwang.ac.kr

This work was supported by the Ministry of Science and Technology/Korea Science and Engineering Foundation through the Vestibulocochlear Research Center at Wonkwang University (grant R13-2002-055-00000-0) .

The authors declare they have no competing financial interests.

Received 15 May 2007 ; accepted 25 February 2008.