title: The protective mechanism of antioxidants in cadmium-induced ototoxicity in vitro and in vivo.
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-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.
authors.affiliation: College of Oriental Medicine, Kyung Hee University, Hoegi-Dong, Dongdaemun-Gu, Seoul, Republic of Korea.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Hyun-Ja
authors.initials: HJ
authors.lastname: Jeong
authors.forename: Noh-Yil
authors.initials: NY
authors.lastname: Myung
authors.forename: Min-chol
authors.initials: MC
authors.lastname: Kim
authors.forename: Jeong-Han
authors.initials: JH
authors.lastname: Lee
authors.forename: Hong-seob
authors.initials: HS
authors.lastname: So
authors.forename: Rae-Kil
authors.initials: RK
authors.lastname: Park
authors.forename: Hyung-Min
authors.initials: HM
authors.lastname: Kim
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Um
authors.forename: Seung-Heon
authors.initials: SH
authors.lastname: Hong
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002104:Cadmium / Q000633:toxicity*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015834:Cochlear Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009925:Organ of Corti / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004785:Environmental Pollutants; D017382:Reactive Oxygen Species; D002104:Cadmium; D020169:Caspases; D000111:Acetylcysteine