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), 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.
Kim
Su-Jin
SJ
College of Oriental Medicine, Kyung Hee University, Hoegi-Dong, Dongdaemun-Gu, Seoul, Republic of Korea.
Jeong
Hyun-Ja
HJ
Myung
Noh-Yil
NY
Kim
Min-chol
MC
Lee
Jeong-Han
JH
So
Hong-seob
HS
Park
Rae-Kil
RK
Kim
Hyung-Min
HM
Um
Jae-Young
JY
Hong
Seung-Heon
SH
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
D000975:Antioxidants; D004785:Environmental Pollutants; D017382:Reactive Oxygen Species; D002104:Cadmium; D020169:Caspases; D000111:Acetylcysteine