Ototoxicity induced by cinnabar (a naturally occurring HgS) in mice through oxidative stress and down-regulated Na(+)/K(+)-ATPase activities.
Cinnabar, a naturally occurring mercuric sulfide (HgS), has long been used in Chinese mineral medicine for more than 2000 years; currently it is still used as a sedative for infants in Asian countries. Since methylmercury is potently ototoxic, whether cinnabar also induces hearing impairment is awaited for delineation. In this study, we attempted to explore the toxic effects of cinnabar on the auditory brainstem response (ABR) system during 2-10 weeks administration at a clinical oral dosage of 10mg/kg/day in mice. The results showed that Hg contents of the brainstem were significantly increased accompanied with gradually progressive abnormality of ABR during 4-10 weeks of cinnabar administration. The progressive increase in hearing thresholds, prolonged absolute and interwave latencies of ABR apparently exhibited a gender difference. Male mice were more sensitive to cinnabar in producing hearing impairment correlated with the biochemical alterations in plasma and brainstem, e.g. an increase of lipid peroxidation (LPO), altered Na(+)/K(+)-ATPase activities and decrease of nitric oxide (NO(x)) levels. Moreover, accumulation of Hg contents in brainstem with a greater extent was found in male mice. These findings provide important information that the clinical dosage of cinnabar (10mg/kg/day) still exhibited ototoxicity after continuously long-term exposure. The signaling pathway of oxidative stress/Na(+)-K(+)-ATPase activities/NO of brainstem (a central auditory regulatory system) probably plays an important role in the toxic mechanisms of cinnabar-induced ototoxicity. The gender difference in cinnabar-induced neurotoxic effects merits further investigation.
Huang
Chun-Fa
CF
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Hsu
Chuan-Jen
CJ
Liu
Shing-Hwa
SH
Lin-Shiau
Shoei-Yn
SY
D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005260:Female; D006304:Health Status; D006311:Hearing Disorders / Q000139:chemically induced* / Q000523:psychology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008628:Mercury / Q000378:metabolism; D017669:Mercury Compounds / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000096:biosynthesis*; D014018:Tissue Distribution
D017669:Mercury Compounds; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D000254:Sodium-Potassium-Exchanging ATPase; D008628:Mercury; C034211:cinnabar