Early Physiological and Cellular Indicators of Cisplatin-Induced Ototoxicity

Cisplatin chemotherapy often causes permanent hearing loss, which leads to a multifaceted decrease in quality of life. Identification of early cisplatin-induced cochlear damage would greatly improve clinical diagnosis and provide potential drug targets to prevent cisplatin’s ototoxicity. With improved functional and immunocytochemical assays, a recent seminal discovery revealed that synaptic loss between inner hair cells and spiral ganglion neurons is a major form of early cochlear damage induced by noise exposure or aging. This breakthrough discovery prompted the current study to determine early functional, cellular, and molecular changes for cisplatin-induced hearing loss, in part to determine if synapse injury is caused by cisplatin exposure. Cisplatin was delivered in one to three treatment cycles to both male and female mice. After the cisplatin treatment of three cycles, threshold shift was observed across frequencies tested like previous studies. After the treatment of two cycles, beside loss of outer hair cells and an increase in high-frequency hearing thresholds, a significant latency delay of auditory brainstem response wave 1 was observed, including at a frequency region where there were no changes in hearing thresholds. The wave 1 latency delay was detected as early cisplatin-induced ototoxicity after only one cycle of treatment, in which no significant threshold shift was found. In the same mice, mitochondrial loss in the base of the cochlea and declining mitochondrial morphometric health were observed. Thus, we have identified early spiral ganglion-associated functional and cellular changes after cisplatin treatment that precede significant threshold shift.     

连翘酯苷对顺铂作用后豚鼠耳蜗c-jun表达的影响

目的：研究连翘酯苷对顺铂作用后豚鼠耳蜗c—jun表达的影响。方法：将30只豚鼠随机分为对照组（10只）,顺铂组（10只）和连翘酯苷组（10只）。腹腔注射顺铂溶液（8mg／kg）,1次／d,连续7d,建立顺铂耳毒性模型;连翘酯苷组在每次注射顺铂溶液30rnin前腹腔注射连翘酯苷25．0mg／kg／d,连续7d;对照组以生理盐水代替顺铂溶液注射,连续7d。实验动物被处死前,检测其DPOAE幅值变化;采用蛋白质印迹杂交（Western Blotting）检测各组豚鼠耳蜗c—jun蛋白的表达,逆转录聚合酶链反应检测各组豚鼠耳蜗c—jun基因mRNA的表达。结果：顺铂组DPOAE幅值明显低于对照组（P〈0．01）;相比于顺铂组,连翘酯苷组DPOAE幅值明显升高（P〈0．05）。顺铂组豚鼠耳蜗c—jun蛋白与mRNA表达水平均显著高于对照组（P〈0．01）;相比于顺铂组,连翘酯苷组C-jun蛋白与mRNA表达水平明显降低（P〈0．05）。结论：连翘酯苷能够通过降低c—jun的表达防护顺铂所致的耳蜗损伤。     

Lead and cadmium levels and balance and vestibular dysfunction among adult participants in the National Health and Nutrition Examination Survey (NHANES) 1999-2004

Background: Few studies have been conducted to identify risk factors for balance and vestibular dysfunction in general populations, but previous studies have reported evidence of adverse effects of lead and cadmium on balance control in high-risk groups.Objective: We evaluated the relationship between blood lead and cadmium levels and balance and vestibular dysfunction in a general population study.Methods: We analyzed data from the 1999–2004 National Health and Nutrition Examination Survey (NHANES) of 5,574 adults ≥ 40 years of age. Balance dysfunction was evaluated by the Romberg Test of Standing Balance on Firm and Compliant Support Surfaces, which examines the ability to stand unassisted using four test conditions to evaluate vestibular system, vision, and proprioception inputs that contribute to balance. Blood levels of lead and cadmium were measured by atomic absorption spectrometry. Associations were estimated using logistic regression models adjusted for potential confounders. Associations with time to loss of balance were estimated using adjusted Cox proportional hazard models.Results: The adjusted odds ratio (OR) for balance dysfunction in association with the highest quintile (3.3–48 µg/dL) versus the lowest quintile (< 1.2 µg/dL) of lead was 1.42 [95% confidence interval (CI): 1.07, 1.89]. The corresponding OR for cadmium (0.9–7.4 µg/L vs. < 0.2 µg/L) was 1.27 (95% CI: 1.01, 1.60). The adjusted hazard ratio for time to failure for the most physiologically challenging balance test among subjects with the highest vs. lowest quintiles of blood lead was 1.24 (95% CI: 1.04, 1.48). Cadmium levels were not associated with time to failure.Conclusions: Our findings suggest that blood lead and cadmium levels may be associated with balance and vestibular dysfunction in a general sample of U.S. adults.     

Platinum-induced ototoxicity in pediatric cancer survivors: GSTP1 c.313A>G variant association

Hearing damage is one of the main toxic effects of platinum compounds, it derives from the irreversible degeneration of hair cells of the ear. Genetic association studies have suggested an association between GSTP1 c.313A>G variant and platinum-induced ototoxicity in childhood cancer survivors. We aimed to detect the frequency of ototoxicity and associated risk factors in survivors of childhood cancer receiving platinum-based chemotherapy and to detect the relation between GSTP1 c.313A>G (rs1695) polymorphisms and ototoxicity. We conducted a cross-sectional study on 64 cancer survivors who received platinum agents (cisplatin and/or carboplatin) at least 2 years after the end of chemotherapy. The patients underwent comprehensive audiological evaluations and genotyping to detect the presence of the GSTP1 c.313A>G polymorphisms. Hearing loss (HL) was identified in 16/64 patients (25%), including 62.5% treated with cisplatin and 37.5% treated with carboplatin. The greater incidence of ototoxicity was found in children treated for osteosarcoma (28.1%) followed by patients with germ cell tumors (25%) and neuroblastoma (21.9%). The AA, AG, and GG types of GSTP1 c.313A>G variant were detected in 84.4%, 9.4%, and 6.3%, respectively, of patients with HL with a significant association between mutant genotype of GSTP1 rs1695 and platinum-induced ototoxicity (P = .035). HL was not significantly associated with the total cumulative dose of cisplatin and carboplatin. GSTP1 c.313A>G variant may increase the risk of HL in pediatric oncology patients treated with cisplatin or carboplatin chemotherapy.     

Brief-Tone Audiometry in Persons Treated with Salicylate

The ability to integrate acoustic energy over a period of time has been measured by brief-tone audiometry on 14 young persons treated with salicylate and after the salicylate has been excreted. The investigation showed that the temporal integration can be reversible reduced by salicylate treatment, and a relation was demonstrated between the change in temporal integration and the salicylate concentration in the blood. As the test persons had had general anaesthesia, a control test was performed on seven persons. It was shown that anaesthesia does not influence temporal integration. Experimental investigations have shown that the hearing loss produced by salicylate is due to an inhibition of enzymatic systems in the cochlea

Taking into consideration the results of brief-tone audiometry and the cochlear effect of the salicylates, one must conclude that reduced cochlear function caused reduced temporal integration     

Abolition of the negative endocochlear potential as a consequence of the gentamicin-furosemide interaction

The DC endocochlear potential and the AC cochlear potential in response to a 4 kHz tone were recorded in pigmented guinea pigs before and during ototoxic damage induced by sequential administration of the aminoglycoside antibiotic, gentamicin, and the loop diuretic, furosemide. Within 4 h significant diminution of the amplitude of the AC cochlear potential was accompanied by an almost complete abolition of the negative diffusion potential revealed by either furosemide administration or terminal anoxia. Thus, one of the effects of this interaction appears to involve a reduction in the potassium permeability of the cochlear partitions.