Music as a unique source of noise-induced hearing loss.

Music is among the most important artistic, cultural, and entertainment modalities in any society. With the proliferation of music genres and the technological advances that allow people to consume music in any location and at any time, music over-exposure has become a significant public health issue. Music-induced hearing loss has a great deal in common with noise-induced hearing loss. However, there are important differences that make music a unique insult to the auditory system and a unique threat to public health. Its unique properties also make it a potentially valuable asset in sound conditioning paradigms. This review discusses hearing loss from noise and music, comparing and contrasting the two. Recent research on music-induced hearing loss is reviewed, followed by discussion of the differences in music-induced hearing loss between performers and consumers. The review concludes with a discussion of the potential of music as a sound conditioning stimulus to protect against acquired hearing loss.

Mild hearing loss in C57BL6/J mice after exposure to antiretroviral compounds during gestation and nursing.

OBJECTIVE: There is evidence of ototoxicity from antiretrovirals (ARVs), and ARV therapy in pregnant/nursing mothers can expose offspring to these compounds. The current work modelled whether exposure to ARVs in utero and during nursing altered the functioning of the auditory system in offspring mice. DESIGN: The females of seven breeding pairs of C57BL6/J mice were given daily doses of ARVs lamivudine and tenofovir disoproxil fumarate by oral gavage during gestation and nursing. Three breeder females were given equivalent volumes of water as controls. At wean age (3 weeks after birth), the offspring mice were tested with auditory brainstem responses (ABRs). At the conclusion of the experiment, the offspring mice's cochleae were examined for hair cell counts. STUDY SAMPLE: Ten breeder female C57BL6/J mice and 69 offspring mice. RESULTS: The offspring mice exposed to ARVs during development showed higher ABR thresholds than the control offspring. No differences were found in supra-threshold ABRs. There was no evidence of missing hair cells. CONCLUSIONS: Hearing impairment may be a possible consequence of exposure to ARVs during gestation and development. Because the threshold differences were not large, if they are occurring in humans, it is unlikely they would be identified in any hearing screening tests.

Hearing Loss in Offspring Exposed to Antiretrovirals During Pregnancy and Breastfeeding.

Over 27 million people worldwide currently receive daily antiretroviral therapy for the management of HIV/AIDS. In order to prevent the continued spread of HIV, the World Health Organization (WHO) recommends the use of highly active antiretroviral therapy by pregnant and nursing women. There is currently little research into the auditory effects of this therapy on children exposed during pregnancy and breastfeeding, and research to date on the direct effects of antiretroviral exposure on the auditory system is inconclusive. The current study examined the effects of WHO-recommended first-line antiretrovirals in a well-controlled animal model to evaluate the potential for auditory damage and dysfunction following these exposures. Female breeding mice were each exposed to one of four antiretroviral cocktails or a vehicle control once daily during pregnancy and breastfeeding. Offspring of these mice had their auditory status evaluated after weaning using auditory brainstem responses and distortion-product otoacoustic emissions (DPOAEs). Auditory brainstem response thresholds following antiretroviral exposure during gestation and breastfeeding showed elevated thresholds and increased wave latencies in offspring of exposed mice when compared to unexposed controls, but no corresponding decrease in DPOAE amplitude. These differences in threshold were small and so may explain the lack of identified hearing loss in antiretroviral-exposed children during hearing screenings at birth. Minimal degrees of hearing impairment in children have been correlated with decreased academic performance and impaired auditory processing, and so these findings, if also seen in human children, suggest significant implications for children exposed to antiretrovirals during development despite passing hearing screenings at birth.

Cochlear Preconditioning as a Modulator of Susceptibility to Hearing Loss.

Significance: Acquired sensorineural hearing loss is a major public health problem worldwide. The leading causes of sensorineural hearing loss are noise, aging, and ototoxic medications, with the key underlying pathology being damage to the cochlea. The review focuses on the phenomenon of preconditioning, in which the susceptibility to cochlear injury is reduced by exposing the ear to a stressful stimulus. Recent Advances: Cochlear conditioning has focused on the use of mono-modal conditioning, specifically conditioning the cochlea with moderate noise exposures before a traumatic exposure that causes permanent hearing loss. Recently, cross-modal conditioning has been explored more thoroughly, to prevent not only noise-induced hearing loss, but also age-related and drug-induced hearing losses. Critical Issues: Noise exposures that cause only temporary threshold shifts (TTSs) can cause long-term synaptopathy, injury to the synapses between the inner hair cells and spiral ganglion cells. This discovery has the potential to significantly alter the field of cochlear preconditioning with noise. Further, cochlear preconditioning can be the gateway to the development of clinically deployable therapeutics. Therefore, understanding the underlying mechanisms of conditioning is crucial for optimizing clinical protection against sensorineural hearing loss. Future Directions: Before the discovery of synaptopathy, noise exposures that caused only TTSs were believed to be either harmless or potentially beneficial. Any considerations of preconditioning with noise must consider the potential for injury to the synapses. Further, the discovery of different methods to precondition the cochlea against injury will yield new avenues for protection against hearing loss in the vulnerable populations. Antioxid. Redox Signal. 36, 1215-1228.

Changing the time intervals between cisplatin cycles alter its ototoxic side effect.

Various methods have been tested and deployed clinically to identify and minimize cisplatin ototoxicity. Upon early identification of hearing loss, one of the possible approaches to reducing future ototoxicity is to increase the gaps or breaks between cycles or doses of cisplatin. However, recent findings about the retention of cisplatin in the cochlea and the potential for its long-term ototoxic effects call into question whether such an approach is effective in reducing hearing loss. The current study was undertaken to determine whether increasing the rest intervals between cycles of cisplatin altered the resulting ototoxicity. CBA/CaJ mice were exposed to a cumulative dose of 48 mg/kg cisplatin delivered in three cycles of 16 mg/kg (4 mg/kg per day for 4 consecutive days). The cycles were separated by either 10, 17, or 87 days to determine if the inter-cycle rest intervals affected resulting ototoxicity. Ototoxicity was measured using auditory brainstem response threshold shifts and hair cell losses. Results indicated that longer intervals between cycles of cisplatin led to lower threshold shifts and outer hair cell lesions. The results support the principle that 'slowing down' cisplatin dosing by increasing rest intervals between doses can reduce the ototoxic side effect. Further testing is needed to optimize the timing and to determine the impact of longer inter-cycle intervals on cisplatin's anti-tumor efficacy.

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.

Cisplatin-induced threshold shift in the CBA/CaJ, C57BL/6J, BALB/cJ mouse models of hearing loss.

The development of a clinically-relevant rodent model of cisplatin-induced hearing loss presents the challenges of finding the cumulative dose, dosing schedule, and rodent strain to induce a consistent level of threshold shift with low mortality. This study was undertaken to model hearing loss at 16, 32, and 48 mg/kg cumulative doses of cisplatin in the CBA/CaJ, C57BL/6J, and BALB/cJ mouse strains. Mice were exposed to three cycles of 16 mg/kg cisplatin, for a cumulative dose of 48 mg/kg. Equal numbers of male and female mice were used in each strain, and the cisplatin was delivered in three different dosing schedules: a single bolus dose of 16 mg/kg followed by 20 days of recovery, 8 mg/kg doses delivered every ten days, and 4 mg/kg delivered daily for four consecutive days followed by 17 days of recovery. Auditory brainstem response threshold shifts indicated increased hearing loss with increasing cumulative dose in all strains and dosing schedules. The BALB/cJ experienced the largest threshold shifts, and the C57BL/6J the smallest. However, the BALB/cJ mice had the lowest mortality (0%) of the strains. The dosing schedule had minimal effects on threshold shift, but did affect mortality, with the 16 mg/kg single dose inducing more mortality than the other two schedules. In the BALB/cJ mice, the males experienced more threshold shift than the females. The results mirror past work comparing the three strains' susceptibility to kanamycin ototoxicity, with highest pigmentation showing the lowest acute susceptibility to cisplatin-induced hearing loss, and the albino strain showing the highest susceptibility.

Pharmaceutical otoprotection strategies to prevent impulse noise-induced hearing loss.

One of the ongoing challenges for hearing researchers is successful protection of the ear from noise injury. For decades, the most effective methods have been based on modifying the acoustic properties of the noise, either by reducing noise output from various sources, interfering in the acoustic exposure path with environmental controls, or altering the noise dose for the individual with personal hearing protection devices. Because of the inefficiencies of some of the acoustic modification procedures, pharmaceutical otoprotection is targeted at making the cochlea less susceptible to injury. Short-duration, high-level impulse noises, typically caused by small-scale explosions, cause different sets of injuries in the ear than long-duration, low-variance noise exposures. Therefore, the expectation is that the ears exposed to impulse noise may need different pharmaceutical interventions, both in type of compounds used and the time course of administration of the compounds. The current review discusses four different classes of compounds that have been tested as impulse noise otoprotectants. In the process of describing those experiments, particular emphasis is placed on the acoustic properties of the impulses used, with the goal of providing context for evaluating the relevance of these different models to human impulse noise-induced hearing loss.

Advances and Challenges in Pharmaceutical Therapies to Prevent and Repair Cochlear Injuries From Noise.

Noise induces a broad spectrum of pathological injuries to the cochlea, reflecting both mechanical damage to the delicate architecture of the structures of the organ of Corti and metabolic damage within the organ of Corti and lateral wall tissues. Unlike ototoxic medications, the blood-labyrinth barrier does not offer protection against noise injury. The blood-labyrinth barrier is a target of noise injury, and can be weakened as part of the metabolic pathologies in the cochlea. However, it also offers a potential for therapeutic intervention with oto-protective compounds. Because the blood-labyrinth barrier is weakened by noise, penetration of blood-borne oto-protective compounds could be higher. However, systemic dosing for cochlear protection from noise offers other significant challenges. An alternative option to systemic dosing is local administration to the cochlea through the round window membrane using a variety of drug delivery techniques. The review will discuss noise-induced cochlear pathology, including alterations to the blood-labyrinth barrier, and then transition into discussing approaches for delivery of oto-protective compounds to reduce cochlear injury from noise.

Assessing Hidden Hearing Loss After Impulse Noise in a Mouse Model.

INTRODUCTION: There are several key differences between impulse and continuous noise: the nature of the noise itself, the cochlear and neuronal structures affected, the severity to which they damage the auditory system, and the period of time in which damage occurs. Notably, no work on hidden hearing loss after impulse noise exposure has been done to this point, though it has been extensively studied after continuous noise. Hidden hearing loss manifests physiologically with reductions in suprathreshold amplitudes of the first wave of the auditory brainstem response, while auditory thresholds can remain relatively normal. OBJECTIVE: This study aimed to assess the extent to which, if at all, hidden hearing loss is present after exposure to impulse noise in C57BL6/J mice. METHODS: Thirty-one C57BL6/J mice were used in the experiment, in accordance with IACUC protocols. Auditory brainstem responses were recorded before and after noise exposures. The noise exposures consisted of 500 impulses at 137 dB peSPL. RESULTS: Suprathreshold amplitude reductions in the P1 wave of the mouse auditory brainstem response were seen, but only at frequencies with significant threshold shift. CONCLUSION: These amplitude changes were consistent with hidden hearing loss, and we conclude that impulse noise can cause hidden hearing loss, but future studies are required to determine the specific mechanisms involved and if they parallel those of hidden hearing loss after continuous noise.

Chronotolerance for cisplatin ototoxicity in the rat.

Cisplatin is a potent chemotherapeutic compound for which ototoxicity is a significant side effect. Cisplatin has shown sensitivity to circadian time, in that cisplatin is most effective as an anti-tumor compound, and least nephrotoxic, when given in the active (dark) period of the light-dark cycle in rodents. The objective of the study was to determine the sensitivity of cisplatin ototoxicity to circadian time. Fifty-seven Fischer 344/NHsd rats were exposed to 12 mg/kg cisplatin by intra-peritoneal injection at one of six time points on a 12 h light-12 h dark cycle: 2, 6, or 10 h after light onset or 2, 6, or 10 h after light offset. Cochlear injury was evaluated using auditory brainstem response threshold shifts and postmortem outer hair cell counts. All animals experienced threshold shift in the highest frequencies tested (30 and 40 kHz). The animals exposed to cisplatin at 6 h after light onset (the inactive period) had significantly higher mid-frequency threshold shifts and outer hair cell losses than the groups exposed during the dark hours. The results indicate that cisplatin is less likely to cause ototoxicity in the Fischer 344/NHsd rat when given during the active period. This finding is consistent with the lower nephrotoxicity that has been detected in cisplatin-exposed animals treated during the dark hours, and the magnitude of differences in threshold shifts between the light and dark exposure indicates that circadian timing has a significant impact on susceptibility to cisplatin ototoxicity.

Little evidence for a chronotolerance effect for impulse noise exposure in the C57BL/6J mouse.

Noise-induced hearing loss affects a large number of adults and children worldwide, and continues to be a major public health problem. The cochlea is an organ that maintains delicate metabolic homeostasis and precise mechanical architecture. Disruption of either can cause temporary or permanent injury. Impulse noises, which are short-duration, high-level bursts of sound caused by explosions, such as gunfire, can injure the cochlea through combinations of mechanical and metabolic injury. Susceptibility to the metabolic component of noise injury may vary with the circadian rhythm, a phenomenon known as chronotolerance. Chronotolerance to noise injury has been demonstrated for a one-hour noise exposure at a fixed level, but chronotolerance for impulse noise-induced hearing loss has never been studied. Forty-four mice were exposed to 500 short-duration clicks at 137 dB peSPL at one of four hours after light onset: 2, 8, 14, or 20. Auditory brainstem response threshold shifts were measured at 3, 7, and 21 days after the exposure to measure hearing loss, and post mortem outer hair cell counts were used to confirm cochlear injury. The testing revealed no significant differences between the four exposure times for hearing threshold shifts, but did detect a small, but statistically significant, difference in outer hair cell loss, in which the loss was greatest for the mice exposed two hours after light offset. Therefore, a weak chronotolerance effect for impulse noise was detected, though the functional significance of the effect is low. Further investigation is required to more fully understand the relationship between circadian rhythm and hearing loss from different types of noise exposure.

Long-Term Synergistic Interaction of Cisplatin- and Noise-Induced Hearing Losses.

OBJECTIVE: Past experiments in the literature have shown that cisplatin interacts synergistically with noise to create hearing loss. Much of the previous work on the synergistic interaction of noise and cisplatin tested exposures that occurred very close together in time. The present study assessed whether rats that have been exposed to cisplatin continue to show increased susceptibility to noise-induced hearing loss months after conclusion of the cisplatin exposure. DESIGN: Thirty-two Fischer 344/NHsd rats were exposed to one of five conditions: (1) cisplatin exposure followed by immediate cochlear tissue harvest, (2) cisplatin exposure and a 20-week monitoring period before tissue harvest, (3) cisplatin exposure followed immediately by noise exposure, (4) cisplatin exposure followed by noise exposure 16 weeks later, and (5) noise exposure without cisplatin exposure. The cisplatin exposure was an 8-week interval in which cisplatin was given every 2 weeks. Cochlear injury was evaluated using auditory brainstem response thresholds, P1 wave amplitudes, and postmortem outer hair cell counts. RESULTS: The 8-week cisplatin exposure induced little threshold shift or P1 amplitude loss, and a small lesion of missing outer hair cells in the basal half of the cochlea. The rats exposed to noise immediately after the cisplatin exposure interval showed a synergistic interaction of cisplatin and noise. The group exposed to noise 16 weeks after the cisplatin exposure interval also showed more severe threshold shift and outer hair cell loss than control subjects. The controls exposed to cisplatin and monitored for 20 weeks showed little threshold shift or outer hair cell loss, but did show P1 wave amplitude changes over the 20-week monitoring period. CONCLUSIONS: The results from the groups exposed to cisplatin followed by noise, combined with the findings from the cisplatin- and noise-only groups, suggest that the cisplatin induced cochlear injuries that were not severe enough to result in threshold shift, but left the cochlea in a state of heightened susceptibility to future injury. The heightened susceptibility to noise injury was still present 16 weeks after the conclusion of the cisplatin exposure.

Ototoxicity of 12 mg/kg cisplatin in the Fischer 344/NHsd rat using multiple dosing strategies.

Ototoxicity continues to be a major dose-limiting side effect of cis-diamminedichloroplatinum(II) (cisplatin). With an ongoing need to develop pharmaceutical protection strategies for cisplatin's ototoxicity, there is also a need to develop stable in-vivo mammalian models of cisplatin ototoxicity. The current study examined the difference in ototoxicity of a cumulative 12 mg/kg dose of cisplatin in the Fischer 344/NHsd rat when administered over four different dosing protocols. Hearing sensitivity was measured using free-field auditory brainstem response thresholds under anesthesia. Rats were divided into four groups. The first group was administered 12 mg/kg of cisplatin in a single bolus infusion. The second group was administered two 6 mg/kg infusions separated by 7 days. The third group was administered 3 mg/kg injections once per day for 4 consecutive days. The fourth group was administered 3 mg/kg injections in four injections separated by 3 days each. Hearing thresholds and body weights were measured at 3 and 7 days after the final cisplatin exposure. Postmortem sensory cell counts were used to confirm injury to the auditory system. The 4 consecutive days of 3 mg/kg induced a greater mortality rate and greater hearing loss at day 3 than the other experimental protocols. The 3 mg/kg administered every 3 days induced less sensory cell loss than the other conditions. The findings indicate that 4 consecutive days of 3 mg/kg cisplatin is not a viable ototoxicity model in the Fischer 344/NHsd rat, but that the other models are all effective in inducing comparable cochlear injuries.

Protection from noise-induced hearing loss with Src inhibitors.

Noise-induced hearing loss is a major cause of acquired hearing loss around the world and pharmacological approaches to protecting the ear from noise are under investigation. Noise results in a combination of mechanical and metabolic damage pathways in the cochlea. The Src family of protein tyrosine kinases could be active in both pathways and Src inhibitors have successfully prevented noise-induced cochlear damage and hearing loss in animal models. The long-term goal is to optimize delivery methods into the cochlea to reduce invasiveness and limit side-effects before human clinical testing can be considered. At their current early stage of research investigation, Src inhibitors represent an exciting class of compounds for inclusion in a multifaceted pharmacological approach to protecting the ear from noise.

Utility of the Vivosonic Integrity™ auditory brainstem response system as a hearing screening device for difficult-to-test children.

OBJECTIVE: Inability to complete a behavioral hearing screening is a challenge for children with developmental disorders or who are otherwise difficult to test, defined here as unable or unwilling to complete a behavioral screening. The study compared referral rates from screenings that used behavioral methods alone, with screenings that added a screen with the Vivosonic Integrity™ auditory brainstem response (ABR) device. DESIGN: Behavioral screening was performed first. Those children who failed were re-screened with the Vivosonic Integrity ABR device. Changes in referral and screening completion rates after the second screening were calculated and analysed. STUDY SAMPLE: The participant population (n = 43) consisted of children with diagnosed developmental disorders. RESULTS: Adding the Vivosonic Integrity to the screening protocol significantly increased the proportion of children who completed the screening, from 57% after behavioral screening to 81% after behavioral and ABR screening. The addition of the ABR screen did not change that overall pass/refer rate, in part because four participants who did not complete the behavioral screen received a 'Refer' outcome on the ABR screen. CONCLUSIONS: The results indicate that the Vivosonic Integrity device could be a useful tool for hearing screening of children who are difficult to screen using behavioral procedures.

A low-dose regimen of cisplatin before high-dose cisplatin potentiates ototoxicity.

OBJECTIVES/HYPOTHESIS: Cochlear preconditioning with low doses of kanamycin or noise can reduce susceptibility to noise- and ototoxic drug-induced hearing loss. The current study was undertaken to investigate whether a preconditioning regimen of low-dose cisplatin would alter susceptibility to ototoxicity induced by a single large dose of cisplatin. STUDY DESIGN: In vivo study using an animal model. METHODS: Twenty-six Fischer 344/NHsd rats were used in the study. The low-dose regimen consisted of cisplatin (2 or 3 mg/kg) given every 2 weeks by intraperitoneal injection. Control animals received injections of saline on the same schedule as the cisplatin injections. Four injections were done in total. Following the preconditioning interval, seven of the animals were sacrificed for hair cell analyses. The remaining 19 animals were exposed to 12 mg/kg cisplatin by intraperitoneal infusion to induce cochlear injury. Auditory brainstem response (ABR) thresholds were measured 3 days after cisplatin, and the cochleae from the 19 animals were harvested and analyzed. RESULTS: Statistical analyses revealed no threshold shifts, but mild outer hair cell losses, after the low-dose regimen. ABR threshold shifts in the rats exposed to the 12 mg/kg cisplatin dose were significantly higher at day 3 in the animals that underwent preconditioning with low-dose cisplatin. Outer hair cell losses were also greater in the preconditioned animals. CONCLUSIONS: Preconditioning with low-dose cisplatin, using the protocol applied in the current experiment, created potentiation of cisplatin ototoxicity, rather than protection from it. There are numerous possible explanations for this effect that should be considered. LEVEL OF EVIDENCE: NA.

A putative role of p53 pathway against impulse noise induced damage as demonstrated by protection with pifithrin-alpha and a Src inhibitor.

Exposure to high-level noise leads to oxidative stress and triggers apoptosis of the hair cells. This study examined whether p53, a tumor suppressor protein, is activated in the cochlea following impulse noise exposure. Inhibition of p53 with pifithrin alpha, a specific p53 inhibitor, or KX1-004, a Src-protein tyrosine kinase inhibitor, was tested to determine if p53 inhibition could reduce noise-induced hearing loss and cochlear damage. Chinchillas were pre-treated with a local administration of pifithrin alpha or KX1-004 and exposed to impulse noise. The chinchillas were assessed for threshold shift at 1 and 24h after the noise. At 4 or 24h post noise, the cochleae were removed and organs of Corti were examined to assess the damage to the cells and upregulation of p53 by the noise. Apoptosis was evident in both outer hair cells and supporting cells. Phospho-p53 (Ser 15) was upregulated 4h and 24h after the noise. KX1-004 and pifithrin alpha both decreased threshold shift and the number of missing outer hair cells. These results indicate that p53 is involved in the early stages of noise-induced cell death and inhibition of this signaling pathway is a potential protective strategy against noise-induced hearing loss.

Influence of dose and duration of isoflurane anesthesia on the auditory brainstem response in the rat.

OBJECTIVE: Isoflurane anesthesia can have significant effects on processing of sounds at the peripheral and central levels, manifesting in changes in auditory-evoked potentials. The current study tested whether duration of isoflurane anesthesia changes thresholds, amplitudes, and latencies of the auditory brainstem response (ABR). DESIGN: The study tested ABRs in a rat animal model under isoflurane anesthesia. Study variables were duration of isoflurane anesthesia, stimulus frequency, stimulus level, and the dose of isoflurane. Rats were anesthetized with 1.5% or 2% isoflurane. ABRs were collected from 90 to 5 dB SPL at 5-40 kHz. Three full ABR series were collected over a 105-minute period. Thresholds were assigned, and ABR wave amplitudes and latencies were measured at each stimulus frequency and level. STUDY SAMPLE: Ten Sprague-Dawley rats were tested in a repeated measures design. RESULTS: Statistical analyses revealed no significant effects of dose or duration on threshold, but a series of significant interactions between test variables for the amplitude and latency measurements. CONCLUSIONS: In the rat, dose and duration of isoflurane anesthesia induced inconsistent changes in latency and amplitude of the ABR. At 40 kHz, isoflurane dose had more powerful effects on latency and amplitude than occurred at other frequencies.

Age-related hearing loss patterns in Fischer 344/NHsd rats with cisplatin-induced hearing loss.

The current study was undertaken to explore the impact of cisplatin ototoxicity at a young adult age on the development of age-related hearing loss, both in terms of age of onset and severity of the hearing loss. For the study, 21 Fischer 344/NHsd rats were tested. All rats were tested for auditory brainstem responses (ABRs) at age 7 months and then 15 of the rats were exposed to 7 mg/kg cisplatin by intra-peritoneal infusion. The other 6 rats received saline infusions to serve as controls. Seven of the cisplatin rats were euthanized after an ABR test 7 days after cisplatin exposure to assess acute damage. The other 14 rats were tested monthly until age 18 months. Cisplatin caused acute ABR threshold shift at 30 and 40 kHz, but that acute hearing loss led to less age-related hearing loss at those frequencies. Cisplatin exposure led to a primarily additive interaction with age-related hearing loss at 20 kHz, with some exacerbation of hearing loss at age 16-18 months, along with a larger lesion of missing outer hair cells in the corresponding region of the cochlea. ABR P1 amplitude input-output functions were not significantly affected by the cisplatin exposure when controlling for threshold shift. Results indicate that cisplatin ototoxicity and age-related hearing loss interact antagonistically in the cochlear region damaged by cisplatin, and primarily show an additive interaction in the frequencies lower than the focus of the cisplatin damage.