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Thesis (M. Sc.) -- University College London, 1998. / A project submitted (to the Institute of Laryngology and Otology) as a requirement for the degree of Master of Science in Audiological Medicine, University College London. Bibliography: leaves 83-101.

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La presbyacousie est une perte de l'audition liée au vieillissement qui représente la troisième maladie chronique la plus répandue chez les personnes âgées. À ce jour, il est admis que le stress oxydant peut causer des dommages irréversibles à l'ADN et entraîner une sénescence prématurée dans les cellules en cycle. Cependant, il n'existe aucune donnée concernant le rôle des dommages de l'ADN dans la dégénérescence des cellules cochléaires liée à l’âge. En plus le lien entre le stress oxydant, les dommages à l'ADN et le vieillissement des cellules cochléaires demeure obscure.Le premier objet de ce travail était d'élucider le rôle des dommages de l'ADN dans la dégénérescence des cellules cochléaires. Pour ce faire, nous avons utilisé des approches de biologie moléculaire et cellulaire pour identifier des voies de signalisation associées aux lésions de l'ADN dans des explants cochléaires issus de souris âgées de 3 jours traitées au cisplatine (CDDP), molécule connue pour son effet secondaire ototoxique. De plus, nous avons étudié l'implication de p53, un des effecteurs clés de la signalisation des dommages de l'ADN, in vivo en traitant avec le CDDP des souris dont le gène codant pour ce facteur de transcription a été invalidé. Les possibilités de protéger l’audition contre l’effet nocif du CDDP ont été également étudiées en utilisant des inhibiteurs spécifiques ciblant les étapes clés des voies de signalisation. Enfin, nous avons utilisé des modèles murins porteurs de xénogreffes de cancer du sein humain afin de vérifier si les co-traitements permettaient de préserver l’audition sans compromettre l’efficacité anti-tumorale du CDDP. Nos résultats montrent que le CDDP induit des cassures doubles brins de l'ADN dans les cellules ciliées qui sont à l'origine de l'activation de la voie ATM-Chk2-p53 et, in fine, de la mort de ces cellules par apoptose. Nous avons également montré que l'absence de p53 in vivo prévient la perte de l'audition et la dégénérescence des cellules ciliées externes après injection intrapéritonéale de CDDP. L’application systémique ou locale de PFT-α, un inhibiteur de p53 prévient efficacement la perte auditive sans compromettre l’efficacité anti tumorale du CDDP.Le deuxième objectif de ma thèse a reposé sur l’identification des liens existant entre la surproduction des espèces réactives de l'oxygène (ROS), les dommages de l’ADN et l’apparition précoce des marqueurs de la sénescence cellulaire et de la perte de l’audition liée à l’âge. Pour ce faire, j’ai utilisé des explants cochléaires de souris âgées de 3 jours traitées au peroxyde hydrogène (H2O2). L’apparition des dommages à l’ADN et des cellules en sénescence a été étudiée en utilisant des techniques d’immunomarquage et de Western blot. Les résultats ainsi obtenus in vitro ont été ensuite validés in vivo sur les cochlées provenant de souris SAMP8 et de souris SAMR1. Afin de confirmer le rôle du stress oxydant dans l’apparition précoce de la presbyacousie, nous avons utilisé une lignée de souris invalidées pour le gène P66Shc, qui est un gène d'adaptation au stress connu pour ses rôles dans la surproduction de ROS et dans l’inhibition des enzymes antioxydants. Enfin, nous avons évalué la possibilité de prévenir ou de ralentir la perte de l’audition liée à l’âge en traitant les souris SAMP8 avec un mimétique de SOD/catalase, le EUK207. Nos résultats ont montré que: i) la surproduction de ROS est l'un des principaux facteurs causaux de la dégénérescence des cellules sensorielles de la cochlée liée à l’âge ; ii) L’activation de la voie p53-p21 entraînant l’apparition précoce de la sénescence dans les cellules cochléaires post-mitotiques, peut expliquer le vieillissement prématuré de la cochlée; iii) Le EUK207, un piégeur du superoxyde et du peroxyde d'hydrogène peut atténuer la ARHL chez les souris SAMP8. L’ensemble de ces résultats mettent en évidence des stratégies novatrices et efficaces pour la protection de l'audition. / Presbycusis or age-related hearing loss is the third most common chronic disease. It represents a major health issue in our modern society. This is due to its evolving feature and the invalidating character of this disease. To date, it is generally accepted that oxidative stress can cause irreversible DNA damage and lead to premature senescence in cycling cells. However, there is no data on the role of DNA damage in age-related cochlear cell degeneration. Moreover, the link between oxidative stress, DNA damage and cochlear cell aging remains unclear.The main objective of this work was therefore to elucidate the role of DNA damage in the degeneration of cochlear cells. To do this, we used molecular and cellular biology approaches to identify signaling pathways associated with DNA damage in cochlear explants from 3-days old mice treated with cisplatin (CDDP). This antineoplastic drug is cytotoxic by causing DNA damage and is known for its harmful effects on hearing. In addition, we investigated the involvement of p53, one of the key effectors of DNA damage signaling, in vivo by treating p53ko mice with cisplatin. Using specific inhibitors targeting key steps of signaling pathways, hearing protection from the harmful effect of CDDP have also been studied. Finally, we used mouse models carrying xenografts of human breast cancer to check whether the co-treatments we had implemented made it possible to preserve the hearing without compromising the anti-tumor efficacy of the CDDP. Our results show that CDDP induces DNA double-strand breaks in the hair cells that are responsible for the activation of the ATM-Chk2-p53 pathway and, ultimately, for the death of these cells by apoptosis. . We have also shown that the absence of p53 in vivo prevents hearing loss and external hair cells degeneration upon intraperitoneal injection of CDDP. The systemic or local treatment using the p53 inhibitor PFT-α effectively prevents hearing loss without compromising the anti-tumor efficacy of CDDP.The second objective of my thesis was to identify the links between the overproduction of reactive oxygen species (ROS), DNA damage, markers of cell senescence and age-related hearing loss. To do this, I used cochlear explants of 3-days old mice treated with increasing concentrations of hydrogen peroxide (H2O2). The appearance of DNA damage and senescent cells was investigated using immunolabeling and Western blotting technics. The results obtained in vitro were then validated in vivo on cochleae from SAMP8 (Senescence Accelerated Mouse Prone 8) and SAMR1 (Senescence Accelerated Mouse Resistant 1) mice. In order to confirm the role of oxidative stress in the early onset of presbycusis, we used a mouse line invalidated for the P66Shc gene, which is a stress adaptation gene known for its roles in ROS overproduction and in the inhibition of antioxidant enzymes. Finally, we assessed the possibility of preventing or slowing-down age-related hearing loss by treating SAMP8 mice with a SOD/catalase mimetic; EUK207. Our results showed that: i) overproduction of ROS is one of the major causal factors of age-related cochlear sensorial cells degeneration; ii) Activation of the p53-p21 pathway resulting in the early onset of senescence in postmitotic cochlear cells may explain premature aging of the cochlea; iii) EUK207 which is a superoxide and hydrogen peroxide scavenger, can attenuate ARHL in SAMP8 mice.All together our results highlight innovative and effective strategies for hearing protection.

Hair cell trauma from aminoglycosides, which may lead to permanent loss of hair cells in mammals, was studied physiologically in frogs by measuring an auditory evoked potential (AEP) in Rana pipiens. The AEP was evaluated in order to measure threshold shift (TS) and recovery from TS after the administration of the aminoglycoside antibiotic, gentamicin. To obtain an AEP, chronic electrodes were implanted into the cranium near the cochlear nucleus. The frogs were then exposed to frequency-specific narrow band ~clicks" which included a single period 1 kHz sinewave, and a computer synthesized high frequency and low frequency click. Amphibians have two hearing organs, the amphibian and basilar papillae, sensitive to low (150-1500) and high (1500-2000) frequencies, respectively. The low (AP) and high (BP) frequency clicks were created to stimulate specifically the corresponding papillae. After normal thresholds were recorded for each frog, gentamicin sulfate, 200 μM, 300 μM, or 400 μM, was injected bilaterally into the otic capsules. Thresholds were recorded until the TS had disappeared, allowing the threshold recovery period to be measured. The injections of 200 μM yielded a 10 dB change in one animal and no change in two others. The injection of 300 μM into 10 frogs and 400 μM into 20 frogs yielded at least a 10 dB change in 60% and 93% of the frogs, respectively, with the concentration of 400 μM producing threshold shifts of 20 dB. Thus, the threshold shifts were dose-dependent. Recovery times varied between six and fourteen days. No apparent differences between thresholds for the high frequency click, low frequency click and sinewave clicks were observed.

Previous studies show that pure tone thresholds are strongly correlated with distortion product otoacoustic emission amplitudes when evaluating the frequency range from 1 to 8 kHz (Avan & Bonfils, 1993). Little is known about correlations between these two measures at higher frequencies from 9-16 kHz. This study compared pure tone thresholds and distortion product otoacoustic emissions (DPOAEs) in this high frequency range for 29 normal hearing subjects ages 18-30. Pure tone thresholds were obtained at 250-16 kHz and distortion product otoacoustic emissions (DPOAE) 2,211-17,675 were measured in the same ears. DPOAE amplitudes were measured using a constant F1/F2 ratio of 1.2, with F2 values ranging from 2,211-17,675 Hz. Data obtained from 50 ears showed a decline in DPOAE amplitude with increasing frequency of the F1 and F2 primary stimulus tones. Behavioral thresholds demonstrated an increase with increasing frequency of the pure tone stimulus. Pearson r-correlation analysis demonstrated a weak relationship between measures. Further investigation revealed that equipment variables prevented accurate readings.

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With the worldwide increase in numbers of individuals infected with the human-immune deficiency virus (HIV) and acquired immune deficiency syndrome (AIDS), the need for more information became essential. The devastating influences and fatal outcome of this disease is inevitable. These individuals are confronted with mortality and various disabling conditions. One of these disabling conditions is the possible development of a hearing loss. Loss of hearing sensitivity related to HIV/AIDS is only one of numerous effects the virus may have on humans and their quality of life. Therefore increased awareness of HIV/AIDS and the influences of this disease is inevitable for the modern audiologist. The precise nature and the extent of the influence that HIV/AIDS and antiretroviral therapy (ART) has on the hearing ability of a person are unknown to date. Even though a relationship between hearing loss, HIV/AIDS and the administration of relevant medication is expected, no clear explanation is available to provide the public or clinicians with the necessary information on assessments, interventions and aural rehabilitation techniques. Without being able to identify the specific cause, symptoms and place of lesion of the hearing loss, it will be difficult to ensure appropriate monitoring and treatment. Information regarding the influences of HIV/AIDS and ART on hearing sensitivity had to be established to ensure appropriate intervention and rehabilitation options. The first part of this research project reviews the evidence available regarding the possible influences of HIV/AIDS on hearing. Throughout the research a cross-sectional design with quantitative and qualitative approaches were followed comprising of a structured interview, basic and specialized audiometric battery to obtain the necessary case history, as well as results for these different audiological tests that were conducted. The specialised tests included immittance measurements, distortion-product otoacoustic emission (DPOAE) and auditory brainstem response (ABR). The results of this study were discussed in terms of the three sub aims in accordance with the different audiological tests that were conducted. The results indicated that those participants with ART exposure had a significantly higher incidence of hearing loss. The pure tone averages were mainly found within normal limits but decreased with the progression of the final stages of HIV/AIDS. The high and low frequencies of the audiogram were often affected with loss of hearing sensitivity suggesting the presence of a high and low frequency slope. The final three stages of HIV/AIDS had a significantly higher incidence of bilateral hearing loss. ART exposure were associated with more severe degrees of hearing loss. The DPOAE and ABR indicated that cochlear and retro-cochlear damage existed often among these participants. Only 20% participants had abnormal tympanograms suggestive of conductive pathology. The results revealed that the type of pathology varied across the stages of HIV/AIDS. The conclusions and implications of this study are discussed. Recommendations incorporate the development of HIV/AIDS awareness campaigns that includes audiological information on the possible influences, where to refer or where to seek assistance; issues regarding the improvement of the modern audiologists’ knowledge in terms of the management of the audiological needs of individuals with HIV/AIDS and the application of these results in the industrial setting to utilize when they consider granting compensation claims. / Dissertation (MCommunication Pathology)--University of Pretoria, 2008. / Speech-Language Pathology and Audiology / unrestricted