Donald Henderson, Ph.D. - US grants

DESCRIPTION: (Adapted from the Applicant's Abstract.) The research proposal consists of series of studies designed to define the effects of impulse/impact noise on cochlear structure and function. The first goal is to understand the relationship between the parameters of impulse and impact noise (peak, pressure, duration, number, repetition rate and spectrum) and their effects on cochlear sensitivity and pathology. The second goal is to understand the sequence of pathological changes in the cochlea associated with exposure to high levels of impact or impulse noise. The final goal is to begin to understand processes contributing to individual susceptibility to noise damage. In addition to investigating individual differences,the experiments will help to understand how the auditory system develops resistance to noise induced hearing loss. The results of this experimental program are important for developing noise standards. A consistent theme of the experiments is to develop a better understanding of how the Equal Energy Hypothesis describes the ear's reaction to impact/impulse noise.

The proposed conference is designed to integrate the current state of knowledge on the biological bases and applied aspects of noise-induced hearing loss. In the past five years scientists have made considerable progress in understanding the active processes in the cochlea and the cell biology and biochemistry of hair cells. Advances have also been made in hearing loss and how the effects of noise can be influenced by other non- acoustic variables (particularly impulse/impact noise). In addition, engineers have developed devices that more accurately capture the "noise dose" under a wide range of exposure conditions. Progress has also been made in the design of hearing protection devices. For society to use the new information and for future research. The proposed conference will bring together experts from most of the disciplines interested in noise- induced hearing loss. Each participant will present a critical review of a topic along with their most recent findings. To disseminate this information to an even broader audience, the papers and discussions will be edited and published.

Research from several laboratories have shown that the auditory system can be made more resistant to the effects of noise by prior exposure to lower levels or "conditioning" noise exposures. This proposal has the general goal of elucidating the acoustic parameters of the "conditioning" exposure that leads to a more resistant auditory system. There are six specific objectives (1) What parameters optimize the "conditioning" effect?; (2) What is the bandwidth of the increased resistance?; (3) How permanent is the state of increased resistance?; (4) How long does the "conditioning" exposure need to be and what is the latency of the increased resistance?; (5) Does the increased resistance protect the auditory system from impulse noise? (6) Does the presence of stress related proteins in the cochlea covary with noise exposure. Are these proteins specifically Heat Shock Protein 70 involved in the "toughening process"? The experimental animal model is the chinchilla. Its hearing is measured before and at various times after exposure to the conditioning exposure and the traumatizing exposure. Thirty days after the exposures the animal is sacrificed and the population of sensory, supporting and nerve cells of the cochlea are analyzed. The results may be important for understanding differences in the individual's susceptibility to noise.

DESCRIPTION: (Adapted from the Applicant's Abstract.) The research proposal consists of series of studies designed to define the effects of impulse/impact noise on cochlear structure and function. The first goal is to understand the relationship between the parameters of impulse and impact noise (peak, pressure, duration, number, repetition rate and spectrum) and their effects on cochlear sensitivity and pathology. The second goal is to understand the sequence of pathological changes in the cochlea associated with exposure to high levels of impact or impulse noise. The final goal is to begin to understand processes contributing to individual susceptibility to noise damage. In addition to investigating individual differences,the experiments will help to understand how the auditory system develops resistance to noise induced hearing loss. The results of this experimental program are important for developing noise standards. A consistent theme of the experiments is to develop a better understanding of how the Equal Energy Hypothesis describes the ear's reaction to impact/impulse noise.

This research focuses on the relation between the cochlea's antioxidant system and resistance to noise or carboplatin. The project is a logical extension of previous research in our lab that showed (1) the ear could acquire resistance to noise by prior exposure to benign moderate level noise; (2) the antioxidant enzymes catalase, glutathione reductase and gamma-glutamyl cysteine synthtase (GCS) are increased in concentration in both stria and organ of Corti after prophylactic noise exposures; (3) the degree of temporary and permanent hearing loss as well as hair loss from exposures to a traumatic noise could be reduced by prior treatment of R- phenylisopropyladenoisine (R-PIA). Collectively, these results suggest that high level noise exposures produce hearing loss by the mechanism of reactive oxygen intermediates (ROI) cytotoxicity and that prophylactic noise exposures, as well as intervention by R-PIA, can reduce both the effects of noise and cisplatin (Ryback et al., 1995). The proposed set of experiments has four specific aims: (1) What is the relation between glutathione related enzymes (specifically GCS), and susceptibility to noise? (2) Can the susceptibility to noise-induced hearing loss be decreased with drugs that up-regulate GCS or increased with drugs that suppress GCS? (3) What is the normal anatomical distribution of glutathione (GSH) and does it change with exposure to noise? (4) Is the otoxicity of carboplatin influenced by drugs that up-regulate or down- regulate the antioxidant system? These experiments will be conducted on chinchillas. Hearing functions will be measured by evoked potentials and otoacoustic emissions. GCS levels will be assessed by our collaborator Dr. Howard Steinman at Albert Einstein College of Medicine. Cochlear analysis will include cell counts from surface preparations and confocal studies of GSH distribution.

Age-related hearing loss (ARHL) is one of the most prevalent disorders associated with aging. For over 30 years, the role of oxidative stress has been known in the aging literature. In the last 5 years, it has become apparent that oxidative stress is also a primary cause of acquired hearing loss from noise exposure and ototoxic drugs. This project is designed to evaluate the role of oxidative stress in ARHL and second, explore the possibility of preventing or reversing ARHL with antioxidant drugs that have been shown to prevent noise- or drug-induced hearing loss. The experiments will be conducted with Fischer 344 rats, ages 4, 12, 24 and 30 months. All animals will be evaluated for hearing function using evoked potentials and distortion product otoacoustic emission (DPOAE). The status of the endolymphatic potential and perilymph concentration of glutathione will be measured. The cochleas will then be harvested and morphological measures of sensory cell, VIII nerve cell bodies and stria vascularis will be done. In addition, some of the cochleas will be analyzed for oxidative stress using dichlorofluorescein (DCF) and succinic dehydrogenase (SDH). Finally, a third group of cochleas will be analyzed for the status of oxidative enzymes in strial, organ of Corti and spiral ganglion. The biochemical, morphological and histological measures will be correlated with hearing threshold.