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Figure 1.

 Electron micrograph of a young C57BL/6 mouse (aged 10 weeks) (basal turn) shows granules in the cytoplasm of the marginal and intermediate cells that are sparsely distributed throughout the stria vascularis (arrows) (uranyl acetate and lead citrate, original magnification [approximate], ×4600). B indicates basal cell; C, capillary; I, intermediate cell; and M, marginal cell.

Electron micrograph of a young C57BL/6 mouse (aged 10 weeks) (basal turn) shows granules in the cytoplasm of the marginal and intermediate cells that are sparsely distributed throughout the stria vascularis (arrows) (uranyl acetate and lead citrate, original magnification [approximate], ×4600). B indicates basal cell; C, capillary; I, intermediate cell; and M, marginal cell.

Figure 2.

 Electron micrograph of the stria vascularis in an old C57BL/6 mouse (aged 100 weeks) (basal turn) shows granules in lobules of marginal cells (M) that are adjacent to intermediate cells (I) (between arrowheads) (A); occasional granules containing single or multiple large, oval, homogeneous, lipoid globules (arrow) (B); and granules in intermediate cells in the cytoplasm near the nuclei (C) (uranyl acetate and lead citrate, original magnification [approximate], ×4600 [A]; ×22 500 [B], and ×45 500 [C]). B indicates basal cell; C, capillary.

Electron micrograph of the stria vascularis in an old C57BL/6 mouse (aged 100 weeks) (basal turn) shows granules in lobules of marginal cells (M) that are adjacent to intermediate cells (I) (between arrowheads) (A); occasional granules containing single or multiple large, oval, homogeneous, lipoid globules (arrow) (B); and granules in intermediate cells in the cytoplasm near the nuclei (C) (uranyl acetate and lead citrate, original magnification [approximate], ×4600 [A]; ×22 500 [B], and ×45 500 [C]). B indicates basal cell; C, capillary.

1.
Savin  C The blood vessels and pigment cells of the inner ear. Ann Otol Rhinol Laryngol 1965;74611- 622
PubMed
2.
Navarrete  CMRuah  CBSchachern  PPaparella  MM Normal and metastatic melanin in the temporal bone. Am J Otolaryngol 1995;1633- 39
PubMedArticle
3.
Conlee  JWJensen  RPParks  TNCreel  DJ Turn-specific and pigment-dependent differences in the stria vascularis of normal and gentamicin-treated albino and pigmented guinea pigs. Hear Res 1991;5557- 69
PubMedArticle
4.
Larsson  BS Interaction between chemicals and melanin. Pigment Cell Res 1993;6127- 133
PubMedArticle
5.
Conlee  JWBennett  MLCreel  DJ Differential effects of gentamicin on the distribution of cochlear function in albino and pigmented guinea pigs. Acta Otolaryngol 1995;115367- 374
PubMedArticle
6.
Crifo  S Shiver-audiometry in the conditioned guinea-pig (simplified Anderson-Wedenberg test). Acta Otolaryngol 1973;7538- 44
PubMedArticle
7.
Conlee  JWAbdul-Baqi  KJMcCandless  GACreel  DJ Differential susceptibility to noise-induced permanent threshold shift between albino and pigmented guinea pigs. Hear Res 1986;2381- 91
PubMedArticle
8.
Porta  EA Pigments in aging: an overview. Ann N Y Acad Sci 2002;95957- 65
PubMedArticle
9.
Commo  SGaillard  OBernard  A Human hair graying is linked to a specific depletion of hair follicle melanocytes affecting both the bulb and the outer root sheath. Br J Dermatol 2004;150435- 443
PubMedArticle
10.
Prota  G Recent advances in the chemistry of melanogenesis in mammals. J Invest Dermatol 1980;75122- 127
PubMedArticle
11.
Persad  SMenon  IAHaberman  HF Comparison of the effects of UV-visible irradiation of melanins and melanin-hematoporphyrin complexes from human black and red hair. Photochem Photobiol 1983;3763- 68
PubMedArticle
12.
Sarna  TSealy  RC Photoinduced oxygen consumption in melanin systems: action spectra and quantum yields for eumelanin and synthetic melanin. Photochem Photobiol 1984;3969- 74
PubMedArticle
13.
Barrenäs  ML Hair cell loss from acoustic trauma in chloroquine-treated red, black and albino guinea pigs. Audiology 1997;36187- 201
PubMedArticle
14.
Barrenäs  MLHolgers  KM Ototoxic interaction between noise and pheomelanin: distortion product otoacoustic emissions after acoustical trauma in chloroquine-treated red, black, and albino guinea pigs. Audiology 2000;39238- 246
PubMedArticle
15.
Ito  SIFPCS, The IFPCS presidential lecture: a chemist's view of melanogenesis. Pigment Cell Res 2003;16230- 236
PubMedArticle
16.
Gratton  MAWright  CG Hyperpigmentation of chinchilla stria vascularis following acoustic trauma. Pigment Cell Res 1992;530- 37
PubMedArticle
17.
Conlee  JWGerity  LCWestenberg  ISCreel  DJ Pigment-dependent differences in the stria vascularis of albino and pigmented guinea pigs and rats. Hear Res 1994;72108- 124
PubMedArticle
18.
Bartels  SIto  STrune  DRNuttall  AL Noise-induced hearing loss: the effect of melanin in the stria vascularis. Hear Res 2001;154116- 123
PubMedArticle
19.
McFadden  SLDing  DSalvi  R Anatomical, metabolic and genetic aspect of age-related hearing loss in mice. Audiology 2001;40313- 321
PubMedArticle
20.
Staecker  HZheng  QYVan De Water  TR Oxidative stress in aging in the C57B16/J cochlea. Acta Otolaryngol 2001;121666- 672
PubMedArticle
21.
Seidman  MDAhmad  NBai  U Molecular mechanisms of age-related hearing loss. Ageing Res Rev 2002;1331- 343Article
22.
Bustamante  JBredeston  LMalanga  GMordoh  J Role of melanin as a scavenger of active oxygen species. Pigment Cell Res 1993;6348- 353
PubMedArticle
23.
Zheng  QYJohnson  KRErway  LC Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses. Hear Res 1999;13094- 107
PubMedArticle
24.
Spongr  VPFlood  DGFrisina  RDSalvi  RJ Quantitative measures of hair cell loss in CBA and C57BL/6 mice throughout their life spans. J Acoust Soc Am 1997;1013546- 3553
PubMedArticle
25.
White  JABurgess  BJHall  RDNadol  JB Pattern of degeneration of the spiral ganglion cell and its processes in the C57BL/6J mouse. Hear Res 2000;14112- 18
PubMedArticle
26.
Keithley  EMCanto  CZheng  QYFischel-Ghodsian  NJohnson  KR Age-related hearing loss and the ahl locus in mice. Hear Res 2004;18821- 28
PubMedArticle
27.
Ichimiya  ISuzuki  MMogi  G Age-related changes in the murine cochlear lateral wall. Hear Res 2000;139116- 122
PubMedArticle
28.
Hequembourg  SLiberman  MC Spiral ligament pathology: a major aspect of age-related cochlear degeneration in C57BL/6 mice. J Assoc Res Otolaryngol 2001;2118- 129
PubMed
29.
Lang  HSchulte  BASchmiedt  RA Endocochlear potentials and compound action potential recovery: functions in the C57BL/6J mouse. Hear Res 2002;172118- 126
PubMedArticle
30.
Ito  S Advances in chemical analysis of melanins.  In: Nordlund  JJ, Boissy  RE, Hearing  VJ, King  RA, Ortonne  JP, eds.The Pigmentary System. New York, NY: Oxford Press; 1998:439-450
31.
Wakamatsu  KIto  SRees  JL The usefulness of 4-amino-3-hydroxyphenylalanine as a specific marker of pheomelanin. Pigment Cell Res 2002;15225- 232
PubMedArticle
32.
Hayashi  HSone  MIto  S  et al.  A novel RFP-RET transgenic mouse model with abundant eumelanin in the cochlea. Hear Res 2004;19535- 40
PubMedArticle
33.
Sohal  RSWeindruch  R Oxidative stress, caloric restriction, and aging. Science 1996;27359- 63
PubMedArticle
34.
Kimura  RSSchuknecht  HF The ultrastructure of the human stria vascularis, I. Acta Otolaryngol 1970;69415- 427
PubMedArticle
35.
Sauer  HWartenberg  MHescheler  J Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell Physiol Biochem 2001;11173- 186
PubMedArticle
Original Article
February 2007

Comparison of the Quantity of Cochlear Melanin in Young and Old C57BL/6 Mice

Author Affiliations

Author Affiliations: Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, Nagoya (Drs Hayashi, Sone, and Nakashima), and Department of Chemistry, Fujita Health University School of Health Sciences, Toyoake (Dr Wakamatsu), Aichi, Japan; and Department of Otolaryngology, Otitis Media Research Center, University of Minnesota (Drs Hayashi and Paparella and Ms Schachern), International Hearing Foundation (Dr Hayashi), and Minnesota Ear Head and Neck Clinic (Dr Paparella), Minneapolis.

Arch Otolaryngol Head Neck Surg. 2007;133(2):151-154. doi:10.1001/archotol.133.2.151
Abstract

Objective  To elucidate the functional relationship between cochlear melanin and aging.

Design  Melanin has been described in the cochlear labyrinth and has been suggested to protect the cochlea from various types of trauma. The quantity of melanin has been shown to change with aging in several organs; however, to our knowledge, aging changes in the cochlea have not been documented. Therefore, we chemically quantified cochlear eumelanin and pheomelanin contents and compared these in young and old C57BL/6 mice using high-performance liquid chromatography. Because melanin deposits in the cochlea present most extensively in the stria vascularis, we morphologically examined the stria using transmission electron microscopy.

Subjects  Cochleae from an inbred strain of C57BL/6 male and female mice; 6 at the age of 10 weeks and 5 at the age of 100 weeks were studied.

Results  The quantities of cochlear eumelanin and pheomelanin were 421 and 480 ng per cochlea in young mice, and 2060 and 765 ng per cochlea in old mice, respectively. Under transmission electron microscopy, the number of pigmented granules seemed to be greater in older mice compared with younger mice, especially in marginal cells.

Conclusion  To our knowledge, our findings are the first quantitative evidence to show an age-related overexpression of cochlear melanin and an alteration in the proportion of eumelanin and pheomelanin with aging, suggesting a possible otoprotective function of eumelanin against age-related cochlear deterioration.

Melanin has been described in the cochlear labyrinth,1,2 and it has been suggested that its function is to protect the cochlea from various types of trauma, including the effects of ototoxic drugs, such as aminoglycoside antibiotics,35 and noise-induced sensorineural hearing loss.6,7 The quantity of melanin in various organs has been shown to vary with age (eg, age-related reduction of melanin in the hair bulb and shaft, epidermis, retinal pigmented epithelial cells, and certain areas of the central nervous system; and age-related increase in senile lentigo).8,9 In a light microscopic study2 of human temporal bones, cochlear melanin was reported to increase with aging; however, to our knowledge, there have been no quantitative studies of age-related alterations of cochlear melanin.

There are 2 basic types of melanin, eumelanin and pheomelanin, in mammalian neural crest–derived melanocytes.10 Each of them has been suggested to possess different chemical and biological properties (eg, eumelanin may principally scavenge toxic reactive oxygen species [ROS] and play an otoprotective role, whereas pheomelanin may produce toxic ROS and exert toxic effects on the cochlea).1115 Studies regarding cochlear melanin, therefore, should be designed to evaluate the quantity and proportion of both types of melanin.

The stria vascularis (SV) has been reported to have the most extensive quantity of melanin deposits in the cochlea,2 and many studies3,1618 have focused on melanin deposits at this site. While the function of strial melanin on age-related strial degeneration has not been determined, we anticipated that strial melanin could have a protective effect on strial aging, because ROS has been suggested to be one mechanism associated with age-related cochlear degeneration1921 and melanin has been demonstrated to be able to scavenge ROS.22 The C57BL/6 inbred strain of mouse develops extensive hearing loss by the age of 24 months,23 and the cochlear pathological features with aging of this strain have been characterized by early degeneration of the organ of Corti and spiral ganglion cells2426 or the spiral ligament.27,28 Endocochlear potential declines little with age in this strain.29 We assumed that it would be beneficial to study an animal model whose SV remains functional with aging, like the C57BL/6 mouse, to determine if the lack of damage to the SV might be related to an increase in strial melanin. In this study, we, therefore, quantitatively compared cochlear eumelanin and pheomelanin contents in young and old C57BL/6 mice using high-performance liquid chromatography (HPLC). We also examined the SV in these young and old mice using transmission electron microscopy to address ultrastructural changes of melanin at this particular site.

METHODS
SUBJECTS

Cochleae from C57BL/6 male and female mice, 6 at the age of 10 weeks and 5 at the age of 100 weeks, were studied. All aspects of animal care and experiments were approved by the Nagoya University Animal Research Committee. The mice were housed at 22°C with free access to food and water and with 12-hour light and dark cycles. They were raised and maintained by mating in a closed colony in a quiet vivarium at the institute. All mice were deeply anesthetized with sodium pentobarbital, and both sides of their otic capsules were removed. One side was processed for evaluation for HPLC and the other for transmission electron microscopy. Both cochleae from one older mouse were damaged and were not available for HPLC analysis.

QUANTITATIVE ANALYSIS OF EUMELANIN AND PHEOMELANIN

For HPLC evaluation, the stapes was dislocated and the vestibule and semicircular canals were trimmed from the cochlea under an operating microscope. Each cochlea was then placed in a separate microcentrifuge tube at −80°C. The quantity of eumelanin and pheomelanin in each cochlea was measured by HPLC after chemical degradation. Briefly, this method is based on the formation of pyrrole-2,3,5-tricarboxylic acid by permanganate oxidation of eumelanins and of 4-amino-3-hydroxyphenylalanine by hydriodic acid hydrolysis of pheomelanins. The yields of pyrrole-2,3,5-tricarboxylic acid and 4-amino-3-hydroxyphenylalanine were shown previously to be approximately 2% from eumelanins and 11% from pheomelanins.3032

Because the processed cochleae were small and the quantity of melanin in individual cochlea was not sufficient for evaluation, tissue was pooled in each group and evaluated by HPLC. The quantity of melanin per cochlea in both groups was then compared.

MORPHOLOGICAL EXAMINATION

For transmission electron microscopic studies, the stapes was dislocated, the bony labyrinth at the apical turn was opened, and cold fixative (2.5% glutaraldehyde and 2% paraformaldehyde in 0.1M phosphate buffer, pH 7.4) was injected by perilymphatic perfusion. Fixation was continued by immersion for 2 hours. The lateral walls of the basal turn of the cochlea, containing the SV and spiral ligament, were dissected and rinsed in phosphate buffer, postfixed with 2% osmium tetroxide in phosphate buffer for 1 hour, rinsed again in phosphate buffer, dehydrated in a graded series of alcohol and propylene oxide, and embedded in epoxy resin. All fixation and dehydration procedures were performed at 4°C. Specimens were sectioned along a midmodiolar plane at about 100 nm, stained with 2% uranyl acetate and lead citrate, and examined with a transmission electron microscope (model H7100; Hitachi, Tokyo, Japan).

RESULTS
QUANTITATIVE ANALYSIS OF EUMELANIN AND PHEOMELANIN

In our study, the detection limits for pyrrole-2,3,5-tricarboxylic acid and 4-amino-3-hydroxyphenylalanine were calculated to be 0.3 and 0.4 ng per cochlea, respectively. The amounts of eumelanin and pheomelanin in the young and old mice were higher than the detection limits. The cochlea of the old mice contained about 5 times the amount of eumelanin compared with that of young animals (2060 vs 421 ng), whereas the amount of pheomelanin in old mice was less than 2 times the amount in young mice (765 vs 480 ng).

TRANSMISSION ELECTRON MICROSCOPY

The most apparent ultrastructural alterations with aging were loss of the basolateral infoldings of marginal cells and loss of the dendritic processes of the intermediate cells. There were few mitochondria remaining within the processes of the intermediate cells and a reduction of interdigitations between the marginal and intermediate cells. In the older mice, there was dilatation of the interstitial spaces between the marginal and intermediate cells with some amorphous material scattered throughout. These changes were patchily distributed in the SV of the basal turn and varied in degree among specimens. In the basal and marginal cell layer, however, interconnections at tight junctions between these cells were well preserved, even in areas of severe pathological alterations. No membrane blebbing from the luminal surface was observed in either group. Granular and spherical profiles of inclusions were sparsely distributed in the SV of the basal turn in young and old mice. They were of medium to high electron density and varied in shape, size, and quantity. The SV from the older mice seemed to contain more granules than the SV from the younger mice (Figure 1 and Figure 2A); however, the ultrastructural appearance did not seem to differ with aging. Granules in marginal cells were generally located adjacent to intermediate cells and inside of their lobules. Granules in the marginal cells occasionally demonstrated a lysosome-like appearance (Figure 2B). In intermediate cells, the granules were located within the cytoplasm, near the nuclei (Figure 2C). Granules were also sporadically present in basal cells.

COMMENT

Oxidative stress due to damage from accumulation of ROS, a natural product of aerobic metabolism,33 has been suggested to be one mechanism associated with age-related cochlear degeneration.1921 Studies have suggested a correlation between ROS and melanin in the cochlea. There are 2 types of melanin, eumelanin and pheomelanin, in melanocytes derived from the neural crests of mammals.10 Eumelanin is thought to principally scavenge ROS and may, therefore, play an otoprotective role in the cochlea, whereas pheomelanin may produce ROS and exert toxic effects on the cochlea.1114 By using HPLC, we demonstrated that the cochleae of old mice contained about 5 times the amount of eumelanin compared with the cochleae of young mice; however, the amount of pheomelanin content in old mice was less than 2 times the amount in young animals. Because the cochlea has been suggested to be exposed to increased levels of free radicals with aging,20 the predominant overexpression of cochlear eumelanin with aging, compared with pheomelanin, might support the potential of cochlear melanin to protect the cochlea against the age-related hyperproduction of ROS.

Although it was not possible to distinguish the subtypes of melanin morphologically, we did observe an increased expression of spherical granules of high electron density in the SV in old mice. These granules had similar structural characteristics to melanin granules that have been identified to be heterogeneous, to be extremely electron dense, and to have numerous tiny vesicles.16 Because the SV possesses the largest quantity of melanin deposits in the cochlea,2 we would expect the proportion of the melanin subtype in the SV to correlate with the ratio obtained in our quantitative evaluation. Because the SV is an area that contains numerous mitochondria,34 and although the mitochondrial respiratory chain is the primary intracellular source of ROS,35 it seems reasonable to assume that the SV is the area most profoundly involved in the action of eumelanin against the age-related hyperproduction of ROS in the cochlea.

In this study, age-related strial degeneration of this strain was patchily distributed and was not apparent in some areas of the stria. While older mice seemed to contain more granules than younger mice, the ultrastructural characteristics did not seem to change with aging. Although we cannot rule out the possible contribution of environmental factors to the age-related alteration of cochlear melanin, exogenous factors, including environmental noise exposure, diet, and ototoxic chemical intake, were controlled. To our knowledge, our findings are the first quantitative evidence to show an age-related overexpression of cochlear melanin and an alteration in the proportion of eumelanin and pheomelanin with aging, suggesting the possible otoprotective potential of cochlear eumelanin against age-related cochlear deterioration.

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Article Information

Correspondence: Patricia A. Schachern, BS, Department of Otolaryngology, Otitis Media Research Center, University of Minnesota, 2001 Sixth St SE, Room 226, Lions Research Building, Minneapolis, MN 55455 (schac002@umn.edu).

Submitted for Publication: May 31, 2006; final revision received September 29, 2006; accepted October 16, 2006.

Author Contributions: Dr Hayashi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Hayashi, Sone, Schachern, Paparella, and Nakashima. Acquisition of data: Hayashi and Wakamatsu. Analysis and interpretation of data: Hayashi, Sone, Schachern, and Wakamatsu. Drafting of the manuscript: Hayashi, Sone, and Schachern. Critical revision of the manuscript for important intellectual content: Hayashi, Sone, Schachern, Wakamatsu, Paparella, and Nakashima. Statistical analysis: Hayashi. Obtained funding: Schachern and Paparella. Administrative, technical, and material support: Sone, Schachern, Wakamatsu, and Paparella. Study supervision: Sone, Schachern, Paparella, and Nakashima.

Financial Disclosure: None reported.

Funding/Support: This study was supported by the International Hearing Foundation, the Hubbard Foundation, and the Starkey Foundation.

Role of the Sponsor: The funding bodies had no role in data extraction and analyses, in the writing of the manuscript, or in the decision to submit the manuscript for publication.

References
1.
Savin  C The blood vessels and pigment cells of the inner ear. Ann Otol Rhinol Laryngol 1965;74611- 622
PubMed
2.
Navarrete  CMRuah  CBSchachern  PPaparella  MM Normal and metastatic melanin in the temporal bone. Am J Otolaryngol 1995;1633- 39
PubMedArticle
3.
Conlee  JWJensen  RPParks  TNCreel  DJ Turn-specific and pigment-dependent differences in the stria vascularis of normal and gentamicin-treated albino and pigmented guinea pigs. Hear Res 1991;5557- 69
PubMedArticle
4.
Larsson  BS Interaction between chemicals and melanin. Pigment Cell Res 1993;6127- 133
PubMedArticle
5.
Conlee  JWBennett  MLCreel  DJ Differential effects of gentamicin on the distribution of cochlear function in albino and pigmented guinea pigs. Acta Otolaryngol 1995;115367- 374
PubMedArticle
6.
Crifo  S Shiver-audiometry in the conditioned guinea-pig (simplified Anderson-Wedenberg test). Acta Otolaryngol 1973;7538- 44
PubMedArticle
7.
Conlee  JWAbdul-Baqi  KJMcCandless  GACreel  DJ Differential susceptibility to noise-induced permanent threshold shift between albino and pigmented guinea pigs. Hear Res 1986;2381- 91
PubMedArticle
8.
Porta  EA Pigments in aging: an overview. Ann N Y Acad Sci 2002;95957- 65
PubMedArticle
9.
Commo  SGaillard  OBernard  A Human hair graying is linked to a specific depletion of hair follicle melanocytes affecting both the bulb and the outer root sheath. Br J Dermatol 2004;150435- 443
PubMedArticle
10.
Prota  G Recent advances in the chemistry of melanogenesis in mammals. J Invest Dermatol 1980;75122- 127
PubMedArticle
11.
Persad  SMenon  IAHaberman  HF Comparison of the effects of UV-visible irradiation of melanins and melanin-hematoporphyrin complexes from human black and red hair. Photochem Photobiol 1983;3763- 68
PubMedArticle
12.
Sarna  TSealy  RC Photoinduced oxygen consumption in melanin systems: action spectra and quantum yields for eumelanin and synthetic melanin. Photochem Photobiol 1984;3969- 74
PubMedArticle
13.
Barrenäs  ML Hair cell loss from acoustic trauma in chloroquine-treated red, black and albino guinea pigs. Audiology 1997;36187- 201
PubMedArticle
14.
Barrenäs  MLHolgers  KM Ototoxic interaction between noise and pheomelanin: distortion product otoacoustic emissions after acoustical trauma in chloroquine-treated red, black, and albino guinea pigs. Audiology 2000;39238- 246
PubMedArticle
15.
Ito  SIFPCS, The IFPCS presidential lecture: a chemist's view of melanogenesis. Pigment Cell Res 2003;16230- 236
PubMedArticle
16.
Gratton  MAWright  CG Hyperpigmentation of chinchilla stria vascularis following acoustic trauma. Pigment Cell Res 1992;530- 37
PubMedArticle
17.
Conlee  JWGerity  LCWestenberg  ISCreel  DJ Pigment-dependent differences in the stria vascularis of albino and pigmented guinea pigs and rats. Hear Res 1994;72108- 124
PubMedArticle
18.
Bartels  SIto  STrune  DRNuttall  AL Noise-induced hearing loss: the effect of melanin in the stria vascularis. Hear Res 2001;154116- 123
PubMedArticle
19.
McFadden  SLDing  DSalvi  R Anatomical, metabolic and genetic aspect of age-related hearing loss in mice. Audiology 2001;40313- 321
PubMedArticle
20.
Staecker  HZheng  QYVan De Water  TR Oxidative stress in aging in the C57B16/J cochlea. Acta Otolaryngol 2001;121666- 672
PubMedArticle
21.
Seidman  MDAhmad  NBai  U Molecular mechanisms of age-related hearing loss. Ageing Res Rev 2002;1331- 343Article
22.
Bustamante  JBredeston  LMalanga  GMordoh  J Role of melanin as a scavenger of active oxygen species. Pigment Cell Res 1993;6348- 353
PubMedArticle
23.
Zheng  QYJohnson  KRErway  LC Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses. Hear Res 1999;13094- 107
PubMedArticle
24.
Spongr  VPFlood  DGFrisina  RDSalvi  RJ Quantitative measures of hair cell loss in CBA and C57BL/6 mice throughout their life spans. J Acoust Soc Am 1997;1013546- 3553
PubMedArticle
25.
White  JABurgess  BJHall  RDNadol  JB Pattern of degeneration of the spiral ganglion cell and its processes in the C57BL/6J mouse. Hear Res 2000;14112- 18
PubMedArticle
26.
Keithley  EMCanto  CZheng  QYFischel-Ghodsian  NJohnson  KR Age-related hearing loss and the ahl locus in mice. Hear Res 2004;18821- 28
PubMedArticle
27.
Ichimiya  ISuzuki  MMogi  G Age-related changes in the murine cochlear lateral wall. Hear Res 2000;139116- 122
PubMedArticle
28.
Hequembourg  SLiberman  MC Spiral ligament pathology: a major aspect of age-related cochlear degeneration in C57BL/6 mice. J Assoc Res Otolaryngol 2001;2118- 129
PubMed
29.
Lang  HSchulte  BASchmiedt  RA Endocochlear potentials and compound action potential recovery: functions in the C57BL/6J mouse. Hear Res 2002;172118- 126
PubMedArticle
30.
Ito  S Advances in chemical analysis of melanins.  In: Nordlund  JJ, Boissy  RE, Hearing  VJ, King  RA, Ortonne  JP, eds.The Pigmentary System. New York, NY: Oxford Press; 1998:439-450
31.
Wakamatsu  KIto  SRees  JL The usefulness of 4-amino-3-hydroxyphenylalanine as a specific marker of pheomelanin. Pigment Cell Res 2002;15225- 232
PubMedArticle
32.
Hayashi  HSone  MIto  S  et al.  A novel RFP-RET transgenic mouse model with abundant eumelanin in the cochlea. Hear Res 2004;19535- 40
PubMedArticle
33.
Sohal  RSWeindruch  R Oxidative stress, caloric restriction, and aging. Science 1996;27359- 63
PubMedArticle
34.
Kimura  RSSchuknecht  HF The ultrastructure of the human stria vascularis, I. Acta Otolaryngol 1970;69415- 427
PubMedArticle
35.
Sauer  HWartenberg  MHescheler  J Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell Physiol Biochem 2001;11173- 186
PubMedArticle
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