Elsevier

Hearing Research

Volume 224, Issues 1–2, February 2007, Pages 34-50
Hearing Research

Research paper
Genetic dependence of cochlear cells and structures injured by noise

https://doi.org/10.1016/j.heares.2006.11.005Get rights and content

Abstract

The acute and permanent effects of a single damaging noise exposure were compared in CBA/J, C57BL/6 (B6), and closely related strains of mice. Two hours of broadband noise (4–45 kHz) at 110 dB SPL led to temporary reduction in the endocochlear potential (EP) of CBA/J and CBA/CaJ (CBA) mice and acute cellular changes in cochlear stria vascularis and spiral ligament. For the same exposure, B6 mice showed no EP reduction and little of the pathology seen in CBA. Eight weeks after exposure, all mice showed a normal EP, but only CBA mice showed injury and cell loss in cochlear lateral wall, despite the fact that B6 sustained larger permanent threshold shifts. Examination of noise injury in B6 congenics carrying alternate alleles of genes encoding otocadherin (Cdh23), agouti protein, and tyrosinase (albinism) indicated that none of these loci can account for the strain differences observed. Examination of CBA×B6 F1 mice and N2 backcross mice to B6 further indicated that susceptibility to noise-related EP reduction and associated cell pathology are inherited in an autosomal dominant manner, and are established by one or a few large effect quantitative trait loci. Findings support a common genetic basis for an entire constellation of noise-related cochlear pathologies in cochlear lateral wall and spiral limbus. Even within species, cellular targets of acute and permanent cochlear noise injury may vary with genetic makeup.

Introduction

The cellular correlates of cochlear noise injury in mammals have been intensively studied (reviews: Salvi et al., 1982, Slepecky, 1986, Saunders et al., 1991, Borg et al., 1995). From many reports, consensus has emerged concerning both the reversible changes that may underlie transient aspects of hearing loss and irreversible changes associated with permanent hearing loss. Reversible changes may include altered spatial relations within the organ of Corti (Beagley, 1965, Harding et al., 1992, Nordmann et al., 2000), injury to hair cell stereocilia (Liberman and Kiang, 1978, Liberman and Mulroy, 1982, Liberman and Dodds, 1984), injury to afferent dendrites (Robertson, 1983, Puel et al., 1998), and transient depression of the endocochlear potential (EP) (Syka et al., 1981). Irreversible changes causing permanent hearing loss appear concentrated in the organ of Corti, and dominated by hair cell loss and non-lethal hair cell injury (e.g., Covell, 1953, Johnson and Hawkins, 1976, Hamernik et al., 1989, Ou et al., 2000a, Wang et al., 2002). Wang et al. (2002) and Hirose and Liberman, 2003, Hirose et al., 2005 characterized noise injury in CBA/CaJ mouse cochlea extending beyond the organ of Corti to stria vascularis, spiral ligament, and spiral limbus. Acute changes in the cochlear lateral wall were associated with temporary reduction of the EP. Although the EP usually recovered, injury to the lateral wall and spiral limbus was permanent. While such injury may not contribute directly to permanent hearing loss, it may promote ongoing degeneration and accelerate apparent aging processes in the cochlea.

Comparative studies generally suggest that species differences among mammals in cochlear noise injury are largely quantitative (Saunders and Tilney, 1980) rather than qualitative, and support the proposition that there exists an essentially ‘mammalian’ character of cochlear noise injury. The availability of genetically distinct strains of rats and mice have made these useful for discovering genetic contributions to the severity of noise injury. Within rats (Borg, 1982, Axelsson et al., 1983) and mice (Henry, 1982, Li, 1992, Erway et al., 1996, Yoshida et al., 2000, Candreia et al., 2004, Vazquez et al., 2004), different strains show marked variation in noise susceptibility. In mice, moreover, several genetic loci that can mediate such differences are known, (e.g., Ohlemiller et al., 1999, Ohlemiller et al., 2000, Davis et al., 2001, Kozel et al., 2002, Davis et al., 2003). Little evidence, however, has been presented for qualitative differences in noise injury within or across mammalian species. In a follow-up study to the studies of Liberman, Wang, Hirose, and their colleagues (Wang et al., 2002, Hirose and Liberman, 2003), we obtained very different results in C57BL/6J (B6) mice (Ohlemiller et al., 2003). For noise exposure similar to that applied to CBA/CaJ mice, B6 mice show no significant acute EP reduction. This result seemed paradoxical, since B6 mice are known to be more vulnerable to noise-induced threshold shifts than are CBAs (Erway et al., 1993, Erway et al., 1996, Johnson et al., 1997, Davis et al., 2001). We speculated that the cellular targets of noise differ in these two strains, such that the organ of Corti is more noise susceptible in B6, while the cochlear lateral wall is more susceptible in CBAs. If that is true, then genes that modulate noise injury to the organ of Corti versus other structures may exert their influence independently, and any single metric used to compare two strains or individuals may provide an incomplete picture. Here we examine how cochlear stria vascularis, spiral ligament, and spiral limbus of CBA and B6 mice differ in their response to damaging noise. We also explore the underlying genetics using informative congenic models, as well as CBA × B6 F1 hybrid mice and N2 backcross mice to B6.

Section snippets

Animals

All procedures were approved by the Washington University Institutional Animal Care and Use Committee. The basic procedure involved exposing inbred, congenic, and hybrid mice one time to broadband noise followed by hearing assessment and recording of the endocochlear potential (EP), and sacrifice for histology 1–3 h, 24 h, or 8 weeks after exposure. All groups were roughly evenly balanced by gender. Mice were purchased directly from The Jackson Laboratory (JAX) or were derived from breeders

Control CAP threshold and EP

Abnormally elevated thresholds can reduce additional noise-induced hearing loss (Mills et al., 1997) and potential correlates such as EP reduction. To identify potential influences of initial pathology in any of our experimental groups, threshold and EP data were obtained from non-exposed controls. Fig. 1 shows CAP thresholds (A) and EP in basal and apical turns (B) in control mice from each strain at the ages tested. Thresholds were tightly distributed within the expected normal range except

Discussion

To date, mapping of hearing-related genes in mice has relied entirely on distributions of hearing thresholds (e.g., Johnson et al., 2006). Here we report a surprisingly robust phenotype revealed only by noise exposure that is manifested through the EP rather than threshold, and is closely tied to a set of well delineated pathologies of cochlear lateral wall and spiral limbus. These appear to share a ‘co-inherited’ predisposition, either because all affected cells express the underlying gene, or

Acknowledgements

Supported by NIH R01 DC03454 (K.K. Ohlemiller), P30 DC04665 (D.D. Simmons), and Washington University Med. School Department of Otolaryngology. Thanks to Drs. K.P. Steel and K.R. Johnson for advice on informative mouse strains and to J. Lett, J. Bark, and T. Rogers for technical assistance.

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