Genetic basis for susceptibility to noise-induced hearing loss in mice

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Abstract

The C57BL/6J (B6) and DBA/2J (D2) inbred strains of mice exhibit an age-related hearing loss (AHL) due to a recessive gene (Ahl) that maps to Chromosome 10. The Ahl gene is also implicated in the susceptibility to noise-induced hearing loss (NIHL). The B6 mice (Ahl/Ahl) are more susceptible to NIHL than the CBA/CaJ (CB) mice (+Ahl). The B6×D2.F1 hybrid mice (Ahl/Ahl) are more susceptible to NIHL than the CB×B6.F1 mice (+/Ahl) [Erway et al., 1996. Hear. Res. 93, 181–187]. These genetic effects implicate the Ahl gene as contributing to NIHL susceptibility. The present study demonstrates segregation for the putative Ahl gene and mapping of such a gene to Chromosome 10, consistent with other independent mapping of Ahl for AHL in 10 strains of mice [Johnson et al., 2000. Genomics 70, 171–180]. The present study was based on a conventional cross between two inbred strains, CB×B6.F1 backcrossed to B6 with segregation for the putative +/Ahl:Ahl/Ahl. These backcross progeny were exposed to 110 dB SPL noise for 8 h. All of the progeny were tested for auditory evoked brainstem responses and analyzed for any significant permanent threshold shift of NIHL. Cluster analyses were used to distinguish the two putative genotypes, the least affected with NIHL (+/Ahl) and most affected with PTS (Ahl/Ahl). Approximately 1/2 of the backcross progeny exhibited PTS, particularly at 16 kHz. These mice were genotyped for two D10Mit markers. Quantitative trait loci analyses (log of the odds=15) indicated association of the genetic factor within a few centiMorgan of the best evidence for Ahl [Johnson et al., 2000. Genomics 70, 171–180]. All of the available evidence supports a role for the Ahl gene in both AHL and NIHL among these strains of mice.

Introduction

Susceptibility for noise-induced hearing loss (NIHL) can be defined in two ways: one organism is said to be more susceptible than another when equal acoustic energy exposures result in a greater permanent threshold shift (PTS) in the susceptible individual; or alternately, to produce equal PTS in a susceptible individual requires less acoustic energy than the non-susceptible individual. A genetic basis for age-related hearing loss (AHL) and for susceptibility to NIHL in mice appear to be correlated (Erway et al., 1996).

Differing susceptibility to the damaging effects of noise has been documented in human populations. For example, Taylor et al. (1965) demonstrated this phenomenon among jute weavers. Female jute weavers who had been exposed to the same constant noise (99 or 102 dB) for long periods of time (1–54 years), when adjusted for age, showed as much as 70 dB difference in auditory threshold between the least affected and the most affected workers with NIHL.

Erway et al. (1993) studied AHL among five inbred strains of mice and the resulting 10 F1 hybrid strains of mice. They utilized the auditory evoked brainstem response (ABR) to determine hearing thresholds up to 3 years of age. Some strains developed AHL much earlier than other strains, suggesting some genetic basis for accelerating presbycusis. Johnson et al. (1997) made genetic crosses between the normally hearing CAST/Ei strain and the C57BL/6J (abbreviated B6) strain which exhibits AHL. The backcross mice segregated with about 50% developing AHL by 12–18 months and about 50% with nearly normal hearing. A recessive gene designated Ahl for AHL, has been mapped to mouse Chromosome 10. The same Ahl gene with an early-onset AHL has been mapped in 10 other inbred strains, on Chromosome 10 around 24 centiMorgan (cM) (Johnson et al., 2000).

Erway et al. (1996) compared the susceptibility of mice to NIHL in two inbred strains, CBA/CaJ (abbreviated CB) wild type (+/+) and C57BL/6J (Ahl/Ahl), and in two F1 hybrid strains: CB×B6 (+/Ahl) and B6×D2(Ahl/Ahl). The +/+ and +/Ahl mice exhibited no PTS. The inbred B6(Ahl/Ahl) and the B6×D2.F1(Ahl/Ahl) mice exhibited identical patterns of 20–50 dB PTS. Moreover, both inbred and F1 hybrid strains (Ahl/Ahl) exhibited a very significant and similar onset of AHL.

In order to demonstrate segregation and association of the posited Ahl gene, F1 hybrids (CB×B6.F1+/Ahl) were backcrossed to the inbred B6(Ahl/Ahl) mice with an expected ratio of 1/2 less susceptible (+/Ahl) to 1/2 noise-susceptible (Ahl/Ahl) progeny. The present study was conducted to demonstrate association between the Ahl gene mapped to Chromosome 10 and the susceptibility of the Ahl/Ahl mice to NIHL. All of the backcross progeny were exposed to noise. The mice were characterized by their response to noise exposure as revealed by threshold shifts (TS) from before exposure compared to 1, 3, 7 and 14 days after exposure.

All mice exposed to noise were genotyped for heterozygosity or homozygosity via two linked microsatellite markers located on either side of Ahl on mouse Chromosome 10. Any significant correlations between the NIHL response and the Ahl genotypes would support the role of the Ahl gene in susceptibility to NIHL.

Section snippets

Subjects

Both inbred mouse strains were from stock originally obtained from The Jackson Laboratory (Bar Harbor, ME, USA). Inbred mice of the C57BL/6J (B6, Ahl/Ahl) strain were crossed with CBA/CaJ (CB, +/+Ahl). The resulting F1 progeny (CB×B6, +/Ahl) were then backcrossed to the B6 strain, producing an N2 generation consisting of approximately half heterozygous (+/Ahl) and half homozygous (Ahl/Ahl) progeny.

Sixty-one backcross progeny were used in this investigation. The backcross study group included

Preliminary results for intensity of noise exposure in the CB×B6.N2 generation of mice

Erway et al. (1996) showed that the C57BL/6J and B6×D2.F1 (Ahl/Ahl) mice exhibited NIHL after a 2 h exposure to 110 dB SPL, whereas the CB and CB×B6.F1 mice did not exhibit any NIHL. In preparation for the study of NIHL among the CB×B6.N2 generation of mice, preliminary regimes of noise exposure were undertaken, and are summarized here. This included a cohort of the CB×B6.N2 mice exposed to 110 dB SPL for 2 h. However, none of the mice exhibited any PTS. The same cohort of mice was subjected to

Discussion

One may question the possibility that a gene identified for its contribution to AHL could also affect NIHL. Clearly the ear is most sensitive to sound stimulation, and it is especially vulnerable to the most intense and acute acoustic stimuli. We have deduced from the following genetic studies that one gene among highly inbred strains of mice contributes to AHL and to NIHL:

The final ABR threshold at day 14 post-exposure is informative for distinguishing the less and more susceptible phenotypes.

Acknowledgements

Support for this work was provided by the Department of Biological Sciences, University of Cincinnati, the National Institutes of Health (AG 1197) and project funds of the National Institute for Occupational Safety and Health. Our thanks to Mark J. Daly of the Whitehead/MIT Center for Genome Research for calculating the LOD scores for us. Preliminary results were reported in (Newlander et al., 1995, Ling et al., 1995).

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