title: Inheritance patterns of noise vulnerability and "protectability" in (C57BL/6J × CBA/J) F1 hybrid mice.
abstract: BACKGROUND
  Interindividual variation in cochlear vulnerability to noise and ototoxins must in part reflect allelic variation in genes that largely remain unknown. Work in our laboratory has shown that young adult CBA/J mice are more vulnerable to cochlear noise injury than are similar-aged mice of other well-studied strains such as C57BL/6J (B6). Conversely, young CBA/J mice are dramatically protected against noise exposure by low-dose kanamycin (KM) treatment, while B6 mice are not. Genetic differences that distinguish these two strains may include genes that help establish the early "sensitive period" in mammals, as well as genes that shape innate protective responses to stress. These genes may have human homologs that exert similar influences and thereby partly govern individual risk of acquired hearing loss.
  
  
  OBJECTIVE
  We hypothesize that young CBA/J and B6 mice carry different alleles at unknown loci that mediate their characteristic sensitivities to noise and responses to kanamycin. The first step in any experimental genetic analysis of two divergent populations is to examine F1 hybrids formed from these. Accordingly, we evaluated both noise vulnerability and the extent of protection from noise by low-dose KM in 6-wk-old F1 hybrids derived from a B6 × CBA/J cross.
  
  
  METHODS
  The study included 52 CBA/J, 59 C57BL/6J (B6), and 45 (B6 × CBA/J) F1 hybrid mice, aged 6 wk at time of noise exposure. Both genders were included.
  
  
  METHODS
  For experiments aimed at noise vulnerability, B6 and F1 mice were exposed to loud broadband noise (4-45 kHz, 110 dB SPL) for varying durations, and the resulting noise-induced permanent threshold shifts (NIPTSs, measured 2 wk postnoise) were compared with previous data from CBA/J mice. For experiments aimed at KM-based "protectability," CBA/J, B6, and F1 mice received either kanamycin (300 mg/kg, sc) or saline twice daily for 10 days and then were noise exposed for 30 min, followed by measurement of NIPTS at 2 wk postnoise.
  
  
  METHODS
  Data comprised auditory brainstem response (ABR) thresholds examined by two-way ANOVA (threshold × frequency, group) and derived metrics for NIPTS, plotted versus noise duration.
  
  
  RESULTS
  The "threshold" noise exposure duration for NIPTS in F1 hybrid mice was similar to that in CBA/J. Like CBA/J mice, F1 mice were also significantly protected from noise by KM although the protection appeared less robust than in the CBA/J parent strain. B6 mice appeared harmed by KM alone, even without noise exposure. None of the experimental groups provided any evidence for synergistic interactions between noise and KM.
  
  
  CONCLUSIONS
  Our data support the hypothesis that young CBA/J and B6 mice carry different alleles that underlie their divergent responses to KM and sensitivities to noise exposure. While the number and type of genes remain unknown, they are worth pursuing because they establish completely novel hearing phenotypes with potential relevance to humans. Our results lay the foundation for mapping of the underlying genes, and ultimately gene identification.
authors.affiliation: Program in Audiology and Communication Sciences, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Barden
authors.forename: Erin A
authors.initials: EA
authors.lastname: Rellinger
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Ortmann
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Ohlemiller
mesh_terms: D000483:Alleles; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001305:Auditory Fatigue / Q000187:drug effects; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects / Q000235:genetics; D005260:Female; D006317:Hearing Loss, Noise-Induced / Q000235:genetics*; D006824:Hybridization, Genetic / Q000235:genetics*; D007279:Injections, Subcutaneous; D007612:Kanamycin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics*; D008808:Mice, Inbred CBA / Q000235:genetics*; D009622:Noise / Q000009:adverse effects*; D013018:Sound Spectrography
chemical_list: D000900:Anti-Bacterial Agents; D007612:Kanamycin