Effect of auditory stress agents on heterozygous German waltzing guinea pigs

Abstract The German waltzing guinea pig is a strain of animals expressing deafness and severe balance disorders at birth. The mutation arose spontaneously in a breeding facility in Germany and as the affected animals show a characteristic waltzing behavior, the strain is named the German waltzing guinea pig. The strain is presently bred only at Karolinska Institutet. The hereditary inner ear impairment has a recessive mode of inheritance and the strain thus produces not only affected homozygotes but also symptom-free heterozygotes and fully normal offspring. The outcome depends solely on the genotype of the parents. The heterozygotes, which have obtained the “waltzing” gene from one parent only, have normal hearing and no balance dysfunction. The heterozygous animals appear normal but will, in turn, carry the genetic defect to the next generation. The present thesis is focused on these animals. Noise and ototoxic drugs are well known stress factors that interfere negatively with the hearing organ in both humans and animals, causing hearing impairment. However, the inter-individual variability in susceptibility to auditory stress factors is surprisingly large, most likely due to different genetic predisposition. In this study, heterozygous animals of the German waltzing guinea pig, animals carrying a genetic defect known to cause severe hearing impairment, were used to study how an unexplored gene for deafness interacts with auditory stress agents, i.e. noise exposure and the ototoxic drugs gentamicin and cisplatin. Animals were exposed to both narrowband as well as broadband noise at different ages and hearing thresholds were measured using ABRs. Heterozygotes of the German waltzing guinea pig showed less threshold shifts compared to control strains. Older animals were less affected by the noise trauma than younger animals. To test the hypothesis that the efferent system contributes to protection of the inner ear against noise trauma, measurements using a new method of post onset adaptation of DPOAEs and maximum adaptation magnitude were conducted. The post onset adaptation of DPOAEs detected a strain difference at the higher frequency region while in the maximum adaptation magnitude method showed no difference between the strains. The heterozygous German waltzing guinea pigs displayed a distinctly increased resistance to noise exposures, manifested as reduced threshold shifts and faster recovery following acoustic overstimulation. However, when exposed to ototoxic drugs, the heterozygous carriers suffered from a more pronounced hearing loss. It is concluded that endogenous resistance to noise in the heterozygotes does not offer any protection against ototoxic drugs. The detailed mechanisms remain to be explored.