Consequences of combined maternal, fetal and persistent postnatal hypothyroidism on the development of auditory...

Tshrhyt/hyt mutant mice express a point mutation in the gene encoding the thyrotropin receptor, and affected animals are congenitally hypothyroid and profoundly deaf as a consequence when the condition is untreated. In this investigation, a previously unrecognized developmental stage was identified in the hypothyroid, mutant progeny of hypothyroid dams by tracking developmental changes in the auditory brainstem response (ABR). ABR thresholds develop rapidly in normal, euthyroid animals, decreasing as much as 80 dB between P12 (postnatal day 12) and P15, with mature sensitivity being gradually acquired by P18. In contrast, Tshrhyt/hyt mutant mice remained profoundly deaf on P24 and although thresholds improved by approximately 30 dB by P60, residual frequency-dependent deficits of 20-70 dB were observed in animals exhibiting end-stage disease. The rate of threshold improvement in mutant mice was approximately ten times slower than in normal mice. While ABR wave latencies and interpeak intervals decreased early in postnatal life, values decreased over a delayed and protracted time period, reaching adult values well after those of controls attained maturity. As with normal mice, slopes of wave I latency-intensity curves were significantly steeper in immature animals than those observed in adults and decreased during development, but failed to achieve normal adult values and remained significantly steeper than those for controls. Findings reported here suggest that passive aspects of electromechanical transduction achieve maturity in Tshrhyt/hyt progeny of Tshrhyt/hyt mice and that development, limited as it may be, occurs most prominently in the basal half of the cochlea.