Gentamicin-induced chronotoxicity: use of body temperature as a circadian marker rhythm

Aminoglycoside antibiotics produce varying degrees of ototoxicity, dependent on dosage time, in animals synchronized for rhythm study. Herein, we illustrate the use of an economical and reliable system to telemeter body temperature of laboratory animals as an endogenous marker rhythm for gentamicin-induced ototoxicity. Two groups of 3 male Sprague-Dawley rats (250-400 gm) were housed in separate cages in a temperature-controlled room programmed with a 12:12 LD schedule and monitored for hearing thresholds at the frequencies of 8kHz, 16 kHz, 24 kHz and 32 kHz at 2-week intervals. Each rat was dosed with 100 mg/kg/day gentamicin subcutaneously for a duration of 28 days. The animals from one group were dosed at their daily temperature maximum, while the animals of the other group were dosed at their daily temperature minimum. Both after 14 and 28 days of gentamicin treatment there was no important changes in auditory thresholds from baseline values when treatment was timed daily to the circadian peak of body temperature. Animals dosed daily at the trough of the circadian temperature rhythm evidenced an auditory threshold shift of between 5 and 25 dB after 14 days of treatment and a total hearing loss (80-90 dB) after 28 days of such treatment. These results document a dramatically greater level of hearing loss induced in those animals dosed with gentamicin at the body temperature trough (diurnal rest span) as compared to those dosed at the acrophase (nocturnal activity span). The findings indicate that the peak and trough of the circadian pattern of body temperature serve as meaningful markers of the resistance and susceptibility, respectively, of gentamicin-induced ototoxicity in rodent models.