Diurnal variation of cadmium-induced mortality in mice

Circadian timing largely modifies efficacy of many medicinal drugs. This viewpoint has been applied in the clinical medicine, known as chronotherapy. We think this viewpoint should also be introduced into toxicology as "chronotoxicology", however, information about the diurnal variation in toxicant sensitivity is still very scarce. We present here a clear and reproducible diurnal variation of cadmium (Cd)-induced mortality in mice. Male ICR mice kept under standard condition (12 hr light/dark cycle, lights on at 08:00) were injected with CdCl(2) (7.2 mg/kg, one shot) intraperitoneally at different time points in the day (zeitgeber time (ZT) 0, 4, 8, 12, 16 or 20). Survival number was determined at 14 days after injection. Interestingly, mice were sensitive to Cd acute toxicity at ZT8, while tolerant at mid-dark to early-light phase (ZT16, ZT20 and ZT0). Hepatic GSH level showed small daily fluctuation, lowest at ZT8 and highest at ZT20, and this fluctuation was similar to the diurnal variation of Cd sensitivity. In contrast, hepatic metallothionein (MT) level was not significant in these time points, although their level also showed small daily fluctuation. Our results indicated that Cd-induced mortality had clear diurnal variation, and suggested that the hepatic GSH level was one of the important factors for determination of this Cd-induced diurnal mortality.