Diurnal variation of cadmium-induced mortality in mice

Abstract

-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 middark 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.

Multidirectional analyses of hepatic chronotoxicity induced by cadmium in mice

“…The biochemical indicators of hepatic injury (ALT and AST, shown in Fig. 2a, b) showed injection timing difference, as reported earlier (Miura et al, 2012. This experiment was not carried out in our institute (JNIOSH) but in Kinjo Gakuin University, indicating the reproducibility of the Cd-induced chronotoxicity in multiple laboratories.…”

“…Our previous studies indicated that mice showed remarkable daily fluctuations in the severity of Cd-induced toxicity (mortality (Miura et al, 2012, hepatotoxicity , testicular toxicity , and immune toxicity (Ohtani et al, 2016)); mice were sensitive to the Cd acute toxicity during light phase, but were tolerant during dark-phase. In this paper, identical results showing a remarkable difference in severity of the Cd-induced hepatotoxicity were obtained at Kinjo Gakuin University (Fig.…”

“…Indeed, our previous studies clearly indicated that mice showed remarkable daily fluctuations in the severity of the toxic response to Cd; all mice died when injected at zeitgeber time-2 (ZT2: ZT indicates elapsed time from lighting on), but all mice survived when injected at ZT18 (Miura et al, 2012. This injection time difference in the Cd-induced toxic severity was not only observed in mortality, but also in hepatotoxicity , testicular toxicity , and immune toxicity (Ohtani et al, 2016).…”

“…Our previous studies indicated that mice showed remarkable diurnal variation in Cd-induced toxicity such as mortality and hepatotoxicity (Miura et al, 2012). Since the liver is one of the major target organs of acute Cd toxicity (Waalkes et al, 1992), we further estimated the diurnal variation of hepatotoxicity by histopathological techniques.…”

“…We have reported on the Cd-induced chronotoxicity for mortality using both ICR and C57BL/6J mice, and for hepatotoxicity using C57BL/6J mice (Miura et al, 2012. In this report, we examined the strain differences in the susceptibility of hepatotoxicity by Cd injection timing using three mouse strains: ICR and Balb/c mice including C57BL/6J mice as a positive control.…”