title: Mechanisms of cadmium-induced chronotoxicity in mice.
abstract: Biological defense factors show diurnal variations in their expression levels or activities. These variations can induce the different sensitivity to external toxicants of a day. We reported earlier that mice showed clear diurnal variation of cadmium (Cd)-induced toxicity, i.e., chronotoxicity. In this report, we investigated additional new evidences for the cadmium (Cd)-induced chronotoxicity, and considered the mechanisms contributed to this chronotoxicity. Male C57BL/6J mice were injected with CdCl₂ (6.4 mg/kg, one shot) intraperitoneally at 6 different time points of a day (zeitgeber time (ZT); ZT2, ZT6, ZT10, ZT14, ZT18 or ZT22) followed by monitoring the mortality until 14 days after the injection. We observed extreme difference in survival numbers: surprisingly, all mice died at ZT2 injection while all mice survived at ZT18 injection. Moreover, in non-lethal dose of Cd (4.5 mg/kg), the values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) used as indexes of hepatotoxicity markedly increased at ZT6 injection while mostly unchanged at ZT18 injection. To consider the mechanisms of this extreme diurnal variation, we examined biochemical studies and concluded that the diurnal variation was not caused by the differences in hepatic Cd level, basal hepatic metallothionein (MT) level, and induction level or induction speed of hepatic MT. We suggested that one of the candidate determination factors was glutathione. We believe that the "chronotoxicology" for metal toxicity may be classic, yet new viewpoint in modern toxicology field.
authors.affiliation: Division of Health Effects Research, Japan National Institute of Occupational Safety and Health.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Miura
authors.forename: Atsushige
authors.initials: A
authors.lastname: Ashimori
authors.forename: Asuka
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Katsumi
authors.initials: K
authors.lastname: Ohtani
authors.forename: Naoko
authors.initials: N
authors.lastname: Takada
authors.forename: Yukie
authors.initials: Y
authors.lastname: Yanagiba
authors.forename: Masaharu
authors.initials: M
authors.lastname: Mita
authors.forename: Masako
authors.initials: M
authors.lastname: Togawa
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D019256:Cadmium Chloride / Q000008:administration & dosage / Q000633:toxicity*; D002940:Circadian Rhythm / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors
chemical_list: D015415:Biomarkers; D008668:Metallothionein; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D019256:Cadmium Chloride