Cadmium disposition and metallothionein induction in mice: strain-, sex-, age-, and dose-dependent differences

Abstract

The strain- and sex-related differences in tissue cadmium (Cd) and metallothionein (MT) levels were examined in young adult (4–6 months old) C3H/HeJ, DBA/2J, 129/J, CD-1 and A/J mice, 24 h after a subcutaneous (s.c.) injection of 5–30 μgmmol CdCl 2/kg. In many cases the tissue Cd concentrations were inversely related to the tissue weights. Also, the strain and sex differences were more obvious at 20–30-μmol dose levels. At such doses the hepatosensitive C3H males had as much as 30% higher hepatic Cd concentrations as the resistant DBA males, but similar concentrations to the resistant A/J and CD-1 males. This observation suggests that tissue Cd level is not the only determinant of strain differences in hepatotoxicity in males. Among the females, the A/J had 30–47% higher hepatic Cd concentration than the other strains. Livers of male C3H, CD-1 and 129/J mice had 17–57% higher Cd concentrations than those of the females; the greatest difference was in the C3H strain in which only the males exhibited hepatotoxicity at the 30 μmol dose. In all animals the hepatic MT concentration increased with the increasing Cd concentration. However, the 129/J males and all the females reached a plateau in MT concentration at Cd concentrations of 20–30 μg/g liver. Even at the highest Cd concentration, the C3H males had MT concentrations similar to some of the hepatoresistant males, suggesting that their sensitivity to Cd was not due to compromised MT levels. The renal Cd concentration was similar in males of most strains but not in females. For examples, at the 30-μmol dose 129/J females had a Cd concentration which was 70% higher than in the DBA females. Also, at this dose level the A/J, C3H and 129/J females had 30–50% more Cd than the males. The DBA and C3H males had approximately twice the MT concentration of the A/J and 129/J males at 10 μg Cd/g kidney. At similar Cd concentration, the DBA females also had 1.6–2.0 times the MT concentration of the other females. The renal MT levels in females were 1.4–2.9 times higher than in males. Strains susceptible to the testicular toxicity of Cd had up to three times greater testicular Cd accumulation than the resistant strains. However, there was no increase in testicular MT in any strain. The effect of age on Cd and MT levels was studied in 19-month-old A/J and DBA mice at the 25-μmol dose. The aged mice had 15–42% higher hepatic Cd concentration than the younger animals; however, their MT levels were the same. The renal Cd, but not MT, concentration in the older animals was 25–33% lower than in young animals. Despite the larger body weights the Cd-injected aged males had 22–29% smaller testes, but about the same amount of Cd, as the young males, suggesting that the older DBA males may exhibit testicular toxicity at a lower dose of Cd than the young animals. Thus, it is concluded that not only the dose but also the strain, sex and age of the animals are important factors in determining the disposition of Cd in mice. The differences in the tissue Cd accumulation may relate to variations in hormonal and other intinsic factors affecting the cellular uptake and subcellular distribution of Cd and biosynthesis and degradation of MT.