Sexual dimorphism of cadmium-induced toxicity in rats: involvement of sex hormones.

The toxic effect of cadmium varies with sex in experimental animals. Previous studies have demonstrated that pretreatment of male Fischer 344 (F344) rats with the female sex hormone progesterone markedly enhances the susceptibility to cadmium, suggesting a role for progesterone in the sexual dimorphism of cadmium toxicity. In the present study, we attempted to further elucidate the mechanism for sex differences in cadmium-induced toxicity in F344 rats. A single exposure to cadmium (5.0 mg Cd/kg, sc) was lethal in 10/10 (100 %) female compared with 6/10 (60 %) male rats. Using a lower dose of cadmium (3.0 mg Cd/kg), circulating alanine aminotransferase activity, indicative of hepatotoxicity, was highly elevated in the cadmium treated females but not in males. However, no gender-based differences occurred in the hepatic cadmium accumulation, metallothionein or glutathione levels. When cadmium (5.0 mg Cd/kg) was administered to young rats at 5 weeks of age, the sex-related difference in lethality was minimal. Furthermore, although ovariectomy blocked cadmium-induced lethality, the lethal effects of the metal were restored by pretreatment with progesterone (40 mg/kg, sc, 7 consecutive days) or β-estradiol (200 μg/kg, sc, 7 consecutive days) to ovariectomized rats. These results provide further evidence that female sex hormones such as progesterone and β-estradiol are involved in the sexual dimorphism of cadmium toxicity in rats.