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

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The toxic effect of cadmium varies with sex in experimental animals.Previous studies have demonstrated that pretreatment of male Fischer 344 (F344) ratswith the female sex hormone progesterone markedly enhances the susceptibility tocadmium, suggesting a role for progesterone in the sexual dimorphism of cadmiumtoxicity. In the present study, weattempted to furtherelucidate the mechanism for sexdifferencesin cadmium-induced toxicity in F344 rats. A single exposure to cadmium(5.0 mg Cd/kg, s.c.) was lethal in 10/10 (100 %) female compared to 6/10 (60 %) malerats. Using a lower dose of cadmium (3.0 mg Cd/kg), circulating alanineaminotransferase (ALT) activity, indicative of hepatotoxicity, was highly elevated in thecadmium treated females but not in males. However, no gender-based differencesoccurred in the hepatic cadmium accumulation, metallothionein (MT) or glutathione(GSH) levels. When cadmium (5.0 mg Cd/kg) was administered to young rats at 5weeks of age, the sex-related difference in lethalitywas minimal. Furthermore,although ovariectomyblocked cadmium-induced lethality, the lethal effectsof the metalwere restored by pretreatment with progesterone (40 mg/kg, s.c., 7 consecutive days) orβ-estradiol (200 μg/kg, s.c., 7 consecutive days) to ovariectomized rats. These resultsprovide further evidence that female sex hormones such as progesterone andβ-estradiolare involved in the sexual dimorphism of cadmium toxicity in rats.
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