Dose- and route-dependent hormonal activity of the metalloestrogen cadmium in the rat uterus.

The toxic heavy metal cadmium (Cd) is regarded as a potential endocrine disruptor, since Cd exerts estrogen-like activity in vitro and can elicit some typical estrogenic responses in rodents upon intraperitoneal (i.p.) injection. But estrogenic effects have not been documented in vivo with other more relevant routes of exposure, although it is known that Cd absorption and distribution in the body is strongly affected by the application route. Therefore, we investigated its hormonal activity in ovariectomized Wistar rats after oral administration of CdCl(2) (0.05-4 mg/kg b.w. on 3 days by gavage and 0.4-9 mg/kg b.w. for 4 weeks in drinking water) in comparison with i.p. injection of CdCl(2) (0.00005-2 mg/kg b.w.). Uterus wet weight, height of uterine epithelium, and modulation of estrogen-regulated gene expression, i.e. uterine complement component 3 (C3), were determined, and also Cd-levels in uterus and liver were measured by atomic absorption spectrometry. The analysis revealed pronounced differences in Cd tissue levels and hormonal potency for the two routes of administration: a single i.p. injection of Cd increased dose-dependently uterine wet weight and thickness of the uterine epithelium. Interestingly, C3 mRNA expression in the uterus was down regulated at low doses of CdCl(2) (0.00005-0.05 mg/kg b.w.), but strongly stimulated at the highest dose of 2 mg/kg b.w. Other than i.p. injection, oral treatment with Cd, by gavage or in drinking water, did neither increase uterine wet weights nor epithelial thickness. But, both 3-day- and 4-week oral Cd administration resulted in a dose-dependent stimulation of C3 expression in the uterus, significant at and above 0.5 mg/kg b.w. In summary, our data demonstrate an estrogenic effect in the uterus upon i.p. injection of Cd, but considerably lower hormonal potency with oral administration: short and long-term oral treatment with Cd did not affect uterus weight or histology, whilst on the molecular level, an induction of estrogen sensitive uterine gene expression was observed, albeit at dose levels far exceeding those of dietary exposure in humans.