Dose- and route-dependent hormonal activity of the metalloestrogen cadmium in the rat uterus
Dose- and route-dependent hormonal activity of the metalloestrogen cadmium in the rat uterus
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DOI：
10.1016/j.toxlet.2009.08.014
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发表时间：
2009-12-15
影响因子：
3.5
通讯作者：
Degen, Gisela H.
中科院分区：
文献类型：
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作者：
Hoefer, Nicola;Diel, Patrick;Degen, Gisela H.
有毒重金属镉（Cd）被认为是一种潜在的内分泌干扰物，因为Cd在体外具有雌激素样活性，并且在啮齿类动物腹腔注射后可引起一些典型的雌激素反应。尽管我们知道镉在体内的吸收和分布受到镉的应用途径的强烈影响，但尚未有其他相关暴露途径在体内的雌激素作用。因此，我们研究了口服CdCl2 （005-4 mg/kg体重，3天灌胃，0.4-9 mg/kg体重，4周饮水）与口服CdCl2 （0.00005-2 mg/kg体重）在去卵巢的Wistar大鼠体内的激素活性。子宫湿重、子宫上皮高度与雌激素调控基因表达的关系。测定子宫补体成分3 （C3）。同时用原子吸收光谱法测定子宫和肝脏的cd水平。分析显示，两种给药途径在Cd组织水平和激素效力方面存在显著差异：单次滴注Cd可增加剂量依赖性子宫湿重和子宫上皮厚度。有趣的是，在低剂量CdCl2 （0.00005-0.05 mg/kg b.w）下，子宫中C3 mRNA的表达被下调，但在最高剂量（2 mg/kg b.w）时，子宫C3 mRNA的表达受到强烈刺激。除了口服注射外，通过灌胃或饮用水给予CdCl2，既没有增加子宫湿重，也没有增加上皮厚度。但是。口服Cd 3天和4周后，子宫中C3表达的剂量依赖性刺激，在0.5 mg/kg b.w.及以上显著。总之，我们的数据表明，阴道注射Cd对子宫有雌激素作用，但口服Cd短期和长期口服治疗不会影响子宫重量或组织学，而在分子水平上，观察到雌激素敏感子宫基因表达的诱导，尽管剂量水平远远超过人类饮食暴露(C) 2009爱思唯尔爱尔兰有限公司版权所有
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 CdCl2 (005-4 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 CdCl2 (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 CdCl2 (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 (C) 2009 Elsevier Ireland Ltd All rights reserved