McKenna I M, Bare R M, Waalkes M P
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201, USA.
Toxicology. 1996 Feb 22;107(2):121-30. doi: 10.1016/0300-483x(95)03252-b.
The rodent testes are generally more susceptible to cadmium (Cd)-induced toxicity than the liver. Cd induces predominantly testicular interstitial cell (TIC) tumors. In order to clarify the molecular mechanism underlying tissue differences in Cd sensitivity, we compared Cd-induced metallothionein (MT) gene expression, MT protein accumulation, and Cd retention in freshly isolated TICs and liver. Adult male Fischer rats received a s.c. injection of 4.0 micromol Cd/kg or vehicle and 24 h later tissues were sampled and TICs isolated. MT-I and MT-II mRNA levels were determined by slot-blot analysis followed by densitometry scanning, and MT was estimated by the Cd-heme method. Testicular lesions were not grossly or histologically observed in rats treated with 4 micromol Cd/kg. Both MT mRNA and MT (as determined by Cd-binding capacity) were constitutively present in TICs as well as the liver. TICs isolated from Cd-treated rats accumulated more Cd (4-fold), and had higher levels of MT-I (1.9-fold) and MT-II (1.4-fold) mRNAs over control, but contained less MT (30% decrease) than TICs isolated from control animals. Cd exposure substantially increased hepatic Cd content (6000-fold), MT (58-fold), and MT-I mRNA (5.3-fold), but did not increase MT-II mRNA. Thus, our findings indicate that, although low-dose Cd exposure results in increases of MT mRNA in TICs it does not enhance MT synthesis within these cells. The inability to induce the metal-detoxicating MT-protein, in response to Cd, might account for higher susceptibility of testes to Cd toxicity and carcinogenesis relative to liver.
啮齿动物的睾丸通常比肝脏更容易受到镉（Cd）诱导的毒性影响。镉主要诱发睾丸间质细胞瘤（TIC）。为了阐明组织对镉敏感性差异背后的分子机制，我们比较了镉诱导的金属硫蛋白（MT）基因表达、MT蛋白积累以及新鲜分离的TIC和肝脏中的镉潴留情况。成年雄性Fischer大鼠皮下注射4.0微摩尔Cd/kg或赋形剂，24小时后采集组织并分离TIC。通过狭缝印迹分析随后进行光密度扫描测定MT-I和MT-II mRNA水平，并通过镉-血红素法估算MT。在用4微摩尔Cd/kg处理的大鼠中，未观察到明显的睾丸病变或组织学病变。MT mRNA和MT（通过镉结合能力测定）在TIC和肝脏中均组成性存在。从镉处理大鼠中分离的TIC积累了更多的镉（4倍），MT-I（1.9倍）和MT-II（1.4倍）mRNA水平高于对照组，但与从对照动物中分离的TIC相比，MT含量更低（降低30%）。镉暴露显著增加了肝脏中的镉含量（6000倍）、MT（58倍）和MT-I mRNA（5.3倍），但未增加MT-II mRNA。因此，我们的研究结果表明，尽管低剂量镉暴露导致TIC中MT mRNA增加，但并未增强这些细胞内的MT合成。响应镉时无法诱导金属解毒MT蛋白，可能是睾丸相对于肝脏对镉毒性和致癌作用更敏感的原因。
