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首页> 外文期刊>International Journal of Environmental Research and Public Health >The L1 Retrotranspositional Stimulation by Particulate and Soluble Cadmium Exposure is Independent of the Generation of DNA Breaks
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The L1 Retrotranspositional Stimulation by Particulate and Soluble Cadmium Exposure is Independent of the Generation of DNA Breaks

机译：L1逆转座刺激的颗粒状和可溶性镉暴露与DNA断裂的产生无关。

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Human exposure to toxic metals is a concern of the highest priority, due to their vast array of biological effects, including carcinogenicity. The particulate (water insoluble) form of several heavy metals presents a higher carcinogenic potential than its soluble counterparts. Our previous work demonstrates that the particulate forms of different heavy metals, such as nickel oxide, cadmium sulfide and mercury sulfide, stimulate human L1 mobile element activity leading to genomic instability. We present data demonstrating that the soluble form of CdCl2 also stimulates L1 retrotransposition in a dose-dependent manner comparable to the insoluble carcinogenic form of this compound. Reproducible results demonstrated a 2 to 3 fold dose-dependent increase in L1 retrotransposition compared to control cells. Heavy metals may cause DNA breaks through the generation of reactive oxygen species. However, evaluation of DNA damage by comet assay revealed no differences between the negative controls and the CdS-treated cells. In addition, active L1 elements express a protein with endonuclease activity that can generate toxicity through the creation of double strand breaks. To determine the contribution of the L1 endonuclease to the toxicity observed in our metal treatment assays, we compared the wildtype L1 vector with an L1 endonuclease-mutant vector. The presence of an active L1 endonuclease did not contribute significantly to the toxicity observed in any of the CdCl2 or CdS doses evaluated. No correlation between the creation of DNA breaks and L1 activity was observed. Alternatively, heavy metals inhibit enzymatic reactions by displacement of cofactors such as Zn and Mg from enzymes. Concomitant treatment with Mg(Ac)2 and Zn(Ac)2 ppb suppresses the stimulatory effect on L1 activity induced by the 3.8 ppb CdS treatment. Overall, these results are consistent with our previous observations, suggesting that the mechanism of L1 stimulation by heavy metals is most likely due to an overall inhibition of DNA repair proteins or other enzymes caused by the displacement of Mg and Zn from cellular proteins.
机译：人体接触有毒金属是头等大事，这是因为它们具有广泛的生物效应，包括致癌性。几种重金属的颗粒（水不溶性）形式比其可溶形式具有更高的致癌潜力。我们以前的工作表明，不同重金属（例如氧化镍，硫化镉和硫化汞）的颗粒形式会刺激人类L1移动元素的活性，从而导致基因组不稳定。我们目前的数据表明，可溶形式的CdCl2也可刺激L1逆转座，其剂量依赖性方式可与该化合物的不溶性致癌形式相比。可重现的结果表明，与对照细胞相比，L1逆转座的剂量依赖性增加了2到3倍。重金属可能通过产生活性氧而导致DNA断裂。但是，通过彗星试验评估的DNA损伤表明阴性对照和CdS处理的细胞之间没有差异。此外，活性L1元件表达具有核酸内切酶活性的蛋白，该蛋白可通过产生双链断裂而产生毒性。为了确定L1核酸内切酶对我们在金属处理测定法中观察到的毒性的贡献，我们将野生型L1载体与L1核酸内切酶突变载体进行了比较。活性L1核酸内切酶的存在对所评估的任何CdCl2或CdS剂量中观察到的毒性没有明显贡献。没有观察到DNA断裂的产生与L1活性之间的相关性。或者，重金属通过从酶中置换辅因子（例如Zn和Mg）来抑制酶促反应。 Mg（Ac）2和Zn（Ac）2 ppb的同时处理抑制了3.8 ppb CdS处理对L1活性的刺激作用。总体而言，这些结果与我们之前的观察结果一致，表明重金属对L1的刺激机制最可能是由于DNA修复蛋白或其他酶（从细胞蛋白中置换Mg和Zn引起的）总体抑制所致。

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