Nagy Gabor, Baksa Viktoria, Kiss Alexandra, Turani Melinda, Banfalvi Gaspar
Department of Biotechnology and Microbiology, University of Debrecen, 1 Egyetem Square, Debrecen, 4010, Hungary.
Apoptosis. 2017 Feb;22(2):188-199. doi: 10.1007/s10495-016-1311-9.
The toxicity of gadolinium is reduced by chelating agents that render this heavy metal into contrast complexes used for medical magnetic resonance imaging. However, the dissociation of gadolinium chelates is known to generate Gd ions, the cellular toxicity of which has not been tested in details. The cytotoxic effects of Gd(III) ions were evaluated by monitoring the proliferation, measuring the cellular motility and following chromatin changes in various cell lines upon Gd treatment. Measurements applied long-term scanning microscopy and a perfusion platform that replaced the medium with test solutions, bypassed physical contact with the cell culture during experiments, and provided uninterrupted high time-resolution time-lapse photomicrography for an extended period of time. Genotoxicity specific chromatin changes characteristic to Gd(III) were distinguished in human skin keratinocytes (HaCaT), human limbal stem cells (HuLi), colorectal adenocarcinoma (CaCO), murine squamous carcinoma (SCC) and Indian muntjac (IM) cell lines. Characteristic features of Gd(III) toxicity were: loss of cellular motility, irreversible attachment of cells to the growth surface and cell death. Injury-specific chromatin changes manifested at micromolar Gd concentrations as premature chromatin condensation and highly condensed sticky chromatin patches. Gd(III) concentration- and cell type-dependent reduction of normal adherence, as well as premature chromatin condensation confirmed apoptosis. The risk related to the release of toxic Gd ions from gadolinium complexes and their effects on mono- and multi-layer cellular barriers have to be reconsidered when these chelated complexes are used as contrasting agents especially in relation to possible blood-brain barrier damages.
螯合剂可降低钆的毒性，这些螯合剂将这种重金属转化为用于医学磁共振成像的造影剂复合物。然而，已知钆螯合物的解离会产生钆离子，其细胞毒性尚未得到详细测试。通过监测细胞增殖、测量细胞运动性以及观察钆处理后各种细胞系中的染色质变化，评估了钆（III）离子的细胞毒性。测量采用了长期扫描显微镜和灌注平台，该平台用测试溶液替换培养基，在实验过程中避免与细胞培养物进行物理接触，并在较长时间内提供不间断的高时间分辨率延时显微摄影。在人皮肤角质形成细胞（HaCaT）、人角膜缘干细胞（HuLi）、结肠腺癌（CaCO）、小鼠鳞状细胞癌（SCC）和印度麂（IM）细胞系中，区分了钆（III）特有的基因毒性染色质变化。钆（III）毒性的特征包括：细胞运动性丧失、细胞不可逆地附着在生长表面以及细胞死亡。在微摩尔浓度的钆作用下，损伤特异性染色质变化表现为染色质过早凝聚和高度凝聚的粘性染色质斑块。钆（III）浓度和细胞类型依赖性的正常黏附减少以及染色质过早凝聚证实了细胞凋亡。当这些螯合复合物用作造影剂时，尤其是考虑到可能对血脑屏障造成的损害，必须重新考虑与钆复合物释放有毒钆离子及其对单层和多层细胞屏障的影响相关的风险。
