Hexavalent Chromium-Induced Chromosome Instability Drives Permanent and Heritable Numerical and Structural Changes and a DNA Repair-Deficient Phenotype.
Hexavalent Chromium-Induced Chromosome Instability Drives Permanent and Heritable Numerical and Structural Changes and a DNA Repair-Deficient Phenotype.
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DOI：
10.1158/0008-5472.can-18-0531
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发表时间：
2018-08-01
期刊：
影响因子：
11.2
通讯作者：
Wise JP Sr
中科院分区：
文献类型：
--
作者：
Wise SS;Aboueissa AE;Martino J;Wise JP Sr
关于六价铬（Cr（VI））如何导致癌症的一个关键假设是它驱动染色体不稳定性（CIN），从而导致肿瘤转化。研究表明，慢性Cr（VI）可影响DNA修复并诱导中心体扩增，这可导致结构和数量CIN。然而，没有研究考虑这些结果是暂时的还是永久的。在这项研究中，我们将人肺细胞暴露于颗粒Cr（VI）连续三个24小时的时间段，每个时间段间隔约一个月。每次处理后，以集落形成密度接种细胞，克隆、扩增和再处理，产生3代克隆细胞系。每一代的克隆进行了测试，铬敏感性，染色体互补，DNA修复能力，中心体扩增，并在软琼脂中生长的能力。第一次治疗后，铬（VI）处理的克隆表现出正常的染色体互补，但一些克隆表现出修复缺陷的表型和扩增的中心体。第二次暴露后，超过一半的处理过的克隆获得了异常核型，包括数量和结构的改变，许多表现出缺陷的DNA双链断裂修复和扩增的中心体。第三次治疗产生了新的异常克隆，以前异常的克隆获得额外的异常和大多数克隆表现出修复缺陷。CIN、修复缺陷和中心体扩增都是重复Cr（VI）暴露的永久性和可遗传的表型。这些结果支持CIN是Cr（VI）诱导的致癌作用的关键机制的假设。
A key hypothesis for how hexavalent chromium (Cr(VI)) causes cancer is that it drives chromosome instability (CIN), which leads to neoplastic transformation. Studies show chronic Cr(VI) can impact DNA repair and induce centrosome amplification, which can lead to structural and numerical CIN. However, no studies have considered whether these outcomes are transient or permanent. In this study, we exposed human lung cells to particulate Cr(VI) for three sequential 24-hour periods, each separated by about a month. After each treatment, cells were seeded at colony forming density, cloned, expanded and retreated, creating 3 generations of clonal cell lines. Each generation of clones was tested for chromium sensitivity, chromosome complement, DNA repair capacity, centrosome amplification, and the ability to grow in soft agar. After the first treatment, Cr(VI)-treated clones exhibited a normal chromosome complement, but some clones showed a repair-deficient phenotype and amplified centrosomes. After the second exposure, more than half of the treated clones acquired an abnormal karyotype including numerical and structural alterations, with many exhibiting deficient DNA double strand break repair and amplified centrosomes. The third treatment produced new abnormal clones, with previously abnormal clones acquiring additional abnormalities and most clones exhibiting repair deficiency. CIN, repair deficiency, and amplified centrosomes were all permanent and heritable phenotypes of repeated Cr(VI) exposure. These outcomes support the hypothesis that CIN is a key mechanism of Cr(VI)-induced carcinogenesis.