Transgenerational transmission of radiation- and chemically induced tumors and congenital anomalies in mice: studies of their possible relationship to induced chromosomal and molecular changes
Transgenerational transmission of radiation- and chemically induced tumors and congenital anomalies in mice: studies of their possible relationship to induced chromosomal and molecular changes
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DOI：
10.1159/000077499
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发表时间：
2004-01-01
影响因子：
1.7
通讯作者：
Tanaka, H
中科院分区：
文献类型：
--
作者：
Nomura, T;Nakajima, H;Tanaka, H
本文广泛概述了我们早期关于在 X 射线照射或化学处理的小鼠后代中诱导肿瘤和先天性异常的研究，以及我们随后的（已发表、迄今未发表和正在进行的）研究，旨在利用细胞遗传学和分子方法确定生殖细胞中诱导的遗传变化与表现为肿瘤和先天性异常的不利影响之间的潜在关系。早期的研究证明了这样一个事实：肿瘤和先天性异常可以通过辐射或某些化学物质（例如氨基甲酸乙酯）治疗来诱发，并且这些表型是可遗传的，即可以遗传到第一代之后的几代人。这些发现支持了以下观点：涉及可传染的诱导基因变化。先天性异常和肿瘤的诱发率比文献中记录的特定位点突变的经典突变研究的发生率高出约两个数量级。细胞遗传学研究解决了诱导易位和诱导肿瘤之间是否存在任何关系的问题。现有数据可以推断，可能不涉及总体染色体变化，但不排除较小的诱导遗传变化，这些变化超出了这些研究中使用的技术的分辨率。其他关于可见染色体异常（在骨髓制剂中）与肿瘤之间可能关系的研究同样是否定的。然而，有迹象表明，某些诱发的细胞遗传学变化可能是诱发先天性异常的基础，即在诱发性和遗传性先天性异常（例如侏儒、尾部异常）中观察到三体性、缺失和倒位。探索 Pc-3 位点小卫星突变诱导与肿瘤之间可能关系的研究结果为阴性。然而，对受辐射雄性小鼠的后代的肿瘤（肝癌）易感后代的基因表达分析显示，许多基因表达异常。其中，只有极少数是癌基因。这为我们的假设提供了一些支持，即许多执行正常细胞功能的基因的基因表达的累积变化可能导致受辐射或化学处理的小鼠的后代发生肿瘤。
This article provides a broad overview of our earlier studies on the induction of tumors and congenital anomalies in the progeny of X-irradiated or chemically treated mice and our subsequent (published, hitherto unpublished and ongoing) investigations aimed at identifying potential relationships between genetic changes induced in germ cells and the adverse effects manifest as tumors and congenital anomalies using cytogenetic and molecular approaches. The earlier studies document the fact that tumors and congenital anomalies can be induced by irradiation or treatment with certain chemicals such as urethane and that these phenotypes are heritable i.e., transmitted to generations beyond the first generation. These findings support the view that transmissible induced genetic changes are involved. The induced rates of congenital abnormalities and tumors are about two orders of magnitude higher than those recorded in the literature from classical mutation studies with specific locus mutations. The cytogenetic studies addressed the question of whether there were any relationships between induced translocations and induced tumors. The available data permit the inference that gross chromosomal changes may not be involved but do not exclude smaller induced genetic changes that are beyond the resolution of the techniques used in these studies. Other work on possible relationship between visible chromosomal anomalies (in bone marrow preparations) and tumors were likewise negative. However, there were indications that some induced cytogenetic changes might underlie induced congenital anomalies, i.e., trisomies, deletions and inversions were observed in induced and transmissible congenital anomalies (such as dwarfs, tail anomalies). Studies that explored possible relationships between induction of minisatellite mutations at the Pc-3 locus and tumors were negative. However, gene expression analysis of tumor (hepatoma)-susceptible offspring of progeny descended from irradiated male mice showed abnormal expression of many genes. Of these, only very few were oncogenes. This lends some support to our hypothesis that cumulative changes in gene expression of many genes, which perform normal cellular functions, may contribute to the occurrence of tumors in the offspring of irradiated or chemically treated mice.