Exposure to anticancer drugs can result in transgenerational genomic instability in mice
Exposure to anticancer drugs can result in transgenerational genomic instability in mice
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DOI：
10.1073/pnas.1119396109
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发表时间：
2012-02-21
影响因子：
11.1
通讯作者：
Dubrova, Yuri E.
中科院分区：
文献类型：
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作者：
Glen, Colin D.;Dubrova, Yuri E.
人类接触抗癌药物的遗传效应仍然知之甚少。为了确定接触抗癌药物是否不仅会导致受试动物生殖系的突变诱导，还会导致其后代的突变率发生变化，我们评估了三种常用化疗药物：环磷酰胺、丝裂霉素C和丙卡巴肼处理的雄性小鼠的后代突变率。父亲暴露的剂量与临床使用的剂量大致相同。用单分子聚合酶链式反应，从处理雄鼠后代的精子和骨髓提取的DNA样本中，建立了小鼠扩展的简单串联重复序列座位Ms6-hm的突变频率。在父亲接触这三种药物中的任何一种后，他们后代的生殖系(精子)和骨髓中扩展的简单串联重复序列突变频率显著增加。这种观察到的跨代不稳定性归因于来自暴露的父亲和未暴露的母亲的等位基因的突变率升高，从而意味着全基因组的不稳定。我们的结果表明，父亲接触到各种各样的诱变剂会导致后代表现出跨代不稳定。我们的数据还提出了关于抗癌治疗幸存者子女的延迟跨代效应的重要问题。
The genetic effects of human exposure to anticancer drugs remain poorly understood. To establish whether exposure to anticancer drugs can result not only in mutation induction in the germ line of treated animals, but also in altered mutation rates in their offspring, we evaluated mutation rates in the offspring of male mice treated with three commonly used chemotherapeutic agents: cyclophosphamide, mitomycin C, and procarbazine. The doses of paternal exposure were approximately equivalent to those used clinically. Using single-molecule PCR, the frequency of mutation at the mouse expanded simple tandem repeat locus Ms6-hm was established in DNA samples extracted from sperm and bone marrow of the offspring of treated males. After paternal exposure to any one of these three drugs, expanded simple tandem repeat mutation frequencies were significantly elevated in the germ line (sperm) and bone marrow of their offspring. This observed transgenerational instability was attributed to elevated mutation rates at the alleles derived from both the exposed fathers and from the nonexposed mothers, thus implying a genome-wide destabilization. Our results suggest that paternal exposure to a wide variety of mutagens can result in transgenerational instability manifesting in their offspring. Our data also raise important issues concerning delayed transgenerational effects in the children of survivors of anticancer therapy.