Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom.
Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2984-8. doi: 10.1073/pnas.1119396109. Epub 2012 Jan 30.
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.
人类接触抗癌药物的遗传效应仍知之甚少。为了确定抗癌药物的暴露不仅会导致治疗动物生殖系中的突变诱导，而且还会导致其后代突变率的改变，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）处理的雄性小鼠后代的突变率。亲代暴露的剂量大约与临床上使用的剂量相当。使用单分子 PCR，在从经处理的雄性后代的精子和骨髓中提取的 DNA 样本中，建立了小鼠扩展简单串联重复位点 Ms6-hm 的突变频率。在暴露于这三种药物中的任何一种后，其后代的生殖系（精子）和骨髓中的扩展简单串联重复突变频率显著升高。这种观察到的跨代不稳定性归因于来自暴露父亲和未暴露母亲的等位基因的突变率升高，从而暗示了全基因组的不稳定性。我们的研究结果表明，广泛的诱变剂暴露于亲代可导致其后代的跨代不稳定性。我们的数据还提出了有关抗癌治疗幸存者的子女中延迟的跨代效应的重要问题。
