多年來,，有關(guān)涉及輻射的癌癥療法對幸存者后代的影響進(jìn)行了很多的研究,。這是因為輻射已知能夠?qū)е录?xì)胞內(nèi)的突變,。而有關(guān)癌癥治療中的化療藥物的代際效應(yīng)還沒有很好的研究?，F(xiàn)在，英國萊斯特大學(xué)的Colin Glen和Yuri Dubrova領(lǐng)導(dǎo)的研究表明,，以接受化療藥物的雄性大鼠為父系的幼崽中比它們的父親有多至2倍的突變,。研究結(jié)果發(fā)表于PNAS上。
在過去的10年中,，首席研究員、遺傳學(xué)家Dubrova一直在研究癌癥療法對動物的影響,，大多數(shù)集中于放射治療的后遺癥,。然而最近，他開始調(diào)查化療藥物對后代甚至后面數(shù)代可能的遺傳學(xué)影響,。這類藥物是系統(tǒng)性全身性給藥,，不接受放射治療的其他身體部分也被包含在內(nèi)，這可能使化療的結(jié)果更糟,。為了找到答案,，他和他的同事將3種最常見的化療藥物在雄性小鼠上進(jìn)行了研究，根據(jù)小鼠的大小給予相對的劑量,。隨后將這些雄性小鼠和未接受治療的雌性小鼠進(jìn)行交配,，對產(chǎn)生的雄性后代的部分基因組進(jìn)行了研究，結(jié)果發(fā)現(xiàn)了比父母任一方多至2倍的突變,。
作者認(rèn)為,，公眾不應(yīng)對他們的研究結(jié)果產(chǎn)生恐慌，因為大多數(shù)癌癥患者年齡都太大而無法受孕,，或由于接受治療而不育,，使得接受治療的兒童成為可能存在風(fēng)險的一組人。但他們說,，他們的結(jié)果還需要在適當(dāng)?shù)姆秶鷥?nèi)開展,。研究中使用的小鼠只生存了幾年，在接受化學(xué)物質(zhì)之后很快產(chǎn)生了后代,，而那些接受化療藥物的兒童要達(dá)到生育年齡還需要很長的時間,。要查明時間的滯后是否能夠在生育之前對受損的基因進(jìn)行修復(fù)，則需要用壽命更長的動物進(jìn)行研究,。
研究的另一個有趣發(fā)現(xiàn)是,，后代中遺傳自未接受任何藥物的母親的DNA，受到了與來自接受藥物的父親同樣方式的影響,，這種情況在以前的其他研究中也存在,，但現(xiàn)在依然不清楚原因。（生物谷bioon.com）
doi:10.1073/pnas.1119396109
PMC:
PMID:
Exposure to anticancer drugs can result in transgenerational genomic instability in mice
Colin D. Glen and Yuri E. Dubrova
Abstract：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.
