Mutation spectrum in sunlight-exposed mouse skin epidermis: small but appreciable contribution of oxidative stress-mediated mutagenesis
Mutation spectrum in sunlight-exposed mouse skin epidermis: small but appreciable contribution of oxidative stress-mediated mutagenesis
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DOI：
10.1016/j.mrfmmm.2004.06.038
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发表时间：
2004-11-22
影响因子：
2.3
通讯作者：
Ono, T
中科院分区：
文献类型：
--
作者：
Ikehata, H;Nakamura, S;Ono, T
我们使用转基因穆塔（TM）小鼠研究了阳光诱导的皮肤突变。日本仙台夏季正午的阳光能有效地诱导表皮和真皮的突变。表皮突变频率（MF）达到近0.5%，在第一个40分钟的照射，但变得饱和在这个水平的外观皮肤炎症后进一步照射。在相同的炎症剂量下，阳光的遗传毒性是313 nm峰值UVB的两倍。在从暴露于阳光的表皮分离的80个lacZ转基因突变体中检测到的81个突变以C -> T转换（89%）为主，仅发生在二嘧啶位点，并且还包括CC -> TT串联取代。因此，阳光诱导的突变谱是高度紫外线特异性的，非常类似于UVB诱导的，但显着不同于UVA诱导的。虽然仅在5个突变体中检测到与氧化损伤相关的C -> A颠换（6%），但其频率升高至背景水平的至少15倍，表明UVA介导的氧化应激的贡献相对较小但相当大。对邻近突变胞嘧啶的碱基的分析表明，阳光诱导的突变偏好5 '-TC-3'二嘧啶位点而不是5 '-CC-3'和5-CT-3 '。转基因中C → T转换位点的分布与CpG基序密切相关，已知CpG基序在基因中完全甲基化，并且与UVB诱导的甲基化非常相似，而不是UVA诱导的甲基化。因此，UVB组分对哺乳动物皮肤中日光诱导的突变的贡献比UVA组分大得多，UVA组分通过活性氧（ROS）介导的诱变的影响仍然是可观的。(C)2004 Elsevier B. V.保留所有权利。
We studied the mutations induced in skin by sunlight using transgenic, Muta(TM) mice. Noon sunlight during summer at Sendai, Japan induced mutations efficiently in both epidermis and dermis. The mutant frequency (MF) in epidermis reached nearly 0.5% during the first 40 min irradiation but became saturated at this level with the appearance of skin inflammation after further irradiation. At the equivalent inflammatory dose, sunlight was twice as genotoxic as 313 nm-peak UVB. The 81 mutations detected in 80 lacZ transgene mutants isolated from the sunlight-exposed epidermis were dominated by C --> T transitions (89%), occurring exclusively at dipyrimidine sites, and also included a CC --> TT tandem substitution. Thus, the sunlight-induced mutation spectrum is highly UV-specific, quite similar to that induced by UVB but significantly different from that induced by UVA. Although oxidative damage-related C --> A transversions were detected only in five mutants (6%), their frequency was elevated to at least 15 times the background level, suggesting that the contribution of UVA-mediated oxidative stress is comparatively small but considerable. An analysis of bases adjacent to the mutated cytosines revealed that the sunlight-induced mutations prefer 5'-TC-3' dipyrimidine sites to 5'-CC-3' and 5-CT-3'. The distribution of the frequent C --> T transition sites in the transgene was well associated with the CpG motif, which is known to be completely methylated in the gene, and quite similar to that induced by UVB rather than that by UVA. Thus, the UVB component contributes to the sunlight-induced mutations in the mammalian skin much more than the UVA component, whose influence through reactive oxygen species (ROS)-mediated mutagenesis is still appreciable. (C) 2004 Elsevier B.V. All rights reserved.