Luch Andreas, Frey Flurina C Clement, Meier Regula, Fei Jia, Naegeli Hanspeter
Department of Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany.
Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich, Switzerland.
PLoS One. 2014 Apr 10;9(4):e94149. doi: 10.1371/journal.pone.0094149. eCollection 2014.
Formaldehyde is still widely employed as a universal crosslinking agent, preservative and disinfectant, despite its proven carcinogenicity in occupationally exposed workers. Therefore, it is of paramount importance to understand the possible impact of low-dose formaldehyde exposures in the general population. Due to the concomitant occurrence of multiple indoor and outdoor toxicants, we tested how formaldehyde, at micromolar concentrations, interferes with general DNA damage recognition and excision processes that remove some of the most frequently inflicted DNA lesions.
METHODOLOGY/PRINCIPAL FINDINGS: The overall mobility of the DNA damage sensors UV-DDB (ultraviolet-damaged DNA-binding) and XPC (xeroderma pigmentosum group C) was analyzed by assessing real-time protein dynamics in the nucleus of cultured human cells exposed to non-cytotoxic (<100 μM) formaldehyde concentrations. The DNA lesion-specific recruitment of these damage sensors was tested by monitoring their accumulation at local irradiation spots. DNA repair activity was determined in host-cell reactivation assays and, more directly, by measuring the excision of DNA lesions from chromosomes. Taken together, these assays demonstrated that formaldehyde obstructs the rapid nuclear trafficking of DNA damage sensors and, consequently, slows down their relocation to DNA damage sites thus delaying the excision repair of target lesions. A concentration-dependent effect relationship established a threshold concentration of as low as 25 micromolar for the inhibition of DNA excision repair.
CONCLUSIONS/SIGNIFICANCE: A main implication of the retarded repair activity is that low-dose formaldehyde may exert an adjuvant role in carcinogenesis by impeding the excision of multiple mutagenic base lesions. In view of this generally disruptive effect on DNA repair, we propose that formaldehyde exposures in the general population should be further decreased to help reducing cancer risks.
尽管已证实甲醛对职业暴露工人具有致癌性，但它仍被广泛用作通用交联剂、防腐剂和消毒剂。因此，了解低剂量甲醛暴露对普通人群可能产生的影响至关重要。由于室内和室外同时存在多种有毒物质，我们测试了微摩尔浓度的甲醛如何干扰一般的DNA损伤识别和切除过程，这些过程可去除一些最常见的DNA损伤。
方法/主要发现：通过评估暴露于无细胞毒性（<100μM）甲醛浓度的培养人类细胞核中的实时蛋白质动态，分析DNA损伤传感器紫外线损伤DNA结合蛋白（UV-DDB）和着色性干皮病C组蛋白（XPC）的整体迁移率。通过监测它们在局部照射点的积累，测试这些损伤传感器对特定DNA损伤的募集情况。在宿主细胞再激活试验中测定DNA修复活性，更直接地是通过测量染色体上DNA损伤的切除情况来确定。综合这些试验表明，甲醛阻碍了DNA损伤传感器在细胞核内的快速运输，因此减缓了它们重新定位到DNA损伤位点的速度，从而延迟了目标损伤的切除修复。浓度依赖性效应关系确定了抑制DNA切除修复的阈值浓度低至25微摩尔。
结论/意义：修复活性受阻的一个主要影响是，低剂量甲醛可能通过阻碍多种诱变碱基损伤的切除，在致癌过程中发挥辅助作用。鉴于甲醛对DNA修复具有普遍的破坏作用，我们建议应进一步降低普通人群的甲醛暴露水平，以帮助降低癌症风险。
