Distribution of DNA Adducts Caused by Inhaled Formaldehyde Is Consistent with Induction of Nasal Carcinoma but Not Leukemia
Distribution of DNA Adducts Caused by Inhaled Formaldehyde Is Consistent with Induction of Nasal Carcinoma but Not Leukemia
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DOI：
10.1093/toxsci/kfq061
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发表时间：
2010-08-01
影响因子：
3.8
通讯作者：
Swenberg, James A.
中科院分区：
文献类型：
--
作者：
Lu, Kun;Collins, Leonard B.;Swenberg, James A.
吸入甲醛被归类为已知的人类和动物致癌物质，会导致鼻咽癌。此外，人类白血病的流行病学证据有限；然而，这在不同的研究中是不一致的。遗传毒性和细胞毒性都是甲醛对大鼠鼻腔致癌的关键事件，但白血病的机制数据还没有很好的建立。DNA加合物的形成是启动肿瘤发生的关键事件。甲醛可诱导DNA单加合物、DNA-DNA交联物和DNA蛋白质交联物。在这项研究中，发展了高灵敏的液相色谱-串联质谱仪-选择的反应监测方法，并利用[(CD2)-C-13]-甲醛暴露，允许区分来自内源性和吸入性甲醛暴露的DNA加合物和DNA-DNA交联链。结果表明，外源甲醛可诱导大鼠呼吸道鼻粘膜DNA中N-2-羟甲基-DG单加合物和DG-DG交联物，但不能在入口处远处形成[(CD2)-C-13]-加合物。此外，在鼻腔DNA中未检测到N-6-(HOCD2)-C-13-da加合物。相反，在所有被检查的组织中都存在高含量的内源性甲醛dg和da单加合物。暴露于10-ppm[(CD2)-C-13]-甲醛1天和5天的大鼠鼻DNA中外源N-2-(HOCD2)-C-13-DG的数量分别为1.28+/-0.49和2.43+/-0.78加合物/10(7)DG，存在2.63+/-0.73和2.84+/-1.13N-2-HOCH2-dG加合物/10(7)dG和3.95+/-0.26和3.61+/-0.95N-6-HOCH2-da内源加合物/10(7)da。这项研究提供了强有力的证据，支持吸入甲醛在呼吸道鼻上皮致癌中具有遗传毒性和细胞毒性作用模式，但不支持吸入甲醛也会导致白血病的生物学合理性。
Inhaled formaldehyde is classified as a known human and animal carcinogen, causing nasopharyngeal cancer. Additionally, limited epidemiological evidence for leukemia in humans is available; however, this is inconsistent across studies. Both genotoxicity and cytotoxicity are key events in formaldehyde nasal carcinogenicity in rats, but mechanistic data for leukemia are not well established. Formation of DNA adducts is a key event in initiating carcinogenesis. Formaldehyde can induce DNA monoadducts, DNA-DNA cross-links, and DNA protein cross-links. In this study, highly sensitive liquid chromatography-tandem mass spectrometry-selected reaction monitoringmethods were developed and [(CD2)-C-13]-formaldehyde exposures utilized, allowing differentiation of DNA adducts and DNA-DNA cross-links originating from endogenous and inhalation-derived formaldehyde exposure. The results show that exogenous formaldehyde induced N-2-hydroxymethyl-dG monoadducts and dG-dG cross-links in DNA from rat respiratory nasal mucosa but did not form [(CD2)-C-13]-adducts in sites remote to the portal of entry, even when five times more DNA was analyzed. Furthermore, no N-6-(HOCD2)-C-13-dA adducts were detected in nasal DNA. In contrast, high amounts of endogenous formaldehyde dG and dA monoadducts were present in all tissues examined. The number of exogenous N-2-(HOCD2)-C-13-dG in 1- and 5-day nasal DNA samples from rats exposed to 10-ppm [(CD2)-C-13]-formaldehyde was 1.28 +/- 0.49 and 2.43 +/- 0.78 adducts/10(7) dG, respectively, while 2.63 +/- 0.73 and 2.84 +/- 1.13 N-2-HOCH2-dG adducts/10(7) dG and 3.95 +/- 0.26 and 3.61 +/- 0.95 N-6-HOCH2-dA endogenous adducts/10(7) dA were present. This study provides strong evidence supporting a genotoxic and cytotoxic mode of action for the carcinogenesis of inhaled formaldehyde in respiratory nasal epithelium but does not support the biological plausibility that inhaled formaldehyde also causes leukemia.