Department of Environmental Sciences and Engineering, The University of North Carolina at Chapel Hill, North Carolina 27599, USA.
Toxicol Sci. 2010 Aug;116(2):441-51. doi: 10.1093/toxsci/kfq061. Epub 2010 Feb 22.
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 [(13)CD(2)]-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 [(13)CD(2)]-adducts in sites remote to the portal of entry, even when five times more DNA was analyzed. Furthermore, no N(6)-HO(13)CD(2)-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)-HO(13)CD(2)-dG in 1- and 5-day nasal DNA samples from rats exposed to 10-ppm [(13)CD(2)]-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)-HOCH(2)-dG adducts/10(7) dG and 3.95 +/- 0.26 and 3.61 +/- 0.95 N(6)-HOCH(2)-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.
吸入甲醛被归类为已知的人类和动物致癌物，可导致鼻咽癌。此外，人类白血病的有限流行病学证据也存在；然而，这些证据在不同的研究中并不一致。在大鼠中，甲醛的鼻致癌性的遗传毒性和细胞毒性都是关键事件，但白血病的机制数据尚未得到很好的建立。DNA 加合物的形成是引发致癌作用的关键事件。甲醛可以诱导 DNA 单加合物、DNA-DNA 交联和 DNA 蛋白质交联。在这项研究中，开发了高度敏感的液相色谱-串联质谱选择反应监测方法，并利用 [(13)CD(2)]-甲醛暴露，允许区分源自内源性和吸入性甲醛暴露的 DNA 加合物和 DNA-DNA 交联。结果表明，外源性甲醛诱导大鼠呼吸鼻黏膜 DNA 中的 N(2)-羟甲基-dG 单加合物和 dG-dG 交联，但即使分析了五倍量的 DNA，也不会在进入门户以外的部位形成 [(13)CD(2)]-加合物。此外，在鼻 DNA 中未检测到 N(6)-HO(13)CD(2)-dA 加合物。相比之下，在所有检查的组织中都存在大量的内源性甲醛 dG 和 dA 单加合物。暴露于 10ppm [(13)CD(2)]-甲醛的大鼠 1 天和 5 天的鼻 DNA 样品中外源性 N(2)-HO(13)CD(2)-dG 的数量分别为 1.28 +/- 0.49 和 2.43 +/- 0.78 个加合物/10(7)dG，而 2.63 +/- 0.73 和 2.84 +/- 1.13 N(2)-HOCH(2)-dG 加合物/10(7)dG 和 3.95 +/- 0.26 和 3.61 +/- 0.95 N(6)-HOCH(2)-dA 内源性加合物/10(7)dA。这项研究为吸入性甲醛在呼吸道鼻上皮致癌作用的遗传毒性和细胞毒性作用模式提供了强有力的证据，但并不支持吸入性甲醛也会导致白血病的生物学合理性。
