Distribution of DNA Adducts Caused by Inhaled Formaldehyde Is Consistent with Induction of Nasal Carcinoma but Not Leukemia

Abstract

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.

Formation, Accumulation, and Hydrolysis of Endogenous and Exogenous Formaldehyde-Induced DNA Damage

“…2; Tables 1-3). These results were in accord with our previous studies (Lu et al, 2010aMoeller et al, 2011), providing compelling evidence that inhaled formaldehyde does not reach tissues distant to the site of initial contact. Thus, the plausibility of speculative hypotheses that inhaled formaldehyde causes leukemia via direct DNA damage must be seriously questioned.…”

“…The question remains why exogenous N 2 -HOMe-dG adducts were not found in the other 94 exposed rats. Considering all the bone marrow samples we have previously analyzed (Lu et al, 2010aMoeller et al, 2011), this was the only instance out of 121 rats and primates where exogenous adducts were detected in bone marrow samples. Moreover, the amounts of endogenous adducts in air control rat bone marrow match very nicely with the corresponding amounts measured in the 28-day-exposed rat bone marrow.…”

“…However, whether or not inhaled formaldehyde exposure causes leukemia remains debatable. Previous experimental results have not supported the induction of leukemia (Lu et al, 2010a), and epidemiological reports have been inconsistent across different studies (Beane Freeman et al, 2009;Coggon et al, 2014). K.J.…”

“…All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com bind and induce DNA monoadducts (McGhee and von Hippel, 1977), DNA-DNA crosslinks (Lu et al, 2010a), DNA-protein crosslinks (DPCs) (Casanova-Schmitz and Heck, 1983;MaganaSchwencke and Ekert, 1978;Solomon and Varshavsky, 1985), and DNA-glutathione crosslinks . The carcinogenic mode of action is based on the synergism among the formation of DNA mono-adducts, DPCs, and increased cell proliferation that lead to mutations (International Agency for Research on Cancer, 2006).…”

“…Fourth, the NRC recommended that biologically based dose-response models be used. Fifth, the NRC recommended that EPA carefully consider the implications of recent analytical techniques that achieve superior sensitivity and can be highly informative in accurately distinguishing between and quantifying separately exogenous and endogenous formaldehydeinduced DNA mono-adducts and DPCs in tissues (Lu et al, 2010a).…”