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Edited by James E. Cleaver, University of California, San Francisco, CA, and approved May 23, 2018 (received for review March 20, 2018)
Significance
Tobacco smoke (TS) contains numerous carcinogens. Intriguingly, while TS itself is a weak carcinogen in animal models, many of the TS components, such as 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) and polycyclic aromatic hydrocarbons (PAHs), are strong carcinogens. We found that TS induces mainly aldehyde-DNA adducts in mice and humans. TS reduces DNA repair activity and repair proteins in mouse lung. All of these TS-induced effects can be reduced by diet polyphenols. Aldehydes prevent PAHs and NNK from inducing DNA damage in human cells. We propose that, because they act to damage DNA, reduce DNA repair activity, and inhibit NNK and PAHs from becoming DNA-damaging agents, aldehydes are the major TS carcinogens. These insights allow for better TS cancer risk assessment and the design of effective preventive measures.
Abstract
Tobacco smoke (TS) contains numerous cancer-causing agents, with polycyclic aromatic hydrocarbons (PAHs) and nitrosamines being most frequently cited as the major TS human cancer agents. Many lines of evidence seriously question this conclusion. To resolve this issue, we determined DNA adducts induced by the three major TS carcinogens: benzo(a)pyrene (BP), 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanoe (NNK), and aldehydes in humans and mice. In mice, TS induces abundant aldehyde-induced γ-hydroxy-propano-deoxyguanosine (γ-OH-PdG) and α-methyl-γ-OH-PdG adducts in the lung and bladder, but not in the heart and liver. TS does not induce the BP- and NNK-DNA adducts in lung, heart, liver, and bladder. TS also reduces DNA repair activity and the abundance of repair proteins, XPC and OGG1/2, in lung tissues. These TS effects were greatly reduced by diet with polyphenols. We found that γ-OH-PdG and α-methyl-γ-OH-PdG are the major adducts formed in tobacco smokers’ buccal cells as well as the normal lung tissues of tobacco-smoking lung cancer patients, but not in lung tissues of nonsmokers. However, the levels of BP- and NNK-DNA adducts are the same in lung tissues of smokers and nonsmokers. We found that while BP and NNK can induce BPDE-dG and O6-methyl-dG adducts in human lung and bladder epithelial cells, these inductions can be inhibited by acrolein. Acrolein also can reduce DNA repair activity and repair proteins. We propose a TS carcinogenesis paradigm. Aldehydes are major TS carcinogens exerting dominant effect: Aldehydes induce mutagenic PdG adducts, impair DNA repair functions, and inhibit many procarcinogens in TS from becoming DNA-damaging agents.
Footnotes
↵1M.-w.W., H.-W.L., S.-H.P., Y.H., and H.-T.W. contributed equally to this work.
- ↵2To whom correspondence should be addressed. Email: moon-shong.tang{at}nyumc.org.
Author contributions: M.-w.W., H.-W.L., S.-H.P., Y.H., H.-T.W., and M.-s.T. designed research; M.-w.W., H.-W.L., S.-H.P., Y.H., and H.-T.W. performed research; C.S.Y. contributed new reagents/analytic tools; M.-s.T. analyzed data; and L.-C.C., W.N.R., W.C.H., H.L., X.-R.W., and M.-s.T. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1804869115/-/DCSupplemental.
- Copyright © 2018 the Author(s). Published by PNAS.
This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Aldehydes are the predominant forces inducing DNA damage and inhibiting DNA repair in tobacco smoke carcinogenesis
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