Cellular evidence on how nicotine and e-cigarettes increase cancer risk in humans (and mice)

It is an article of faith at the FDA and among e-cigarette enthusiasts that nicotine is not carcinogenic and that e-cigarettes do not pose any substantial cancer risk because the levels of carcinogens in e-cigarette aerosol is much lower than in a conventional cigarette.

These beliefs are challenged by a recent paper, “E-cigarette smoke damages DNA and reduces repair

activity in mouse lung, heart, and bladder as well as in human lung and bladder cells,” by Hyun-Wook Lee and colleagues at NYU.  They exposed live mice to light levels of e-cigarette aerosol and found damage to the DNA in lung, heart and bladder cells as well as in human lung and bladder cells.  They found that the cells themselves converted nicotine to carcinogenic NNN and NNK even if it was not in the original e-cigarette aerosol.  They also found that exposure to nicotine and e-cigarette aerosol damaged normal DNA repair mechanisms.

Here is how they sum up the significance of their findings:

E-cigarette smoke (ECS) delivers nicotine through aerosols without burning tobacco. ECS is promoted as noncarcinogenic. We found that ECS induces DNA damage in mouse lung, bladder, and heart and reduces DNA-repair functions and proteins in lung. Nicotine and its nitrosation product 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone can cause the same effects as ECS and enhance mutations and tumorigenic cell transformation in cultured human lung and bladder cells. These results indicate that nicotine nitrosation occurs in the lung, bladder, and heart, and that its products are further metabolized into DNA damaging agents. We propose that ECS, through damaging DNA and inhibiting DNA repair, might contribute to human lung and bladder cancer as well as to heart disease, although further studies are required to substantiate this proposal.

This paper is particularly important because it is identifying direct molecular mechanisms by which this damage occurs.

This study also directly starts to fill the data gap identified in the recent National Academies of Science, Engineering, and Medicine report on e-cigarettes, which states, “There is no available evidence whether or not e-cigarette use is associated with intermediate cancer endpoints in humans.”  This new paper demonstrates such an association at the subcellular level.

It’s too bad that the paper did not include a comparison group exposed to cigarette smoke, but these results nevertheless indicate that the FDA (and others) need to stop being so glib in making statements that nicotine doesn’t have any cancer effects.

Here is the abstract:

E-cigarette smoke delivers stimulant nicotine as aerosol without tobacco or the burning process. It contains neither carcinogenic incomplete combustion byproducts nor tobacco nitrosamines, the nicotine nitrosation products. E-cigarettes are promoted as safe and have gained significant popularity. In this study, instead of detecting nitrosamines, we directly measured DNA damage induced by nitrosamines in different organs of E-cigarette smoke exposed mice. We found mutagenic O6-methyldeoxyguanosines and γ-hydroxy-1,N2-propano-deoxyguanosines in the lung, bladder, and heart. DNA-repair activity and repair proteins XPC and OGG1/2 are significantly reduced in the lung. We found that nicotine and its metabolite, nicotine-derived nitrosamine ketone, can induce the same effects and enhance mutational susceptibility and tumorigenic transformation of cultured human bronchial epithelial and urothelial cells. These results indicate that nicotine nitrosation occurs in vivo in mice and that E-cigarette smoke is carcinogenic to the murine lung and bladder and harmful to the murine heart. It is therefore possible that E-cigarette smoke may contribute to lung and bladder cancer, as well as heart disease, in humans.

Needless to say, the pro-industry Science Media Center is already poo-point the study.

The full citation is: Hyun-Wook Lee, Sung-Hyun Park, Mao-wen Weng, Hsiang-Tsui Wang, William C. Huang, Herbert Lepor, Xue-Ru Wu, Lung-Chi Chen and Moon-shong Tang.   E-cigarette smoke damages DNA and reduces repair activity in mouse lung, heart, and bladder as well as in human lung and bladder cells.  PNAS 2018; published ahead of print January 29, 2018, https://doi.org/10.1073/pnas.1718185115.  It is available here.