DNA damage, DNA repair and carcinogenicity: Tobacco smoke versus electronic cigarette aerosol

Abstract

The allure of tobacco smoking is linked to the instant gratification provided by inhaled nicotine. Unfortunately, tobacco curing and burning generates many mutagens including more than 70 carcinogens. There are two types of mutagens and carcinogens in tobacco smoke (TS): direct DNA damaging carcinogens and procarcinogens, which require metabolic activation to become DNA damaging. Recent studies provide three new insights on TS-induced DNA damage. First, two major types of TS DNA damage are induced by direct carcinogen aldehydes, cyclic-1,N²-hydroxy-deoxyguanosine (γ-OH-PdG) and α-methyl-1, N²-γ-OH-PdG, rather than by the procarcinogens, polycyclic aromatic hydrocarbons and aromatic amines. Second, TS reduces DNA repair proteins and activity levels. TS aldehydes also prevent procarcinogen activation. Based on these findings, we propose that aldehydes are major sources of TS induce DNA damage and a driving force for carcinogenesis. E-cigarettes (E-cigs) are designed to deliver nicotine in an aerosol state, without burning tobacco. E-cigarette aerosols (ECAs) contain nicotine, propylene glycol and vegetable glycerin. ECAs induce O⁶-methyl-deoxyguanosines (O⁶-medG) and cyclic γ-hydroxy-1,N²--propano-dG (γ-OH-PdG) in mouse lung, heart and bladder tissues and causes a reduction of DNA repair proteins and activity in lungs. Nicotine and nicotine-derived nitrosamine ketone (NNK) induce the same types of DNA adducts and cause DNA repair inhibition in human cells. After long-term exposure, ECAs induce lung adenocarcinoma and bladder urothelial hyperplasia in mice. We propose that E-cig nicotine can be nitrosated in mouse and human cells becoming nitrosamines, thereby causing two carcinogenic effects, induction of DNA damage and inhibition of DNA repair, and that ECA is carcinogenic in mice. Thus, this article reviews the newest literature on DNA adducts and DNA repair inhibition induced by nicotine and ECAs in mice and cultured human cells, and provides insights into ECA carcinogenicity in mice.

Keywords: Carcinogenesis; DNA damage; DNA repair; E-cigarette; Tobacco smoke.

Fig. 1.

Acr– dG and BPDE– dG distributions in the TP53 gene. (A and B) Acr– dG and BPDE– dG adduct distribution in exons 5, 7, and 8 of the TP53 gene of normal human lung cells treated with Acr (A) and BPDE (B). In A, normal human bronchial epithelial (NHBE) cells and normal human lung fibroblasts (NHLF) were treated with 20 μM Acr for 6 h, and in B, NHBE cells were treated with 1 μM BPDE for 30 min. Genomic DNA was then isolated, the DNA adduct distribution was mapped by the UvrABC-ligation- mediated PCR (LMPCR) method, and the DNA was separated by electrophoresis (211). AG and TC are Maxam and Gilbert sequencing reaction products. (C and D) Comparisons of the frequency of Acr– dG (C) and BPDE-dG distribution along the TP53 gene in NHBE cells with the frequency of the TP53 mutations in TS-related lung cancer (International Agency for Research on Cancer TP53 Mutation database, http://www-p53.iarc.fr ) (Adapted from Feng et al.(98, 211),).

Fig. 2.. Summary of TS induced DNA damage and effects on DNA repair.

This scheme is based on the results from DNA adduct detection in lung and bladder tissues of mice exposed to MST and SSS, DNA adduct analysis in lung tissues of tobacco smokers versus non-smokers, and results of analysis of aldehyde effect on DNA adduct induction, DNA repair activity, repair protein levels, and mutagenesis susceptibility in cultured human lung and bladder epithelial cells (19, 20, 61). Symbols: NNK, nicotine- derived nitrosamine ketone; NNN, N-nitrosonornicotine; AhR, aromatic hydrocarbon receptor; AAs, aromatic amines; CYPs, cytochrome p450s; NAs, nitrosamines; Acr, acrolein; Cro, crotonaldehyde; Fal, formaldehyde; LPO, lipid peroxidation; PBDs, pyridylic-butylic derivatives; PAHs, polycyclic aromatic hydrocarbons; PAHDEs, PAH diol epoxides.

Fig. 3.. Schematic representation of the uptake and nitrosation of nicotine in E-cig aerosols, the metabolism, subsequent degradation, the induction of DNA damage that follows, and the inhibition of DNA repair.

This scheme is based on the results from the DNA adduct analysis, DNA repair analysis, and tumorigenesis in lung and bladder tissues of mice exposed to ECAs (61, 105, 206). Symbols are the same as in Fig. 2.