Alcohol is classified by the International Agency for Research on Cancer (IARC) as a human carcinogen and its consumption has been associated to an increased risk of liver, breast, colorectum, and upper aerodigestive tract (UADT) cancers. Its mechanisms of carcinogenicity remain unclear and various hypotheses have been formulated depending on the target organ considered. In the case of UADT cancers, alcohol’s major metabolite acetaldehyde seems to play a crucial role. Acetaldehyde reacts with DNA inducing modifications, which, if not repaired, can result in mutations and lead to cancer development. Despite alcohol being mainly metabolized in the liver, several studies performed in humans found higher levels of acetaldehyde in saliva compared to those found in blood immediately after alcohol consumption. These results suggest that alcohol-derived acetaldehyde exposure may occur in the oral cavity independently from liver metabolism. This hypothesis is supported by our recent results showing the presence of acetaldehyde-related DNA modifications in oral cells of monkeys and humans exposed to alcohol, overall suggesting that the alcohol metabolism in the oral cavity is an independent cancer risk factor. This review article will focus on illustrating the factors modulating alcohol-derived acetaldehyde exposure and effects in the oral cavity.

Alcohol consumption is a risk factor for the development of several cancers, including those of the head and neck and the esophagus. The underlying mechanisms of alcohol-induced carcinogenesis remain unclear; however, at these sites, alcohol-derived acetaldehyde seems to play a major role. By reacting with DNA, acetaldehyde generates covalent modifications (adducts) that can lead to mutations. Previous studies have shown a dose dependence between levels of a major acetaldehyde-derived DNA adduct and alcohol exposure in oral-cell DNA. The goal of this study was to optimize a mass spectrometry (MS)-based DNA adductomic approach to screen for all acetaldehyde-derived DNA adducts to more comprehensively characterize the genotoxic effects of acetaldehyde in humans. A high-resolution/-accurate-mass data-dependent constant-neutral-loss-MS³ methodology was developed to profile acetaldehyde-DNA adducts in purified DNA. This resulted in the identification of 22 DNA adducts. In addition to the expected N²-ethyldeoxyguanosine (after NaBH₃CN reduction), two previously unreported adducts showed prominent signals in the mass spectra. MSⁿ fragmentation spectra and accurate mass were used to hypothesize the structure of the two new adducts, which were then identified as N⁶-ethyldeoxyadenosine and N⁴-ethyldeoxycytidine by comparison with synthesized standards. These adducts were quantified in DNA isolated from oral cells collected from volunteers exposed to alcohol, revealing a significant increase after the exposure. In addition, 17 of the adducts identified in vitro were detected in these samples confirming our ability to more comprehensively characterize the DNA damage deriving from alcohol exposures.

The authors would like to make a correction to their published paper