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.

Heterocyclic aromatic amines (HAAs), formed during the cooking of meat, are potential human carcinogens, underscoring the need for long-lived biomarkers to assess exposure and cancer risk. Frequent consumption of well-done meats containing 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a prevalent HAA that is a prostatic carcinogen in rodents and DNA-damaging agent in human prostate cells, has been linked to aggressive prostate cancer (PC) pathology. African American (AA) men face nearly twice the risk for developing and dying from PC compared to White men. We previously demonstrated that scalp hair is a reliable biospecimen for measuring PhIP intake using liquid chromatography-mass spectrometry. This study aimed to determine whether PhIP dietary intake is higher in AA men, potentially contributing to this health disparity. Healthy AA men were found to have a significantly higher mean hair PhIP level (2.12-fold) than White men on free-choice diets. However, this difference was not statistically significant after adjusting for melanin content. Further research is needed to understand how hair pigmentation, follicular density, and other morphological features of hair influence PhIP accumulation. These insights can improve the accuracy of using hair PhIP levels as a biomarker for exposure and its potential associations with cancer risk.