Aldehyde-Associated Mutagenesis─Current State of Knowledge

Abstract

Aldehydes are widespread in the environment, with multiple sources such as food and beverages, industrial effluents, cigarette smoke, and additives. The toxic effects of exposure to several aldehydes have been observed in numerous studies. At the molecular level, aldehydes damage DNA, cross-link DNA and proteins, lead to lipid peroxidation, and are associated with increased disease risk including cancer. People genetically predisposed to aldehyde sensitivity exhibit severe health outcomes. In various diseases such as Fanconi's anemia and Cockayne syndrome, loss of aldehyde-metabolizing pathways in conjunction with defects in DNA repair leads to widespread DNA damage. Importantly, aldehyde-associated mutagenicity is being explored in a growing number of studies, which could offer key insights into how they potentially contribute to tumorigenesis. Here, we review the genotoxic effects of various aldehydes, focusing particularly on the DNA adducts underlying the mutagenicity of environmentally derived aldehydes. We summarize the chemical structures of the aldehydes and their predominant DNA adducts, discuss various methodologies, in vitro and in vivo, commonly used in measuring aldehyde-associated mutagenesis, and highlight some recent studies looking at aldehyde-associated mutation signatures and spectra. We conclude the Review with a discussion on the challenges and future perspectives of investigating aldehyde-associated mutagenesis.

Figure 1

Chemical classification and structures of common environmental and endogenous aldehydes.

Figure 2

Common environmental and endogenous sources of aldehydes.

Figure 3

Chemical structures of the major DNA adducts associated with common environmental and endogenous aldehydes. All adducts are shown on deoxyribonucleosides (nucleobase-linked sugar moiety labeled D in all the above figures). dA, dG, and dC in adduct names indicate whether the nucleoside is in deoxyriboseadenosine, deoxyriboseguanosine, or deoxyribosecytidine, respectively. Refer to the section Aldehyde Adducts and the Genome for details.

Figure 4

Mechanisms of aldehyde-associated genome instability. Major genome-associated pathways are illustrated in open boxes. All the listed processes involve unwinding of the double helix, leading to the generation of single-stranded DNA (ssDNA). In the presence of reactive carbonyls (ball and stick molecules), open circle, genomes can accumulate a variety of lesions on both ssDNA as well as double-stranded DNA (dsDNA), including DNA:protein and DNA:DNA cross-links (broken connectors) and adducts (red hexagons). Failure to repair such lesions or erroneous bypass can result in severe genome instability, which can contribute to aldehyde-related diseases.