Effect of Carcinogenic Acrolein on DNA Repair and Mutagenic Susceptibility

Abstract

Background: Acrolein is highly reactive and abundant in tobacco smoke. Results: Acrolein induces DNA damage, inhibits excision repair and mismatch repair, causes repair protein degradation, and enhances mutagenesis. Conclusion: Acrolein induces DNA damage and inhibits DNA repair that causes mutagenesis and initiates carcinogenesis. Significance: This is the first demonstration that acrolein inhibits DNA repair pathways by induction of repair protein degradation.Acrolein (Acr), a ubiquitous environmental contaminant, is a human carcinogen. Acr can react with DNA to form mutagenic ␣-and ␥-hydroxy-1, N 2 -cyclic propano-2-deoxyguanosine adducts (␣-OH-Acr-dG and ␥-OH-Acr-dG). We demonstrate here that Acr-dG adducts can be efficiently repaired by the nucleotide excision repair (NER) pathway in normal human bronchial epithelia (NHBE) and lung fibroblasts (NHLF). However, the same adducts were poorly processed in cell lysates isolated from Acr-treated NHBE and NHLF, suggesting that Acr inhibits NER. In addition, we show that Acr treatment also inhibits base excision repair and mismatch repair. Although Acr does not change the expression of XPA, XPC, hOGG1, PMS2 or MLH1 genes, it causes a reduction of XPA, XPC, hOGG1, PMS2, and MLH1 proteins; this effect, however, can be neutralized by the proteasome inhibitor MG132. Acr treatment further enhances both bulky and oxidative DNA damage-induced mutagenesis. These results indicate that Acr not only damages DNA but can also modify DNA repair proteins and further causes degradation of these modified repair proteins. We propose that these two detrimental effects contribute to Acr mutagenicity and carcinogenicity.Acrolein, an ␣,␤-unsaturated aldehyde, is abundant in tobacco smoke, cooking fumes, and automobile exhaust fumes (1). Acr 2 is also a by-product of lipid peroxidation generated endogenously in cells under oxidative stress (2). Inhaled Acr is extremely toxic in mouse models (3). In fact, the effects of Acr on lung carcinogenicity in mouse models have not been assessed due to excessive death of Acr-exposed mice (3). Nonetheless, it has been shown that intraperitoneal injection of Acr causes bladder tumors in rat models (4 -7). Acr is a major metabolite of antitumor drugs cyclophosphamide and ifosfamide. Metabolically produced and inhaled Acr are excreted in urine and accumulated in the bladder (5, 6). It has been concluded that Acr is the culprit of bladder cancer in patients who have been administered cyclophosphamide and ifosfamide in long term treatment protocols (4 -7).Acr induces ␣-and ␥-hydroxy-1,N 2 -cyclic propano-2Ј-deoxyguanosine (␣-OH-Acr-dG and ␥-OH-Acr-dG) adducts in human cells (8). It has been found that both types of Acr-dG adducts are mutagenic and that they induce mainly G to T and G to A mutations (9 -18). By mapping Acr-dG adduct distribution at the nucleotide level in Acr-treated normal human bronchial epithelia (NHBE), we have found that the Acr-DNA binding spectrum in the p53 gene coincides with p53 mutational spectrum in lung cancer (19). Because ...

Epigenotoxicity of environmental pollutants evaluated by a combination of DNA methylation inhibition and capillary electrophoresis–laser-induced fluorescence immunoassay

“…Toxicity of α,β-unsaturated aldehydes, such as acrolein and crotonaldehyde, are partly attributable to its high reactivity toward DNA and proteins through Michael addition reaction [32,33]. Recent study suggested that acrolein not only induced DNA damage, but also inhibited excision repair and mismatch repair that might cause mutagenesis and initiate carcinogenesis [34]. However, it is not clear whether the reactive and electrophilic aldehydes can inhibit DNA methylation and cause epigenetoxicity.…”

Mechanisms Underlying Acrolein-Mediated Inhibition of Chromatin Assembly

“…Acr has been implicated in the development of multiple human diseases, such as bladder cancer (4), lung cancer (5-7), Alzheimer's disease (8)(9)(10), and cardiovascular diseases (11,12). Acr contains a carbonyl group and an olefinic double bond, which makes it highly reactive to many cellular molecules, including proteins and DNA (13)(14)(15)(16). Recent studies show that Acr could be a potential major carcinogen of smoking-related lung cancer via induction of DNA damage and inhibition of DNA repair (14,15,17,18).…”

“…Acr contains a carbonyl group and an olefinic double bond, which makes it highly reactive to many cellular molecules, including proteins and DNA (13)(14)(15)(16). Recent studies show that Acr could be a potential major carcinogen of smoking-related lung cancer via induction of DNA damage and inhibition of DNA repair (14,15,17,18). In addition to its role in inducing DNA damage and mutagenicity, the other biological effects of Acr are most likely through its direct interaction with nucleophilic amino acids, primarily cysteine, lysine, and histidine, in critical protein targets (11,12,19).…”

Application of liquid chromatography-mass spectrometry and differential mobility spectrometry-mass spectrometry for detection and quantitation of biomarkers in complex biological matrices

“…Continued methods development will be based on more complete species and time-course response data, further refinement of sample storage and extraction methods, introducing an automated flow injection device, standardization and automation of mass-spectrometric techniques, and continued attention to new bioinformatic methods [50,51]. The gains in sample throughput are to a large extent specific to the analytes described in this paper.…”

“…The same investigators later found that acrolein-DNA adduct has 5-fold higher mutagenicity than 4-ABP-DNA adduct. In this new study, they used the same 32 P-postlabelling method but together with an immunochemical method [51,52] and they concluded that acrolein is one of the major bladder carcinogens in tobacco smoke.…”