Particulate matter inhibits DNA repair and enhances mutagenesis

Mehta, Manju; Chen, Lung Chi; Gordon, Terry; Rom, William N.; Tang, Moon‐shong

doi:10.1016/j.mrgentox.2008.08.015

Cited by 81 publications

(51 citation statements)

References 34 publications

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“…A hypothesis for an explanation at the molecular level of the carcinogenic effects of PM could be in terms of defects in DNA repair function and replication (29). Effects of oxidative stress due to air pollution have also been shown in biomarker studies (30).…”

Section: Discussionmentioning

confidence: 99%

Cancer Mortality Risks from Long-term Exposure to Ambient Fine Particle

Wong

Tsang

Lai

et al. 2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

160

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Background: Few studies have assessed long-term effects of particulate matter (PM) with aerodynamic diameter < 2.5 mm (PM 2.5 ) on mortality for causes of cancer other than the lung; we assessed the effects on multiple causes. In Hong Kong, most people live and work in urban or suburban areas with high-rise buildings. This facilitates the estimation of PM 2.5 exposure of individuals, taking into account the height of residence above ground level for assessment of the long-term health effects with sufficient statistical power.Methods: We recruited 66,820 persons who were !65 in 1998 to 2001 and followed up for mortality outcomes until 2011. Annual concentrations of PM at their residential addresses were estimated using PM 2.5 concentrations measured at fixed-site monitors, horizontal-vertical locations, and satellite data. We

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Section: Discussionmentioning

confidence: 99%

Cancer Mortality Risks from Long-term Exposure to Ambient Fine Particle

Wong

Tsang

Lai

et al. 2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

160

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“…To address these questions, we performed in vitro DDR using UV-irradiated DNA, which is well known NER substrates, and H 2 O 2 -modified DNA as substrates for BER carrying out by cell lysates isolated from Acrtreated NHBE, NHLF and A549 cells. It has been well established that A549 cells are proficient in both NER and BER (19,31,32). Results in Fig.…”

Section: Acrolein Inhibits Dna Repair Via Degrading Repair Proteinsmentioning

confidence: 91%

Effect of Carcinogenic Acrolein on DNA Repair and Mutagenic Susceptibility

Wang

Tong

et al. 2012

Journal of Biological Chemistry

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148

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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 ...

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“…Increasing evidence supporting a link between traffic-associated air pollution and the incidence of childhood asthma has emerged; however, published estimates highlight the variability observed between populations (5,6). Asthma is a common worldwide respiratory symptom complex, frequently involving airway inflammation, which results in clinically significant physiological airway dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial cells

Wang

et al. 2015

Molecular Medicine Reports

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Abstract. Particulate matter 2.5 (PM 2.5 ) is a significant risk factor for asthma. A recent study revealed that autophagy was associated with asthma pathogenesis. However, the specific mechanisms underlying PM 2.5 -induced autophagy in asthma have remained elusive. In the present study, PM 2.5 -induced autophagy was evaluated in Beas-2B human bronchial epithelial cells and the potential molecular mechanisms were investigated. Using electron microscopy, immunofluorescence staining and immunoblot studies, it was confirmed that PM 2.5 induced autophagy in Beas-2B cells as a result of PM 2.5 -mediated inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway in Beas-2B cells. LY294002, a PI3K inhibitor, reduced the accumulation of microtubule-associated protein 1 light chain 3 II and attenuated the effect of PM 2.5 . Phosphorylated (p-)p38, p-extracellular signal-regulated kinase and p-c-Jun N-terminal kinase were dephosphorylated following exposure to PM 2.5 . The roles of p53, reactive oxygen species scavenger tetramethylthiourea and autophagy inhibitor 3-methyladenine in PM 2.5 -induced autophagy in Beas-2B cells were also investigated. The results suggested that the PI3K/Akt/mTOR signaling pathway may be a key contributor to PM 2.5 -induced autophagy in Beas-2B cells. The results of the present study therefore provided an a insight into potential future clinical applications targeting these signaling pathways, for the prevention and/or treatment of PM 2.5 -induced lung diseases. IntroductionAcute and chronic exposure to particulate matter (PM), particularly fine particles with aerodynamic diameters of ≤2.5 µm PM 2.5 , has been shown to increase the number of hospital admissions for respiratory causes amongst the general population (1). Evidence obtained from environmental and epidemiological studies has revealed a marked association between fine particulate air pollution and multiple health issues, including respiratory illnesses (for example, respiratory track inflammation, asthma, acute bronchitis and lung cancer) as well as cardiovascular disease mortality (2-4).Increasing evidence supporting a link between traffic-associated air pollution and the incidence of childhood asthma has emerged; however, published estimates highlight the variability observed between populations (5,6). Asthma is a common worldwide respiratory symptom complex, frequently involving airway inflammation, which results in clinically significant physiological airway dysfunction. Asthma pathogenesis is complex, and multiple factors have roles in the development of the disease (7).Autophagy describes an evolutionarily conserved and tightly regulated lysosomal pathway, responsible for the degradation of macromolecules, including proteins, glycogen, lipids, nucleotides and organelles, via several complex pathways (8).Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial ...

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Particulate matter inhibits DNA repair and enhances mutagenesis

Cited by 81 publications

References 34 publications

Cancer Mortality Risks from Long-term Exposure to Ambient Fine Particle

Cancer Mortality Risks from Long-term Exposure to Ambient Fine Particle

Effect of Carcinogenic Acrolein on DNA Repair and Mutagenic Susceptibility

Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial cells

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