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Journal URL: http://mutage.oxfordjournals.org/

Journal URL: http://www.epidem.com

Journal URL: http://www.sciencedirect.com/science/journal/0041008X

We have studied the influence of individual susceptibility factors on the genotoxic effects of urban air pollution in 106 nonsmoking bus drivers and 101 postal workers in the Copenhagen metropolitan area. We used the frequency of chromosomal aberrations in peripheral blood lymphocytes as a biomarker of genotoxic damage and dimethylsulfate-induced unscheduled DNA synthesis in mononuclear WBCs, the glutathione S-transferase M1 (GSTM1) genotype, and the N-acetyltransferase 2 (NAT2) genotype as biomarkers of susceptibility. The bus drivers, who had previously been observed to have elevated levels of aromatic DNA adducts in their peripheral mononuclear cells, showed a significantly higher frequency of cells with chromosomal aberrations as compared with the postal workers. In the bus drivers, unscheduled DNA synthesis correlated negatively with the number of cells with gaps, indicating a protective effect of DNA repair toward chromosome damage. Bus drivers with the GSTM1 null and slow acetylator NAT2 genotype had an increased frequency of cells with chromosomal aberrations. NAT2 slow acetylators also showed elevated chromosomal aberration counts among the postal workers. Our results suggest that long-term exposure to urban air pollution (with traffic as the main contributor) induces chromosome damage in human somatic cells. Low DNA repair capacity and GSTM1 and NAT2 variants associated with reduced detoxification ability increase susceptibility to such damage. The effect of the GSTM1 genotype, which was observed only in the bus drivers, appears to be associated with air pollution, whereas the NAT2 genotype effect, which affected all subjects, may influence the individual response to some other common exposure or the baseline level of chromosomal aberrations.

Aromatic amines are involved in the etiology of bladder cancer. These compounds are acetylated by N-acetyltransferase 1 (NAT1) and 2 (NAT2), and epidemiological studies have shown that the slow NAT2 acetylator phenotype is associated with increased risk of bladder cancer and may be associated with decreased risk of colorectal cancer. By using PCR-RFLP analyses to identify three known slow acetylator alleles (M1, M2, and M3) and the wild-type, or fast, allele, the NAT2 genotypes were determined. No association between the NAT2 slow acetylator genotype and bladder cancer was found either by crude analyses [odds ratio (OR), 1.32; 95% confidence interval (CI), 0.91-1.92) or by logistic regression analyses adjusted for age, gender, and smoking exposure (OR, 1.22; 95% CI, 0.92-1.62). A similar observation was made when the cases were divided into incident and surviving cases. Dividing the cases by pathological classification (benign or malignant) did not alter this finding. Likewise, analyses of the NAT1 and glutathione S-transferase mu 1 (GSTM1) genotypes showed no associations between the NAT1 or GSTM1 genotypes and bladder cancer risk. However, restricting the analysis to people exposed to potential bladder carcinogens (i.e., smokers) among cases and controls, a small but significant association between the slow acetylator genotype and bladder cancer risk was revealed among all cases with malignant tumors (OR, 1.35; 95% CI, 1.02-1.80) and among incident cases with malignant tumors (OR, 1.50; 95% CI, 1.04-2.16). The allele frequencies in the group consisting of smokers showed an overrepresentation of the NAT2 M1 (NAT2*5) allele in the incident case group. The NAT1 and GSTM1 genotypes were not associated with increased risk of bladder cancer among smokers. Analyses of genetic combinations of NAT1/NAT2 as potential risk factors for bladder cancer seem to indicate that the normal NAT1/fast NAT2 genotype may be a protective genotype compared with the other genotype combinations. Analyses of genetic combinations of NAT2/GSTM1 did not reveal any combination of NAT2 and GSTM1 genotypes associated with increased bladder cancer risk.

Exposure to PAH in foundry workers has been studied by urinary 1-hydroxypyrene (HPU) levels, quantitatively measured by reversed phase HPLC. Seventy male foundry workers and 68 matched controls were investigated. Polycyclic aromatic hydrocarbon (PAH) exposure was defined by 17 breathing zone hygienic samples, consisting of 16 selected PAH compounds. Mean total PAH concentration (SD) was 10.40 (4.04) mu g/m3. A multiple regression model of tobacco consumption, age, airborne PAH-exposure and foundry work on log HPU showed a significant correlation, p

Udgivelsesdato: April

Journal URL: http://www.sciencedirect.com/science/journal/00275107

In cancer patients, plasma often contains mutant DNA released by cancer cells. We have assessed the significance of plasma DNA mutations for subsequent cancer development in healthy subjects in a large longitudinal prospective study. The European Prospective Investigation into Cancer and Nutrition study was analyzed with a nested case-control design. Cases were nonsmokers or ex-smokers for >10 years and newly diagnosed with lung, bladder, or upper aerodigestive tract cancers or leukemia accrued after a median follow-up of 6.3 years. Controls were matched 2:1 for follow-up, age, sex, area of recruitment, and smoking status. KRAS2 mutations were detected by mutant-enriched PCR and sequencing (n = 1,098). TP53 mutations were detected by denaturing high-performance liquid chromatography, temporal temperature gradient electrophoresis, and sequencing (n = 550). KRAS2 or TP53 mutations were detected in 13 of 1,098 (1.2%) and 20 of 550 (3.6%) subjects, respectively, 16 of whom developed cancer on average after 18.3 months of follow-up. Among 137 subjects who developed bladder cancer, 5 had KRAS2 mutations [odds ratio (OR), 4.25; 95% confidence interval (95% CI), 1.27-14.15] and 7 had TP53 mutations (OR, 1.81; 95% CI, 0.66-4.97). There was a nonsignificant trend for association between TP53 mutations and bulky adducts in lymphocyte DNA (OR, 2.78; 95% CI, 0.64-12.17). This is the first report of TP53 or KRAS2 mutations in the plasma of healthy subjects in a prospective study, suggesting that KRAS2 mutation is detectable ahead of bladder cancer diagnosis. TP53 mutation may be associated with environmental exposures. These observations have implications for monitoring early steps of carcinogenesis. (Cancer Res 2006; 66(13): 6871-6)

Lung cancer is the most common malignancy in the Western world, and the main risk factor is tobacco smoking. Polymorphisms in metabolic genes may modulate the risk associated with environmental factors. The glutathione S-transferase theta 1 gene (GSTT1) is a particularly attractive candidate for lung cancer susceptibility because of its involvement in the metabolism of polycyclic aromatic hydrocarbons found in tobacco smoke and of other chemicals, pesticides, and industrial solvents. The frequency of the GSTT1 null genotype is lower among Caucasians (10-20%) than among Asians (50-60%). The authors present a meta- and a pooled analysis of case-control, genotype-based studies that examined the association between GSTT1 and lung cancer (34 studies, 7,629 cases and 10,087 controls for the meta-analysis; 34 studies, 7,044 cases and 10,000 controls for the pooled analysis). No association was observed between GSTT1 deletion and lung cancer for Caucasians (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.87, 1.12); for Asians, a positive association was found (OR = 1.28, 95% CI: 1.10, 1.49). In the pooled analysis, the odds ratios were not significant for either Asians (OR = 0.97, 95% CI: 0.83, 1.13) or Caucasians (OR = 1.09, 95% CI: 0.99, 1.21). No significant interaction was observed between GSTT1 and smoking on lung cancer, whereas GSTT1 appeared to modulate occupational-related lung cancer. This study was partially supported by Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS) contract 513943.