Lack of functional telomeres can cause chromosomal aberrations. This type of genetic instability may promote tumorigenesis. We have investigated the association between mean telomere length in buccal cells (assessed with quantitative real-time PCR) and bladder cancer risk in a case-control study. Patients with bladder cancer displayed significantly shorter telomeres than control subjects (P = 0.001). Median telomere length ratio was 0.95 (range 0.53-3.2) for cases and 1.1 (0.51-2.4) for controls. Moreover, the adjusted odds ratio (OR) for bladder cancer was significantly increased in the quartile with the shortest telomere length OR = 4.5 [95% confidence interval (CI) 1.7-12]. It is known that oxidative stress, alkylation or UV radiation increases shortening of telomeres. Therefore, we also analyzed whether environmental and genetic factors associated with DNA damage, i.e. smoking and polymorphisms in the genes involved in the metabolism of genotoxic carcinogens (EPHX1, GSTA1, GSTM1, GSTP1, GSTT1, NAT1, NAT2 and NQO1) or DNA repair (APE1, NBS1, XPC, XPD, XRCC1, XRCC3 and XRCC4), could modify the association between telomere length and cancer risk. A clear effect of smoking and telomere length could be observed. Current smokers with short telomeres had more than six times as higher risk as non-smokers/former smokers with long telomeres (OR = 6.3, 95% CI 1.7-23). Lack of the biotransformation gene GSTM1 and short telomeres were associated with OR = 6.5 (95% CI 2.4-18), whereas homozygous carriers of 312Asn in the DNA repair gene XPD, with short telomeres, displayed an OR of 17 (95% CI 1.9-150). However, no significant interaction for cancer risk could be proven for telomere length, smoking and susceptibility genotypes of metabolizing and DNA-repairing genes.
Objectives-To study the acute effects of exposure to the increasingly used solvent, N-methyl-2-pyrrolidone (NMP) in male volunteers. Further, to determine the NMP concentration in plasma and urine during and after the exposure.Methods-Six male volunteers were exposed for eight hours on four different days to 0, 10, 25, and 50 mg/ml NMP. In the rat, NMP is readily absorbed through the skin2 and the respiratory3 and gastrointestinal2 tracts, distributed to all major organs,4 and biotransformed to polar metabolites which are excreted in urine, mainly as 5-hydroxy-Nmethyl-2-pyrrolidone.5 The urinary excretion, studied after application of NMP to the skin, suggests a percutaneous uptake of about 70%.2 Animal studies also show that exposure to NMP may cause degenerative changes in the respiratory system and the haematopoietic and the lymphoid tissues. Effects such as lethargy and irregular respiration found after inhalation and oral administration may be due to a neurotoxic effect. The studies on reproductive toxicity show that NMP may cause developmental toxicity at doses causing mild or no maternal toxicity.6The toxicity of NMP in humans is not well known. ' The irritating effect found in the occupational setting on skin and eyes predicts that NMP, in accordance with animal studies,7 may be a moderate to severe irritant. Workers exposed to concentrations of NMP in air ranging from 3-6 mg/m3, for even short periods (30 min), reported severe eye irritation and headache.8 Reversible dermatitis is reported in workers after a few days of work with NMP,9 and experimental skin exposure to NMP in humans caused transient irritation. ' These findings of adverse effects show that exposure to NMP may present a risk of injury to human health. Knowledge of the effect of exposure to NMP in humans is lacking. Human studies involving experimental inhalation are needed for evaluation of the effect of short term exposure. The metabolism in humans needs to be evaluated for assessing the risk of exposure and for studies of the possibility of biological monitoring. Materials and methods SUBJECTS AND STUDY DESIGNSix healthy male volunteers (subjects 1, 2, 3, 4, 5, and 6; age 28, 29, 35, 39, 39, and 41 236 on 11 May 2018 by guest. Protected by copyright.
Fish contain methylamines, especially trimethylamine N-oxide (TMAO), trimethylamine (TMA), and dimethylamine (DMA). Further, DMA may be formed TMA and TMAO. DMA is a precursor of nitrosodimethylamine (NDMA), which is a potent carcinogen. Levels of DMA, TMA, and TMAO in urine were used as indicators of the dietary exposure and in vivo formation of these amines in 44 men, representing 3 groups with different fish consumption habits. The levels of TMA (median 0.24 mmol/mol creatinine; range 0-2.7) and TMAO (median 38 mmol/mol creatinine; range 8-290) were significantly associated with the weekly intake of fish (r = .47, p = .001, and r = .53, p = .0002, respectively), while no such relation was found for DMA (median 24 mmol/mol creatinine; range 5-46). Further, urinary levels of TMA and TMAO were dependent on recent intake of fish.
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