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Abstract Background Worldwide, smoking is a major public health problem, with exposure to environmental tobacco smoke (ETS) affecting both smokers, and passive smokers, including children. Despite ETS also describing secondhand, and thirdhand smoke (SHS, and THS respectively), the health effects of exposure to passive smoking via these sources are not fully understood, particularly in children. Although cotinine, the primary proximate metabolite of nicotine, has been widely used as a biomarker of ETS exposure, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), the metabolite of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), provides a uniquely important contribution, both as a biomarker of exposure, and as a specific risk indicator for pulmonary carcinogenesis. Methods We used LC-MS/MS to study NNK metabolites, cotinine, and 8-oxo-7,8-dihydro-2′-deoxyguanosine (a biomarker of oxidative stress), in the urine of 110 non-smoking adults (age range: 23–62) and 101 children (age range: 9–11), exposed to ETS. Results In our study of passive smoking adults, and children exposed to ETS, we showed that although the children had a similar urinary level of cotinine compared to the adults, the children had approximately two times higher levels of urinary total NNAL (P = 0.002), and free NNAL (P = 0.01), than adults. The children also had three times lower ability to detoxify NNK than adults (P < 0.001). Furthermore, the children showed 1.5 times higher ratio of total NNAL/cotinine than adults (P = 0.01), implying that THS is another important source of ETS in this population. Furthermore, ETS exposure in children appeared to lead to an increase in levels of oxidative stress. Conclusions Taken together, our results demonstrate that, in children, THS may play an important role in the ETS exposure, and that children are at particular risk of ETS-induced health effects. Highlights • Children had a significantly lower ability to detoxify NNK than adults. • Urinary total NNAL:cotinine ratio could inform on the ETS exposure source. • In children, THS might be a more important source of NNK exposure than SHS. • Children have a higher risk of ETS health effects, e.g., oxidative stress. [ABSTRACT FROM AUTHOR]

Sepsis not only leads to short-term mortality during hospitalization, but is also associated with increased mortality during long-term follow-up after hospital discharge. Metabolic stress during sepsis may cause oxidative damage to both nuclear and mitochondrial DNA (mtDNA) and RNA, which could affect long-term health and life span. Therefore, the aim of this study was to assess the association of sepsis with oxidized nucleobases and (mt)DNA damage and long-term all-cause mortality in septic patients. 91 patients with sepsis who visited the emergency department (ED) of the University Medical Center Groningen between August 2012 and June 2013 were included. Urine and plasma were collected during the ED visit. Septic patients were matched with 91 healthy controls. Death rate was obtained until June 2020.The degree of oxidation of DNA, RNA and free nucleobases were assessed in urine by mass-spectrometry. Lipid peroxidation was assessed in plasma using a TBAR assay. Additionally, plasma levels of mtDNA and damage to mtDNA were determined by qPCR. Sepsis patients denoted higher levels of oxidated DNA, RNA, free nucleobases and lipid peroxidation than controls (all p < 0.01). Further, sepsis patients displayed an increase in plasma mtDNA with an increase in mtDNA damage compared to matched controls (p < 0.01). Kaplan meier survival analyses revealed that high degrees of RNA- and nucleobase oxidation were associated with higher long-term all-cause mortality after sepsis (p < 0.01 and p = 0.01 respectively). Of these two, high RNA oxidation was associated with long-term all-cause mortality, independent of adjustment for age, medical history and sepsis severity (HR 1.29 [(1.17–1.41, 95% CI] p < 0.01). Sepsis is accompanied with oxidation of nuclear and mitochondrial DNA and RNA, where RNA oxidation is an independent predictor of long-term all-cause mortality. In addition, sepsis causes mtDNA damage and an increase in cell free mtDNA in plasma. Sepsis leads to mitochondrial DNA damage and oxidized nucleobases which is associated long-term all-cause mortality. Sepsis causes an induction of reactive oxygen species (ROS) which are produced by the mitochondria. DNA, RNA and lipids in mitochondria and cells are damaged by ROS. Both oxidized DNA and RNA are associated with long-term all-cause mortality. [Display omitted] [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a disease characterized by chronic inflammation and irreversible airway obstruction. Cigarette smoking is the predominant risk factor for developing COPD. It is well-known that the COPD is also strongly associated with an increased risk of developing lung cancer. Cigarette smoke contains elevated concentrations of oxidants and various carcinogens (e.g., tobacco-derived nitrosamines) that can cause oxidative and alkylating stresses, which can also arise from inflammation. However, it is surprising that, except for oxidative stress, little information is available on the burden of alkylating stress and the detoxification efficiency of tobacco-derived carcinogens in COPD patients. In this study, we used LC-MS/MS to measure the archetypical tobacco-specific carcinogenic 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), three biomarkers of oxidative stress (8-oxo-7,8-dihydroguanine, 8-oxoGua; 8-oxo-7,8-dihydro-2′-deoxyguanosine, 8-oxodGuo; 8-oxo-7,8-dihydroguanosine, 8-oxoGuo) and two biomarkers of alkylating stress (N7-methylguanine, N7-MeGua and N3-methyladenine, N3-MeAde), in the urine of smoking and non-smoking COPD patients and healthy controls. Our results showed that not only was oxidative stress significantly elevated in the COPD patients compared to the controls, but also alkylating stress. Significantly, levels of alkylating stress (i.e., N7-MeGua) were highly correlated with the COPD severity and not affected by age and smoking status. Furthermore, COPD smokers had significantly higher ratios of free NNAL to the total NNAL than control smokers, implying a lower detoxification efficiency of NNK in COPD smokers. This ratio was even higher in COPD smokers with stages 3–4 than in COPD smokers with stages 1–2. Taken together, our results demonstrated that the detoxification efficiency of tobacco-derived carcinogens (e.g., NNK) was associated with the pathogenesis and possibly the progression of COPD. In addition to oxidative stress, alkylating stress derived from chronic inflammation appears to be also dominant in COPD patients. Image 1 • Alkylating and oxidative stresses were increased in COPD patients. • Alkylating stress was correlated with COPD severity. • Ratio of free NNAL/total NNAL were determined and increased in COPD smokers. • The higher COPD severity the higher ratio of free NNAL/total NNAL. • Cigarette smoke/chronic inflammation induced oxidative and alkylating stresses. [ABSTRACT FROM AUTHOR]

Skin melanisation ranges widely across human populations. Melanin has antioxidant properties and also acts as a filter to solar ultraviolet radiation (UVR) incident upon the skin. In this study we firstly examined whether melanin level might influence baseline levels of systemic oxidative stress, in 65 humans in vivo from the same geographical area ranging from the lightest to darkest skin type (phototype I-VI). This was examined in winter-time (latitude 53.5°N). Remarkably, we found that urinary biomarkers of oxidatively-generated DNA damage (8-oxodG) and RNA damage (8-oxoGuo) were significantly correlated with skin lightness (L*), such that 14–15% of the variation in their baseline levels could be explained by skin colour. Next we exposed 15 humans at the extremes of skin melanisation to a simulated summer-time exposure of solar UVR (95% UVA, 5% UVB; dose standardised to sunburn threshold), following which they provided a sample of every urine void over the next five days. We found that UVR induced a small but significant increase in urinary 8-oxodG and 8-oxoGuo, with differing kinetics between skin types. Thus greater melanisation is associated with protection against systemic oxidative stress, which may reflect melanin's antioxidant properties, and solar UVR exposure also influences systemic oxidative stress levels in humans. These novel findings may have profound implications for human physiology and health. Image 1 • Biomarkers of systemic oxidative stress correlate with human skin lightness level. • Skin colour contributes 14–15% variation in baseline urinary 8-oxodG and 8-oxoGuo. • UVR exposure of the skin elevates biomarkers of systemic oxidative stress. • Both oxidatively-damaged DNA (8-oxodG) and RNA (8-oxoGuo) increase post-UVR. • Kinetics of urinary biomarker responses following UVR differ between skin types. [ABSTRACT FROM AUTHOR]

Abstract: A highly sensitive quantitative LC-MS/MS method was developed for measuring urinary malondialdehyde (MDA). With the use of an isotope internal standard and online solid-phase extraction, urine samples can be directly analyzed within 10min after 2,4-dinitrophenylhydrazine (DNPH) derivatization. The detection limit was estimated as 0.08pmol. This method was further applied to assess the optimal addition of DNPH for derivatization and to measure urinary MDA in 80 coke oven emission (COE)-exposed and 67 nonexposed workers. Derivatization optimization revealed that to achieve complete derivatization reaction, an excess of DNPH is required (DNPH/MDA molar ratio: 893–8929) for urine samples that is about 100 times higher than that of MDA standard solutions (molar ratio: 10–80). Meanwhile, the mean urinary concentrations of MDA in COE-exposed workers were significantly higher than those in nonexposed workers (0.23±0.17 vs 0.14±0.05μmol/mmol creatinine, P <0.005). Urinary MDA concentrations were also significantly associated with the COE (P <0.005) and smoking exposure (P <0.05). Taken together, this method is capable of routine high-throughput analysis and accurate quantification of MDA and would be useful for assessing the whole-body burden of oxidative stress. Our findings, however, raise the issue that derivatization optimization should be performed before it is put into routine biological analysis. [Copyright &y& Elsevier]

Abstract: We measured the levels of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo), a useful biomarker of oxidative injury, in liver (or urine) of maternal mice and their offspring, that were treated with humic acid (HA) and arsenic (As) alone, or their combination during pregnancy. A highly sensitive and specific isotope-dilution LC–MS/MS method was used for 8-oxodGuo quantification. Total arsenic accumulated in the offspring was also measured using ICP–MS. This study demonstrated, for the first time in an animal model, that HA alone treatment led to a significant increase of 8-oxodGuo levels both in liver and urine of maternal mice. No enhanced effect was observed when HA was combined with As, compared with the As alone treatment. With regard to the associated offspring, elevated levels of 8-oxodGuo and total arsenic were observed in offspring only when mother mice were treated with As and its combination with HA, but not for the HA-treated alone. It was worthy to note that the offspring from maternal combined treatment with HA and As had a significantly lower 8-oxodGuo than those of maternal treatment with As alone. This could be explained by that part of As formed complexes with HA and these macromolecules of HA–As complexes may not readily cross the placenta to the fetus, as evidenced by the lower accumulated total As observed in the offspring livers. Overall, it seems that HA may be detrimental to the maternal mice, but in the meantime it can be beneficial to the offspring by reducing free As. [Copyright &y& Elsevier]

Betel quid chewing has been associated with several human cancers. However, the role of betel quid in carcinogenesis remains uncertain. Piper betle contains high concentrations of safrole (an inducer of DNA oxidative damage). Safrole may be metabolized by hepatic sulfotransferase 1A1 (SULT1A1), or glutathione S-transferases (GSTM1, GSTT1, and GSTP1). Thus, we investigated the association of genetic polymorphisms of SULT1A1, GSTM1, GSTT1, and GSTP1 with DNA oxidative damage among betel quid chewers. A biomarker for oxidative stress, urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) level, was analyzed using isotope-dilution LC–MS/MS in 64 betel quid chewers and 129 non-betel quid chewers. Data on demographics and habits (smoking, alcohol drinking, and betel quid chewing) were obtained from questionnaires. Our results revealed that urinary 8-OHdG level was higher in chewers with SULT1A1 Arg-His genotype than in chewers with SULT1A1 Arg-Arg genotype. Urinary 8-OHdG level was also higher in chewers with GSTP1 Ile-Ile genotype. Furthermore, the combined effect of SULT1A1 and GSTP1 genotypes on urinary 8-OHdG was evaluated. Non-chewers with both SULT1A1 Arg-Arg and GSTP1 Val-Val/Ile-Val (reference group) had the lowest mean level (3.6 ng/mg creatinine), whereas chewers with either SULT1A1 Arg-His or GSTP1 Ile-Ile had the highest 8-OHdG mean level (6.2 ng/mg creatinine; vs. reference group, P = 0.04). Chewers with both of SULT1A1 Arg-Arg and GSTP1 Val-Val/Ile-Val (4.6 ng/mg creatinine), and non-chewers with either SULT1A1 Arg-His or GSTP1 Ile-Ile (4.7 ng/mg creatinine) had a moderately increased 8-OHdG level. Thus, the susceptible SULT1A1 and GSTP1 genotypes may modulate increased DNA oxidative stress elicited by betel-quid chewing. [ABSTRACT FROM AUTHOR]

Abstract: Arsenic is a notorious environmental toxicant and was found to cause oxidative stress in cultured cells and animals. However, little work has been done in human studies, especially for the population occupationally exposed to arsenic. In order to investigate the effect of occupational exposure to arsenic in oxidative stress, we measured urinary 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) from 90 semiconductor workers including 50 exposed and 40 nonexposed subjects. A highly sensitive and specific isotope dilution LC-MS/MS method was used for quantification of 8-oxodGuo. The levels of inorganic arsenic (iAs3+, iAs5+), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) in urine were determined by high-performance liquid chromatography-flow injection atomic absorption spectrometry (HPLC-FIAAS). Results showed that the mean urinary concentrations of total arsenic and 8-oxodGuo were significantly higher for exposed workers compared with the nonexposed workers. In addition, elevated urinary 8-oxodGuo concentrations of exposed workers were correlated with urinary levels of MMA (r = 0.44, P < 0.005) and the extent of primary methylation (the ratio of MMA to inorganic arsenic) (r = 0.40, P < 0.005). These findings suggested that occupational exposure to arsenic could result in the induction of oxidative stress. The presence and/or formation of MMA could play an important role in arsenic-involved injuries. [Copyright &y& Elsevier]