Tobacco smoke exposure, the lower airways microbiome and outcomes of ventilated children.

BACKGROUND: Tobacco smoke exposure increases the risk and severity of lower respiratory tract infections in children, yet the mechanisms remain unclear. We hypothesized that tobacco smoke exposure would modify the lower airway microbiome. METHODS: Secondary analysis of a multicenter cohort of 362 children between ages 31 days and 18 years mechanically ventilated for >72 h. Tracheal aspirates from 298 patients, collected within 24 h of intubation, were evaluated via 16 S ribosomal RNA sequencing. Smoke exposure was determined by creatinine corrected urine cotinine levels ≥30 µg/g. RESULTS: Patients had a median age of 16 (IQR 568) months. The most common admission diagnosis was lower respiratory tract infection (53%). Seventy-four (20%) patients were smoke exposed and exhibited decreased richness and Shannon diversity. Smoke exposed children had higher relative abundances of Serratia spp., Moraxella spp., Haemophilus spp., and Staphylococcus aureus. Differences were most notable in patients with bacterial and viral respiratory infections. There were no differences in development of acute respiratory distress syndrome, days of mechanical ventilation, ventilator free days at 28 days, length of stay, or mortality. CONCLUSION: Among critically ill children requiring prolonged mechanical ventilation, tobacco smoke exposure is associated with decreased richness and Shannon diversity and change in microbial communities. IMPACT: Tobacco smoke exposure is associated with changes in the lower airways microbiome but is not associated with clinical outcomes among critically ill pediatric patients requiring prolonged mechanical ventilation. This study is among the first to evaluate the impact of tobacco smoke exposure on the lower airway microbiome in children. This research helps elucidate the relationship between tobacco smoke exposure and the lower airway microbiome and may provide a possible mechanism by which tobacco smoke exposure increases the risk for poor outcomes in children.

Furan Metabolites Are Elevated in Users of Various Tobacco Products and Cannabis.

Humans are exposed to furan, a toxicant and possible human carcinogen, through multiple sources including diet and tobacco smoke. The urinary metabolites of furan are derived from the reaction of its toxic metabolite with protein nucleophiles and are biomarkers of exposure and potential harm. An established isotopic dilution liquid-chromatography mass spectrometry method was used to measure these biomarkers in urine from users of e-cigarettes, cannabis, and/or combustible tobacco with/without reduced nicotine levels. Amounts of furan mercapturic acid metabolites were higher in these individuals relative to nonsmokers, indicating that they may be at risk for potential furan-derived toxicities.

Acrolein Increases the Pulmonary Tumorigenic Activity of the Tobacco-Specific Nitrosamine 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

Tobacco smoke is a complex mixture of more than 7000 chemicals, of which many are toxic and/or carcinogenic. Many hazard assessments of tobacco have focused on individual chemical exposures without consideration of how the chemicals may interact with one another. Two chemicals, the human carcinogen 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) and a possible human carcinogen, acrolein, were hypothesized to interact with one another, possibly owing to the additive effects of DNA adduct formation or influence on the repair of mutagenic DNA adducts. To test our hypothesis that coexposure to NNK and acrolein is more carcinogenic than either chemical alone, A/J mice were exposed to NNK (i.p., 0, 2.5, or 7.5 µmol in saline) in the presence or absence of inhaled acrolein (15 ppmV). While the single 3 h exposure to acrolein alone did not induce lung adenomas, it significantly enhanced NNK's lung carcinogenicity. In addition, mice receiving both NNK and acrolein had more adenomas with dysplasia or progression than those receiving only NNK, suggesting that acrolein may also increase the severity of NNK-induced lung adenomas. To test the hypothesis that the interaction was due to effects on DNA adduct formation and repair, NNK- and acrolein pulmonary DNA adduct levels were assessed. There was no consistent effect of the coexposure on NNK-derived DNA adducts, and acrolein DNA adducts were not elevated above endogenous levels. This study supports the hypothesis that tobacco smoke chemicals combine to contribute to the carcinogenic potency of tobacco smoke, and the mechanism of interaction cannot be explained by alterations of DNA adduct levels.

Coexposure to Inhaled Aldehydes or Carbon Dioxide Enhances the Carcinogenic Properties of the Tobacco-Specific Nitrosamine 4-Methylnitrosamino-1-(3-pyridyl)-1-butanone in the A/J Mouse Lung.

Tobacco smoke is a complex mixture of chemicals, many of which are toxic and carcinogenic. Hazard assessments of tobacco smoke exposure have predominantly focused on either single chemical exposures or the more complex mixtures of tobacco smoke or its fractions. There are fewer studies exploring interactions between specific tobacco smoke chemicals. Aldehydes such as formaldehyde and acetaldehyde were hypothesized to enhance the carcinogenic properties of the human carcinogen, 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) through a variety of mechanisms. This hypothesis was tested in the established NNK-induced A/J mouse lung tumor model. A/J mice were exposed to NNK (intraperitoneal injection, 0, 2.5, or 7.5 µmol in saline) in the presence or absence of acetaldehyde (0 or 360 ppmv) or formaldehyde (0 or 17 ppmv) for 3 h in a nose-only inhalation chamber, and lung tumors were counted 16 weeks later. Neither aldehyde by itself induced lung tumors. However, mice receiving both NNK and acetaldehyde or formaldehyde had more adenomas with dysplasia or progression than those receiving only NNK, suggesting that aldehydes may increase the severity of NNK-induced lung adenomas. The aldehyde coexposure did not affect the levels of NNK-derived DNA adduct levels. Similar studies tested the ability of a 3 h nose-only carbon dioxide (0, 5, 10, or 15%) coexposure to influence lung adenoma formation by NNK. While carbon dioxide alone was not carcinogenic, it significantly increased the number of NNK-derived lung adenomas without affecting NNK-derived DNA damage. These studies indicate that the chemicals in tobacco smoke work together to form a potent lung carcinogenic mixture.

Dietary and plasma carotenoids are positively associated with alpha diversity in the fecal microbiota of pregnant women.

Because microbes use carotenoids as an antioxidant for protection, dietary carotenoids could be associated with gut microbiota composition. We aimed to determine associations among reported carotenoid intake, plasma carotenoid concentrations, and fecal bacterial communities in pregnant women. Pregnant women (n = 27) were enrolled in a two-arm study designed to assess feasibility of biospecimen collection and delivery of a practical nutrition intervention. Plasma and fecal samples were collected and women were surveyed with a 24-hr dietary checklist and recalls. Plasma carotenoids were analyzed by HPLC using photodiode array detection. Fecal bacteria were analyzed by 16S rRNA DNA sequencing. Results presented are cross-sectional from the 36-week gestational study visit combined across both study arms due to lack of significant differences between intervention and usual care groups (n = 23 women with complete data). Recent intake of carotenoid-containing foods included carrots, sweet potatoes, mangos, apricots, and/or bell peppers for 48% of women; oranges/orange juice (17%); egg (39%); tomato/tomato-based sauces (52%); fruits (83%); and vegetables (65%). Average plasma carotenoid concentrations were 6.4 µg/dL α-carotene (AC), 17.7 µg/dL ß-carotene (BC), 11.4 µg/dL cryptoxanthin, 39.0 µg/dL trans-lycopene, and 29.8 µg/dL zeaxanthin and lutein. AC and BC concentrations were higher in women who recently consumed foods high in carotenoids. CR concentrations were higher in women who consumed oranges/orange juice. Microbiota α-diversity positively correlated with AC and BC. Microbiota ß-diversity differed significantly across reported intake of carotenoid containing foods and plasma concentrations of AC. This may reflect an effect of high fiber or improved overall dietary quality, rather than a specific effect of carotenoids. PRACTICAL APPLICATION: Little is known about the association between the gut microbiome and specific dietary microconstituents, such as carotenoids, especially during pregnancy. This research demonstrates that a carotenoid-rich diet during pregnancy supports a diverse microbiota, which could be one mechanism by which carotenoids promote health.

Effects of GSTT1 Genotype on the Detoxification of 1,3-Butadiene Derived Diepoxide and Formation of Promutagenic DNA-DNA Cross-Links in Human Hapmap Cell Lines.

Smoking is a leading cause of lung cancer, accounting for 81% of lung cancer cases. Tobacco smoke contains over 5000 compounds, of which more than 70 have been classified as human carcinogens. Of the many tobacco smoke constituents, 1,3-butadiene (BD) has a high cancer risk index due to its tumorigenic potency and its abundance in cigarette smoke. The carcinogenicity of BD has been attributed to the formation of several epoxide metabolites, of which 1,2,3,4-diepoxybutane (DEB) is the most toxic and mutagenic. DEB is formed by two oxidation reactions carried out by cytochrome P450 monooxygenases, mainly CYP2E1. Glutathione-S-transferase theta 1 (GSTT1) facilitates the conjugation of DEB to glutathione as the first step of its detoxification and subsequent elimination via the mercapturic acid pathway. Human biomonitoring studies have revealed a strong association between GSTT1 copy number and urinary concentrations of BD-mercapturic acids, suggesting that it plays an important role in the metabolism of BD. To determine the extent that GSTT1 genotype affects the susceptibility of individuals to the toxic and genotoxic properties of DEB, GSTT1 negative and GSTT1 positive HapMap lymphoblastoid cell lines were treated with DEB, and the extent of apoptosis and micronuclei (MN) formation was assessed. These toxicological end points were compared to the formation of DEB-GSH conjugates and 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) DNA-DNA cross-links. GSTT1 negative cell lines were more sensitive to DEB-induced apoptosis as compared to GSTT1 positive cell lines. Consistent with the protective effect of GSH conjugation against DEB-derived apoptosis, GSTT1 positive cell lines formed significantly more DEB-GSH conjugate than GSTT1 negative cell lines. However, GSTT1 genotype did not affect formation of MN or bis-N7G-BD cross-links. These results indicate that GSTT1 genotype significantly influences BD metabolism and acute toxicity.

Urinary metabolites of furan in waterpipe tobacco smokers compared to non-smokers in home settings in the US.

OBJECTIVES: Determine uptake of furan, a potential human carcinogen, in waterpipe tobacco (WPT) smokers in home settings. METHODS: We analysed data from a US convenience sample of 50 exclusive WPT smokers, mean age 25.3 years, and 25 non-smokers, mean age 25.5 years. For WPT smokers, data were collected at a home visit by research assistants during which participants smoked one WPT head of one brand for a mean of 33.1 min in their homes. Research assistants provided and prepared a WP for participants by weighing and loading 10 g of WPT in the WP head. At the completion of the smoking session, research assistants measured the remaining WPT. Cotinine and six furan metabolites were quantified in first morning urine samples provided on 2 consecutive days for non-smokers, and on the morning of a WPT smoking session and on the following morning for smokers. RESULTS: WPT smokers consumed a mean of 2.99 g WPT. In WPT smokers, urinary cotinine levels increased significantly 26.1 times the following morning; however, urinary metabolites of furan did not increase significantly. Compared to non-smokers, 2 furan metabolites, N-acetyl-S-[1-(5-acetylamino-5-carboxylpentyl)-1H-pyrrol-3-yl]-L-cysteine and N-acetyl-S-[1-(5-amino-5-carboxypentyl)-1H-pyrrol-3-yl]-L-cysteine sulfoxide, were significantly higher in WPT smokers in pre and in post WPT smoking levels. CONCLUSIONS: To enable a more rigorous assessment of furan exposure from WPT smoking, future research should determine furan concentrations in WPT smoke, quantify furan metabolites from users of various WPT brands; and extend the investigation to social settings where WPT smoking is habitually practiced.

Inhaled Furan Selectively Damages Club Cells in Lungs of A/J Mice.

Furan, a possible human carcinogen, is a product of incomplete combustion and is present in cigarette smoke, engine exhaust, and processed food. Oral administration induces liver toxicity and carcinogenesis in F344 rats and B6C3F1 mice. To assess possible adverse effects from inhalation, A/J mice were nose-only exposed for 3 hours to furan (0, 30, 75, 150, 300, or 600 ppmv) and euthanized after 24 hours, 48 hours, or 1 week. Histopathology evaluation revealed bronchiolar club cell necrosis (diffuse, marked) with airway denudation following exposure to 300 and 600 ppmv furan with evidence of club cell regeneration and partial repair after 1 week. Initial signs of hepatotoxicity were observed in the 150 ppmv furan-exposed group. Acute necrosis and mineralization were observed in livers at 24 and 48 hours with hepatocyte regeneration by 1-week postexposure in mice exposed to 300 and 600 ppmv furan; the 300 ppmv exposed group had multifocal mineralization that evoked a mild granulomatous response. Measurement of urinary furan metabolites confirmed that the mice metabolized furan to the toxic intermediate, cis-2-butene-1,4-dial. These observations indicate that inhaled furan is toxic to lungs with club cells as the target as well as liver.