niman Posted October 7, 2019 Report Posted October 7, 2019 (edited) ECS-exposed mice developed lung adenocarcinoma and bladder urothelial hyperplasia, indicating that ECS is a lung carcinogen and a potential bladder carcinogen in mice. While it is well established that tobacco smoke poses a huge threat to human health, the threat ECS poses to humans is not yet known and warrants in-depth investigation https://www.pnas.org/content/early/2019/10/01/1911321116 Edited October 7, 2019 by niman
niman Posted October 7, 2019 Author Report Posted October 7, 2019 Electronic-cigarette smoke induces lung adenocarcinoma and bladder urothelial hyperplasia in mice Moon-shong Tang, Xue-Ru Wu, Hyun-Wook Lee, Yong Xia, Fang-Ming Deng, Andre L. Moreira, Lung-Chi Chen, William C. Huang, and Herbert Lepor PNAS first published October 7, 2019 https://doi.org/10.1073/pnas.1911321116 Edited by Bert Vogelstein, Johns Hopkins University, Baltimore, MD, and approved September 9, 2019 (received for review July 2, 2019)
niman Posted October 7, 2019 Author Report Posted October 7, 2019 Significance Electronic-cigarette smoke (ECS) is designed to deliver nicotine, and its use is gaining popularity. Previously, we found that ECS induces DNA damage and inhibits DNA repair in the mouse lungs and bladder urothelium. Nicotine induces the same types of DNA adducts and has a similar effect on DNA repair inhibition in human cells. Nicotine also enhances human cells’ mutation and tumorigenic transformation susceptibility. Our current results show that ECS-exposed mice developed lung adenocarcinoma and bladder urothelial hyperplasia, indicating that ECS is a lung carcinogen and a potential bladder carcinogen in mice. While it is well established that tobacco smoke poses a huge threat to human health, the threat ECS poses to humans is not yet known and warrants in-depth investigation.
niman Posted October 7, 2019 Author Report Posted October 7, 2019 Abstract Electronic-cigarettes (E-cigs) are marketed as a safe alternative to tobacco to deliver the stimulant nicotine, and their use is gaining in popularity, particularly among the younger population. We recently showed that mice exposed to short-term (12 wk) E-cig smoke (ECS) sustained extensive DNA damage in lungs, heart, and bladder mucosa and diminished DNA repair in lungs. Nicotine and its nitrosation product, nicotine-derived nitrosamine ketone, cause the same deleterious effects in human lung epithelial and bladder urothelial cells. These findings raise the possibility that ECS is a lung and bladder carcinogen in addition to nicotine. Given the fact that E-cig use has become popular in the past decade, epidemiological data on the relationship between ECS and human cancer may not be known for a decade to come. In this study, the carcinogenicity of ECS was tested in mice. We found that mice exposed to ECS for 54 wk developed lung adenocarcinomas (9 of 40 mice, 22.5%) and bladder urothelial hyperplasia (23 of 40 mice, 57.5%). These lesions were extremely rare in mice exposed to vehicle control or filtered air. Current observations that ECS induces lung adenocarcinomas and bladder urothelial hyperplasia, combined with our previous findings that ECS induces DNA damage in the lungs and bladder and inhibits DNA repair in lung tissues, implicate ECS as a lung and potential bladder carcinogen in mice. While it is well established that tobacco smoke poses a huge threat to human health, whether ECS poses any threat to humans is not yet known and warrants careful investigation.
niman Posted October 7, 2019 Author Report Posted October 7, 2019 It is well established that during the curing and burning of tobacco, nicotine can be transformed into nitrosamines via nitrosation, and that many of these nitrosamines, such as nicotine-derived nitrosamine ketone (NNK) and nitrosonornicotine (NNN), are potent human and animal carcinogens (2, 3, 7). Hence, measuring nitrosamine levels in body fluids has become a gold standard for assessing the potential carcinogenic effect of TS (7, 8). This method has been adapted to address the potential carcinogenic effects of E-cig smoke (ECS) (9). It has been found that the level of 4-(methylnitrosoamino)-4-(3-pyidyl)-1-butanol (NNAL), an NNK derivative, in the urine and saliva of E-cig smokers is only 5% of the levels found in comparable tobacco smokers (9). This has led to the assumption that nicotine nitrosation does not take place in ECS and that only a minute quantity of nitrosamines is present in ECS (9). This finding has supported the recommendation from public health experts, including Public Health England, that E-cigs are 95% safer than conventional cigarettes (10), and has prompted many epidemiologists to speculate that switching from TS to ECS could save millions of lives (11). Likely as a result of this reasoning, the popularity of E-cig smoking is rising rapidly. Currently 3.2% of adults in the United States and 3.6 million junior-high and high-school students have embraced E-cig smoking (10). Given the widespread use of E-cigs, their health effects—particularly their carcinogenicity—deserve careful scrutiny (10). Assessing the safety of E-cigs must examine 3 critical issues. First, is the level of nitrosamines in the E-cig smokers’ urine, saliva, or blood representative of the carcinogenic effects of ECS? Second, while it is established that TS contains substantial amounts of nitrosamines from nicotine nitrosation during tobacco curing and burning, it is unknown if inhaled nicotine in ECS can be nitrosated and transformed into nitrosamines. In light of the findings that human cells have ample cytochrome p450 enzymes that are able to metabolize nitrosamines rapidly into DNA-damaging products (7, 8), we are confronted with the third and the most important question: Can nitrosamine level in the urine, saliva, and blood represent the extent of nitrosation of inhaled ECS nicotine in vivo? These questions led us to assess the effects of ECS and nicotine by determining the DNA damage induced by ECS in different organs rather than measuring NNK, NNN, and NNAL in the blood and urine of a mouse model (12). We previously observed that ECS induces mutagenic DNA adducts (cyclic 1,N2-γ-hydroxy-propano-deoxyguanosine [γ-OH-PdG] and O6-methyl-dG) in the lungs, heart, and bladder mucosa and inhibits DNA repair in the lungs in a mouse model (12). We also found that nicotine and NNK both induce the same DNA adducts, impair DNA repair functions, and enhance cell mutational and tumorigenic transformation susceptibility in human lung and bladder epithelial cells (12). Based on these observations, we propose that ECS, as well as nicotine, may induce lung and bladder cancer (12). In this study, we examined the tumorigenicity of ECS in mice.
niman Posted October 7, 2019 Author Report Posted October 7, 2019 Methods ECS Exposure. A total of 85 male FVB/N mice (6 to 8 wk old; The Jackson Laboratory) were randomly placed into 3 groups. One group (n = 45) was exposed to ECS generated from e-juice (nicotine [36 mg/mL] dissolved in vehicle [Veh; isopolypropylene glycol and vegetable glycerin at a 1:1 ratio]). We maintained the particulate matter concentration in the chamber at 130 mg/m3 and the aerosol nicotine concentration at 0.196 mg/m3 (SI Appendix, Table S1). The second group (n = 20) was exposed to Veh. Aerosols for both groups were generated using an automated 3-port E-cig aerosol generator (e∼Aerosols) set at a constant voltage (1.9 A, 4.0 V) (SI Appendix, Table S1), the same as is done in commercial E-cigs (12, 13). Mice were subjected to whole-body exposure. The exposure conditions were the same as previously described (12). Mice were exposed for 4 h per day and 5 d per week for 54 wk. The third group (n = 20) remained housed in the animal room, exposed to the ambient filtered air (FA). During the 54-wk period, 3 ECS mice were found dead and 2 ECS mice had to be killed because of inactiveness. No lung tumor was observed in these 5 mice, and 1 was found to have a large intestinal polyp. One Veh-exposed mouse was found dead, and 1 was killed due to a paralyzed leg. Two FA-exposed mice were also found dead. No lung tumor was observed in these 2 Veh and 2 FA mice. At the end of the 54-wk exposure, 40 ECS-exposed, 18 Veh-exposed, and 18 FA-exposed mice survived. The average body weights among these 3 groups were similar (FA group, 34.4 ± 5.84 g; Veh group, 34.0 ± 2.78 g; and ECS group, 35.1 ± 2.99 g; ECS vs. FA, P = 0.67; ECS vs. Veh, P = 0.1998), and all mice appeared healthy. These mice were killed to examine tumor formation in different organs. Histopathology. The mice were killed at the end of 54 wk of exposure in accordance with New York University Institutional Animal Care and Use Committee protocols IA17-00048 and 170313-01. The lungs, heart, liver, kidneys, intestine, pancreas, brain, spleen, and bladder were harvested and examined with the naked eye for tumor formation. All organs were immediately fixed in and stored in a 10% formalin solution until section preparation. Slides of lung and bladder samples were prepared and stained with hematoxylin and eosin (H & E) at the Histology Core, New York University Langone Medical Center. In addition to H & E staining, bladder tissue slides were stained with antibodies for the proliferation markers MCM-2 and PCNA and the basal cell marker KRT5 at the New York University Urology Histology Core. All slides were examined independently by 3 pathologists. Statistical Analysis. GraphPad Prism 7.0 and 1-way ANOVA with the least significant difference (LSD) post hoc test were used for statistical analysis of lung adenocarcinoma and bladder urothelium hyperplasia formation, respectively, in the 3 groups (ECS, Veh, and FA) of mice.
niman Posted October 7, 2019 Author Report Posted October 7, 2019 Results ECS Induces Lung Adenocarcinoma. Because it takes over 2 decades for tobacco smokers to develop lung and bladder cancer, and because TS is also related to other human cancers, we examined the tumor formation in different organs after 54 wk of exposure (4, 14, 15). An examination of the gross anatomy of the mice revealed tumor-like growth in the skin, abdominal cavity, intestines, and lungs. A summary of tumor formation observed in all experimental mice is presented in Table 1. These tumor-like tissues were further examined microscopically. The results show that 9 of 40 (22.5%) mice exposed to ECS developed lung tumors. All lung tumors, subjected to histological examination by 3 pathologists, were identified as adenocarcinomas (Fig. 1). Of these 9 lung tumor-bearing mice, 8 had a single lung adenocarcinoma and 1 formed multiple ipsilateral lung adenocarcinomas (Fig. 1). None of the mice exposed to Veh developed lung tumors. Only 1 of 18 (5.6%) mice exposed to FA had 1 adenocarcinoma formed in the lung. The statistical analyses of lung adenocarcinoma occurrence in ECS-, Veh-, and FA-exposed mice are presented in Tables 2 and 3 and SI Appendix, Table S2 A–E. The results show that the higher lung adenocarcinoma incidence in ECS-exposed versus Veh-exposed mice (P = 0.0454), versus the combination of Veh- and FA-exposed mice (P = 0.0154), and versus Veh- and FA-exposed mice (P = 0.0352) is statistically significant. VIEW INLINE VIEW POPUP Table 1. Tumor-like growth found in different organs of mice exposed to FA, Veh, and ECS* Download figure Open in new tab Download powerpoint Fig. 1. ECS exposure induces lung tumor formation in mice. Mice were exposed to FA (n = 20) and aerosols generated by Veh (isopropylene glycol and vegetable glycerin at a 1:1 ratio, n = 20) and ECS (36 mg/mL nicotine in Veh, n = 45) for 4 h per day and 5 d per week for 54 wk as described in the main text. Surviving mice at the end of exposure are as follows: FA-exposed (n = 18), Veh-exposed (n = 18), and ECS-exposed (n = 40). All mice dying before the 54-wk exposure time were lung tumor-free. (A) Lung tumor tissues. Gross anatomy photographs (Left) of ECS-induced lung adenocarcinoma tissues (28-2, 28-4, 30-1, 30-2, 36-1, 38-2, 39-2, 39-5, 40-2) and a lung adenocarcinoma from an FA-exposed mouse (101-1), and histological slides of H & E staining of these lung adenocarcinomas (Center and Right, 100× and 400× magnification, respectively) are presented. (B) Normal lung tissue (Left, 100× magnification; Right, 400× magnification). Notes: (1) Veh exposure does not induce lung tumor. (2) Only a gross anatomy photograph of the lung tumor of ECS-exposed mouse 28-2 is shown. VIEW INLINE VIEW POPUP Table 2. Lung adenocarcinoma incidence in ECS-, Veh-, and FA-exposed mice VIEW INLINE VIEW POPUP Table 3. Statistical analysis of lung adenocarcinoma incidence in mice exposed to ECS, Veh, and FA* ECS Induces Bladder Urothelial Hyperplasia. Although no visible tumors were detected in the urinary bladders of any of the experimental groups, hyperplastic changes to the bladder urothelium were evident in mice exposed to ECS upon histological examination (Fig. 2). These lesions were either simple or nodular hyperplasia, characterized by a significant increase of urothelial layers (5 to 8 layers compared with 3 layers in the control groups), expansion of Krt5-positive basal urothelial cells, and a distinct elevation of the cell proliferation markers MCM-2 and PCNA (16, 17). Overall, 23 of 40 (57.5%) ECS-exposed mice, 1 of 16 (6.3%) Veh-exposed mice, and none of 17 (0%) FA-exposed mice developed urothelial hyperplasia (P < 0.001) (Fig. 2). Notably, the frequency of urothelial hyperplasia is slightly higher in mice with lung tumors (6 of 9, 67%) than in mice without lung tumors (18 of 31, 58%), although the difference is not statistically significant (P = 0.64). Download figure Open in new tab Download powerpoint Fig. 2. ECS exposure induces bladder urothelial hyperplasia in mice. Bladder tissues were harvested from the same mice exposed to ECS, Veh, and FA for 54 wk as described in Fig. 1. The tissue slides were prepared for histology examination and stained by H & E or antibodies for proliferation markers MCM-2 and PCNA and basal cell marker KRT5 (200× magnification). (A) Typical staining result of bladder tissues of mice exposed to FA, Veh, and ECS. (B) Histogram presentation of bladder urothelial hyperplasia in mice exposed to FA (n = 17), Veh (n = 16), and ECS (n = 40). Notes: (1) While we were able to examine bladder tissue samples from all 40 ECS-exposed mice, during sample preparation, 1 bladder from FA-exposed mice and 2 from Veh-exposed mice were inadvertently destroyed. (2) The simple (ECS1 mouse) and nodular (ECS2 mouse) hyperplasia had markedly thickened urothelial layers and strong expression of MCM-2, PCNA, and KRT5 (with the latter indicating expansion of basal cells), compared with FA- and VEH-exposed mice, which had very thin urothelial layers with low expression of the proliferation markers.
niman Posted October 8, 2019 Author Report Posted October 8, 2019 Discussion Nicotine carcinogenicity in animal models has been controversial owing to a large number of conflicting results (18⇓–20). While different tumor types, including leiomyosarcoma, were observed in animals treated with nicotine via drinking water and subcutaneous injection (19, 20), many of these results were criticized for their experimental shortcomings and were deemed to be inadequate evidence for an association between nicotine exposure and its effect on carcinogenesis (19). On the other hand, rats exposed to stream air-vaporized nicotine via inhalation for 2 y showed no significant different tumor formation, including lung tumors (21). However, this particular study was also criticized for lacking necessary bioassays and the small number of experimental animals (22 exposed versus 6 control) (19). Despite of all these inconclusive results, the prevailing thinking remains that nicotine is noncarcinogenic (18). In contrast to the results showing that stream air-vaporized nicotine is not lung carcinogenic in rats (21), our results showed that E-cig nicotine induces lung adenocarcinoma in mice. The sources of this discrepancy are unclear. It has been found that the aerosol size of ECS is smaller than the aerosols generated in TS (22). It is likely that the small size of E-cig aerosol allows the ECS nicotine in it to penetrate deeply into lung tissues, inducing DNA damage in bronchioloalveolar cells, whereas the stream air vapors are mainly deposited in the upper aerodigestive linings and tissues, which are rich in antioxidants such as glutathione, glutathione peroxidase, and superoxide dismutase and can effectively neutralize the metabolites of nitrosamines. We believe that our results support the conclusion that γ-OH-PdG and O6-methyl-dG, the DNA damage induced by metabolites of nicotine nitrosation products, are likely the major causes for lung as well as bladder carcinogenesis in mice (12, 23, 24). Although no bladder cancers/urothelial carcinomas have been observed, flat and/or papillary urothelial hyperplasia with increased mitotic activity was observed in some of the ECS-exposed mice (SI Appendix, Fig. S1). It should be noted that we found the levels of ECS-induced γ-OH-PdG and O6-methyl-dG in bladder mucosa were only one-fourth and one-fifth of the amount found in the lung tissues, respectively, in mice (12). These results raise the possibility that a longer exposure and/or higher doses of ECS are needed in order for the bladder mucosa to accumulate a sufficient level of γ-OH-PdG– and O6-methyl-dG–induced mutations that could trigger bladder tumorigenesis compared with lung carcinogenesis. We previously observed that mice with increased susceptibility to ECS-induced DNA adduct formation in the lungs are also more susceptible to ECS-induced DNA damage in the bladder (12). In the present study, mice more susceptible to ECS-induced lung tumorigenesis were not more prone to developing urothelial hyperplasia, suggesting that ECS-induced lung tumorigenesis and urothelial hyperplasia are divergent events. In summary, we showed that ECS exposure of mice induces lung cancer and bladder urothelial hyperplasia. These observations, combined with our previous findings (12) that ECS induces γ-OH-PdG and O6-methyl-dG adducts in the lungs and bladder urothelium and inhibits DNA repair in lung tissues in mice, and that nicotine and NNK induce the same types of DNA adducts and DNA repair inhibition effect and sensitize mutational and tumorigenic cell transformation susceptibility in the human lung epithelial and urothelial cells, indicate that ECS, as well as nicotine and NNK, is a lung carcinogen and a potential bladder carcinogen in mice. It should be noted that TS is a most dangerous environmental agent to which humans are commonly exposed and that ECS may or may not pose any danger to humans. The public should not equate the risk of ECS with that of TS. Our data simply suggest, on the basis of experimental data in model systems, that this issue warrants in-depth study in the future. Acknowledgments We thank K. Galdane, E. Halzack, A. Chu, M.-w. Weng, and S. H. Park for technical assistance, and Drs. J. Goldberg, J.-S. Hwang, and M.-w. Weng for statistical analysis. Research was supported by NIH Grants, RO1190678, 1PO1CA165980, P30CA16087, and ES00260. Footnotes ↵1To whom correspondence may be addressed. Email: [email protected]. Author contributions: M.-s.T., X.-R.W., L.-C.C., W.C.H., and H.L. designed research; M.-s.T., H.-W.L., Y.X., F.-M.D., and A.L.M. performed research; M.-s.T. and Y.X. contributed new reagents/analytic tools; M.-s.T., X.-R.W., H.-W.L., Y.X., F.-M.D., A.L.M., L.-C.C., W.C.H., and H.L. analyzed data; and M.-s.T., X.-R.W., H.-W.L., Y.X., F.-M.D., A.L.M., L.-C.C., W.C.H., and H.L. wrote the paper. The authors declare no competing interest. This article is a PNAS Direct Submission. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1911321116/-/DCSupplemental. Copyright © 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
niman Posted October 8, 2019 Author Report Posted October 8, 2019 References ↵ N. L. Benowitz , Nicotine addiction. N. Engl. J. Med. 362, 2295–2303 (2010). CrossRefPubMedGoogle Scholar ↵ S. S. Hecht, D. Hoffmann , Tobacco-specific nitrosamines, an important group of carcinogens in tobacco and tobacco smoke. Carcinogenesis 9, 875–884 (1988). CrossRefPubMedGoogle Scholar ↵ S. S. Hecht , Tobacco smoke carcinogens and lung cancer. J. Natl. Cancer Inst. 91, 1194–1210 (1999). CrossRefPubMedGoogle Scholar ↵ N. Howlader et al ., Eds., SEER Cancer Statistics Review, 1975-2014 (National Cancer Institute, Bethesda, MD, 2016). https://seer.cancer.gov/csr/1975_2014/, based on November 2016 SEER data submission, posted to the SEER website, April 2017. Accessed 2 April 2018. Google Scholar ↵ R. Grana, N. Benowitz, S. A. Glantz , E-cigarettes: A scientific review. Circulation 129, 1972–1986 (2014). FREE Full TextGoogle Scholar ↵ P. Hajek et al ., A randomized trial of E-cigarettes versus nicotine-replacement therapy. N. Engl. J. Med. 380, 629–637 (2019). CrossRefPubMedGoogle Scholar ↵ S. S. Hecht , DNA adduct formation from tobacco-specific N-nitrosamines. Mutat. Res. 424, 127–142 (1999). CrossRefPubMedGoogle Scholar ↵ S. S. Hecht, S. G. Carmella, P. G. Foiles, S. E. Murphy, L. A. Peterson , Tobacco-specific nitrosamine adducts: Studies in laboratory animals and humans. Environ. Health Perspect. 99, 57–63 (1993). CrossRefPubMedGoogle Scholar ↵ L. Shahab et al ., Nicotine, carcinogen, and toxin exposure in long-term E-cigarette and nicotine replacement therapy users: A cross-sectional study. Ann. Intern. Med. 166, 390–400 (2017). CrossRefPubMedGoogle Scholar ↵ S. A. Glantz, D. W. Bareham , E-cigarettes: Use, effects on smoking, risks, and policy implications. Annu. Rev. Public Health 39, 215–235 (2018). CrossRefPubMedGoogle Scholar ↵ D. T. Levy et al ., Potential deaths averted in USA by replacing cigarettes with e-cigarettes. Tob. Control 27, 18–25 (2018). Abstract/FREE Full TextGoogle Scholar ↵ H. W. Lee et al ., E-cigarette smoke damages DNA and reduces repair activity in mouse lung, heart, and bladder as well as in human lung and bladder cells. Proc. Natl. Acad. Sci. U.S.A. 115, E1560–E1569 (2018). Abstract/FREE Full TextGoogle Scholar ↵ J. Zhao, G. Pyrgiotakis, P. Demokritou , Development and characterization of electronic-cigarette exposure generation system (Ecig-EGS) for the physico-chemical and toxicological assessment of electronic cigarette emissions. Inhal. Toxicol. 28, 658–669 (2016). Google Scholar ↵ US Department of Health and Human Services , The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General (US Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA, 2006). Google Scholar ↵ US Department of Health and Human Services , The Health Consequences of Smoking-50 Years of Progress: A Report of the Surgeon General (Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA, 2014). Google Scholar ↵ J. Van Batavia et al ., Bladder cancers arise from distinct urothelial sub-populations. Nat. Cell Biol. 16, 982–991, 1–5 (2014). CrossRefPubMedGoogle Scholar ↵ K. Saeb-Parsy et al ., Diagnosis of bladder cancer by immunocytochemical detection of minichromosome maintenance protein-2 in cells retrieved from urine. Br. J. Cancer 107, 1384–1391 (2012). PubMedGoogle Scholar ↵ H. J. Haussmann, M. W. Fariss , Comprehensive review of epidemiological and animal studies on the potential carcinogenic effects of nicotine per se. Crit. Rev. Toxicol. 46, 701–734 (2016). Google Scholar ↵ T. Sanner, T. K. Grimsrud , Nicotine: Carcinogenicity and effects on response to cancer treatment–A review. Front. Oncol. 5, 196 (2015). Google Scholar ↵ S. A. Grando , Connections of nicotine to cancer. Nat. Rev. Cancer 14, 419–429 (2014). CrossRefPubMedGoogle Scholar ↵ H. L. Waldum et al ., Long-term effects of inhaled nicotine. Life Sci. 58, 1339–1346 (1996). CrossRefPubMedGoogle Scholar ↵ E. L. Floyd, L. Queimado, J. Wang, J. L. Regens, D. L. Johnson , Electronic cigarette power affects count concentration and particle size distribution of vaping aerosol. PLoS One 13, e0210147 (2018). Google Scholar ↵ H. W. Lee et al ., Cigarette side-stream smoke lung and bladder carcinogenesis: Inducing mutagenic acrolein-DNA adducts, inhibiting DNA repair and enhancing anchorage-independent-growth cell transformation. Oncotarget 6, 33226–33236 (2015). CrossRefPubMedGoogle Scholar ↵ M. W. Weng et al ., Aldehydes are the predominant forces inducing DNA damage and inhibiting DNA repair in tobacco smoke carcinogenesis. Proc. Natl. Acad. Sci. U.S.A. 115, E6152–E6161 (2018). Abstract/FREE Full TextGoogle Scholar
niman Posted October 8, 2019 Author Report Posted October 8, 2019 Mice that vaped nicotine for a year had a dramatic increase in tumor growth, study finds A salesman at a vape shop in Maine uses an e-cigarette. New research in mice suggests that vaping liquids with nicotine may promote tumor growth. (Associated Press) By EMILY BAUMGAERTNER STAFF WRITER OCT. 7, 2019 12 PM New research in mice suggests that long-term exposure to vaping liquids that contain nicotine greatly increases the risk of cancer. After breathing in the vapor for 20 hours a week for more than a year, 22.5% of the mice had cancerous tumors in the lining of the lungs, and 57.5% developed growths in their bladder tissue that can be precursors to cancer. Meanwhile, only 5.6% of mice in a control group that breathed only filtered air wound up with lung tumors, and none of them had growths in their bladders. In addition, a group of mice exposed to aerosolized vaping chemicals without nicotine developed no lung tumors, and just 6.3% of them had precancerous bladder growths. The scientists who conducted the study stressed that much more research is needed to know whether vaping leads to cancer in humans. But they hope their findings, published Monday in the journal Proceedings of the National Academy of Sciences, will make people think twice before trying e-cigarettes, which are widely perceived by teenagers and young adults as a safe alternative to smoking. “Right or wrong, millions of young people are using these right now, and the long-term, population-wide studies won’t be able to report out results for another decade,” said study leader Moon-Shong Tang, an environmental health expert at NYU School of Medicine. “We needed credible evidence to guide people in their choices, and it is unambiguous that nicotine alone will cause damage to the cells that make up organs, including lungs,” said Tang, who has studied how tobacco smoke promotes cancers of the lung and bladder. “Now, we can try to find measures to prevent incidents of e-cigarettes causing cancer.” Vaping has been linked to heart attacks, seizures and burns from exploding devices. And a growing outbreak of at least 1,080 vaping-related lung injuries serves as a stark reminder that it’s too soon to know whether e-cigarettes are a safe alternative to smoking. To get a better idea of the long-term effects of nicotine, Tang and his collaborators exposed 45 mice to an aerosol of nicotine dissolved in isopropylene glycol and vegetable glycerin, a common vehicle for vaping liquids. Another group of 20 mice was exposed to the same vehicle without nicotine. For 54 weeks, the animals were subjected to the aerosol mixes for four hours per day, five days per week. A third group of 20 mice spent their time in a room with ambient filtered air. (The study was limited to 54 weeks in order to minimize the effects of age-related cancers that could have cropped up occurred regardless of exposure to e-cigarette vapor.) Five mice in the group exposed to nicotine died over the course of the year. So did two of the mice in each of the other groups. When the 54 weeks were up, the remaining animals were killed and the researchers examined their tissues. Nine of the 40 mice in the nicotine group had tumors in their lungs, compared with none of the 18 mice that breathed the nicotine-free aerosol and one of the 18 mice exposed to filtered air. (Tang said he wasn’t surprised that a tumor was found in the control group, since mice typically have increased rates of lung cancer.) In addition, the researchers found that 23 of the 40 mice that inhaled the vapor with nicotine developed bladder hyperplasia, an out-of-control cell reproduction in the lining of the bladder that often precedes cancer. That compares with 1 out of 16 mice that inhaled vapor without nicotine and zero out of 17 mice that breathed filtered air. (Tissue samples from three of the mice were accidentally destroyed and could not be included in the analysis.) The differences were large enough for the researchers to conclude that the aerosolized vaping liquid with nicotine was responsible for the increased risk of tumors. For instance, the mice that inhaled the nicotine mixture were eight times more likely to develop lung tumors than the mice in the other two groups that weren’t exposed to nicotine. “This is compelling, and very scary,” said Dr. Mark Litwin, the chair of UCLA’s Department of Urology. “When the instructions encoded in DNA get mangled, the cells go on a craze and continue multiplying, unable to control themselves. That’s a hallmark of cancer. And at a glance, this already looks like precancer tissue.” The researchers also found that a few of the mice exposed to e-cigarette vapor — with or without nicotine — developed abdominal or skin tumors, while none of their counterparts in the filtered-air group did. However, those differences were small and could have been due to chance. The work was funded by the National Institutes of Health. On a molecular level, the findings make sense. Tang’s team published research last year showing that, when nicotine is introduced to mammalian cells, innate molecules called nitrosonium ions react with the nicotine to form carcinogens — in both mice and humans. “We can’t say that e-cigarettes definitively cause human cancer, but the mechanism at play here is very clear: The same carcinogens are being produced that other studies have shown cause human cancer,” Tang said. “We can extrapolate that, with e-cigarettes, you’ll cause damage in your genetic material, and damage your cells — and that will accumulate the longer you smoke.” Smoke from e-cigarettes “must be more thoroughly studied before it is deemed safe or marketed that way,” he added. The study had several limitations, the authors acknowledged. It included a small number of mice, and they were surrounded by the vapor rather than inhaling it the way human e-cigarette users would. Dr. Herbert Lepor, a study author and the chair of urology at NYU’s Langone Health, said the team plans to use a larger group of mice to test short and long periods of exposure. The researchers also plan to take a closer look at the genetic changes associated with inhaling e-cigarette smoke. Experts agree that the new study doesn’t answer the swirling questions surrounding the current outbreak of lung conditions linked to vaping. But it does validate worries about the long-term effects of e-cigarettes. “Teenagers will tell you that vaping is safer because it eliminates all the carcinogenic parts of a cigarette,” Litwin said. “As it turns out, that might not be the case.” https://www.latimes.com/science/story/2019-10-07/vaping-lung-tumor-risk
A salesman at a vape shop in Maine uses an e-cigarette. New research in mice suggests that vaping liquids with nicotine may promote tumor growth. (Associated Press) By EMILY BAUMGAERTNER STAFF WRITER OCT. 7, 2019 12 PM New research in mice suggests that long-term exposure to vaping liquids that contain nicotine greatly increases the risk of cancer. After breathing in the vapor for 20 hours a week for more than a year, 22.5% of the mice had cancerous tumors in the lining of the lungs, and 57.5% developed growths in their bladder tissue that can be precursors to cancer. Meanwhile, only 5.6% of mice in a control group that breathed only filtered air wound up with lung tumors, and none of them had growths in their bladders. In addition, a group of mice exposed to aerosolized vaping chemicals without nicotine developed no lung tumors, and just 6.3% of them had precancerous bladder growths. The scientists who conducted the study stressed that much more research is needed to know whether vaping leads to cancer in humans. But they hope their findings, published Monday in the journal Proceedings of the National Academy of Sciences, will make people think twice before trying e-cigarettes, which are widely perceived by teenagers and young adults as a safe alternative to smoking. “Right or wrong, millions of young people are using these right now, and the long-term, population-wide studies won’t be able to report out results for another decade,” said study leader Moon-Shong Tang, an environmental health expert at NYU School of Medicine. “We needed credible evidence to guide people in their choices, and it is unambiguous that nicotine alone will cause damage to the cells that make up organs, including lungs,” said Tang, who has studied how tobacco smoke promotes cancers of the lung and bladder. “Now, we can try to find measures to prevent incidents of e-cigarettes causing cancer.” Vaping has been linked to heart attacks, seizures and burns from exploding devices. And a growing outbreak of at least 1,080 vaping-related lung injuries serves as a stark reminder that it’s too soon to know whether e-cigarettes are a safe alternative to smoking. To get a better idea of the long-term effects of nicotine, Tang and his collaborators exposed 45 mice to an aerosol of nicotine dissolved in isopropylene glycol and vegetable glycerin, a common vehicle for vaping liquids. Another group of 20 mice was exposed to the same vehicle without nicotine. For 54 weeks, the animals were subjected to the aerosol mixes for four hours per day, five days per week. A third group of 20 mice spent their time in a room with ambient filtered air. (The study was limited to 54 weeks in order to minimize the effects of age-related cancers that could have cropped up occurred regardless of exposure to e-cigarette vapor.) Five mice in the group exposed to nicotine died over the course of the year. So did two of the mice in each of the other groups. When the 54 weeks were up, the remaining animals were killed and the researchers examined their tissues. Nine of the 40 mice in the nicotine group had tumors in their lungs, compared with none of the 18 mice that breathed the nicotine-free aerosol and one of the 18 mice exposed to filtered air. (Tang said he wasn’t surprised that a tumor was found in the control group, since mice typically have increased rates of lung cancer.) In addition, the researchers found that 23 of the 40 mice that inhaled the vapor with nicotine developed bladder hyperplasia, an out-of-control cell reproduction in the lining of the bladder that often precedes cancer. That compares with 1 out of 16 mice that inhaled vapor without nicotine and zero out of 17 mice that breathed filtered air. (Tissue samples from three of the mice were accidentally destroyed and could not be included in the analysis.) The differences were large enough for the researchers to conclude that the aerosolized vaping liquid with nicotine was responsible for the increased risk of tumors. For instance, the mice that inhaled the nicotine mixture were eight times more likely to develop lung tumors than the mice in the other two groups that weren’t exposed to nicotine. “This is compelling, and very scary,” said Dr. Mark Litwin, the chair of UCLA’s Department of Urology. “When the instructions encoded in DNA get mangled, the cells go on a craze and continue multiplying, unable to control themselves. That’s a hallmark of cancer. And at a glance, this already looks like precancer tissue.” The researchers also found that a few of the mice exposed to e-cigarette vapor — with or without nicotine — developed abdominal or skin tumors, while none of their counterparts in the filtered-air group did. However, those differences were small and could have been due to chance. The work was funded by the National Institutes of Health. On a molecular level, the findings make sense. Tang’s team published research last year showing that, when nicotine is introduced to mammalian cells, innate molecules called nitrosonium ions react with the nicotine to form carcinogens — in both mice and humans. “We can’t say that e-cigarettes definitively cause human cancer, but the mechanism at play here is very clear: The same carcinogens are being produced that other studies have shown cause human cancer,” Tang said. “We can extrapolate that, with e-cigarettes, you’ll cause damage in your genetic material, and damage your cells — and that will accumulate the longer you smoke.” Smoke from e-cigarettes “must be more thoroughly studied before it is deemed safe or marketed that way,” he added. The study had several limitations, the authors acknowledged. It included a small number of mice, and they were surrounded by the vapor rather than inhaling it the way human e-cigarette users would. Dr. Herbert Lepor, a study author and the chair of urology at NYU’s Langone Health, said the team plans to use a larger group of mice to test short and long periods of exposure. The researchers also plan to take a closer look at the genetic changes associated with inhaling e-cigarette smoke. Experts agree that the new study doesn’t answer the swirling questions surrounding the current outbreak of lung conditions linked to vaping. But it does validate worries about the long-term effects of e-cigarettes. “Teenagers will tell you that vaping is safer because it eliminates all the carcinogenic parts of a cigarette,” Litwin said. “As it turns out, that might not be the case.” https://www.latimes.com/science/story/2019-10-07/vaping-lung-tumor-risk
niman Posted October 8, 2019 Author Report Posted October 8, 2019 Researchers find e-cigarettes cause lung cancer in mice in first study tying vaping to cancer PUBLISHED 6 HOURS AGOUPDATED 3 HOURS AGO Jessica Bursztynsky@JBURSZ KEY POINTS Exposure to nicotine from e-cigarette vapor causes lung cancer in mice, according to new research from New York University. Funded by the National Institutes of Health, the study is the first to definitively link vaping nicotine to cancer. The amount of smoke the mice were exposed to was similar to a person who’s vaped for about three to six years. Jose Luis Gonzalez | Reuters E-cigarette vapor causes lung cancer and potentially bladder cancer in mice, damaging their DNA and leading researchers at New York University to conclude that vaping is likely “very harmful” to humans as well. “It’s foreseeable that if you smoke e-cigarettes, all kinds of disease comes out” over time, Moon-Shong Tang, the study’s lead researcher, said in an interview. “Long term, some cancer will come out, probably. E-cigarettes are bad news.” How carcinogenic e-cigarette use is for humans “may not be known for a decade to come,” but the study is the first to definitively link vaping nicotine to cancer. Funded by the National Institutes of Health, the study was published Monday in the Proceedings of the National Academy of Sciences. WATCH NOW VIDEO01:36 CDC: Vaping-related lung illness cases rise to 1,080 from 805 A February study by the University of Southern California found that e-cigarette users developed some of the same molecular changes in oral tissue that cause cancer in cigarette smokers, according to the study published in the International Journal of Molecular Sciences. In the NYU study, researchers found that e-cigarette vapor caused DNA damage in the lungs and bladder and “inhibits DNA repair in lung tissues.” Out of 40 mice exposed to e-cigarette vapor with nicotine over 54 weeks, 22.5% developed lung cancer and 57.5% developed precancerous lesions on the bladder. None of the 20 mice exposed to e-cigarette smoke without nicotine developed cancer over the four years they studied the mice, researchers said. That’s “statistically very significant,” said Tang, who’s a professor at the NYU School of Medicine. Tang said his results heighten the need for more research about the relationship between e-cigarette use and cancer in humans. Because the market is still relatively young, he said it might be another decade before its impact on humans is more thoroughly understood. Based on his findings in mice, Tang said he doesn’t think the research will show e-cigarette use is safe for human consumption. The amount of smoke the mice were exposed to was similar to what a human would inhale if they vaped regularly for about three to six years, Tang estimated. “If they use e-cigarettes regularly, that’s probably similar,” he said. Much like combustible cigarettes, Tang said his findings suggest that secondhand vaping fumes also pose a risk to other people within close proximity. There were limitations to the study. The mice did not inhale the vapor as deeply as a human would, for instance. It also was conducted in a small number of mice that were more likely to develop cancer over their lifetime, researchers noted. However, the data comes at a time of increased scrutiny of e-cigarettes as underage use rises and U.S. health officials trace an outbreak of a deadly lung disease back to vaping, mostly THC, the active compound in marijuana. Some of the more than 1,000 victims who have fallen ill have reported using only nicotine, leading doctors to say they can’t rule anything out. Flavored e-cigarettes have fueled what government regulators are calling a teen vaping epidemic. The Food and Drug Administration is currently finalizing its guidance to remove all nontobacco flavors of e-cigarettes, including mint and menthol, from the market to deter underage usage. Some state and local governments are starting the removal process, too. Market leader Juul, which didn’t respond to a request for comment, is under investigation for marketing their products as a safer alternative to smoking and as a way that adults can wean themselves off of cigarettes. Some research does back up those claims. The Federal Trade Commission also opened a probe in August of the industry’s marketing practices, seeking information from Juul and five other companies. However, Tang noted there’s a difference between being safer than cigarettes and safe in general. “Young kids think it’s safer,” Tang said. “But it will cause cancer in mice.” https://www.cnbc.com/2019/10/07/e-cigarettes-cause-lung-cancer-in-mice-finds-first-study-tying-vaping-to-cancer.html
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