Environmental and Occupational Research
Investigating the role of PAHs in respiratory diseases induced by 2nd-hand smoke and other environmental exposures
Secondhand smoke (2nd-hand) is associated with many diseases including respiratory diseases, such as chronic obstructive pulmonary disease (COPD), childhood and adult asthma, and lung cancer.[1,2] In certain occupations in the U.S., 2nd-hand smoke exposure was or still is greater than many occupations, such as flight attendants and casino workers.[3-7] Little is currently known about the human health effects of thirdhand (3rd-hand) smoke, components of 2nd-hand smoke that persist on walls, carpets and other areas in indoor environments, and contain PAHs, such as fluoranthene, among other cigarette components.However, based on multiple assessments of 3rd-hand smoke constituents[7,10-14], inhalation of these toxicants should not be overlooked. Unfortunately, due to the latency of many chronic pulmonary diseases, individuals exposed to 2nd-and 3rd-hand smoke can observe effects years after exposure. Thus, the effects of these exposures are a real concern for human health at all ages.
Our current research focuses on the most abundant PAHs in 2nd-hand and 3rd-hand smoke, the low molecular weight fractions, particularly the two-four-ringed PAHs (such as fluoranthene)[15-17]and their role in pulmonary inflammation and tumor promotion (see Osgood et al, (2013).For example, cell-cell communication is inhibited by many of these toxicants. In addition, many of these LMW PAH species are also considered U.S.E.P.A. priority PAHs based on their potential for human exposure and abundance at hazardous waste sites, among others.
Investigating the role of V2O5 as a lung tumor promoter
Vanadium pentoxide (V2O5) exposure occurs both occupationally in industries such as the manufacturing of steel and aluminum, mining, petroleum production and refining, and welding, as well as environmentally as a component of particulate matter, and has been associated with respiratory conditions in humans and pulmonary inflammation and carcinogenesis in rodents. We previously demonstrated that V2O5 can function as a lung tumor promoter in mice in a strain dependent manner. Current studies focus on innate immune pathways and oxidative stress in response to V2O5.
1. CDC (2008) Smoking-Attributable Mortality, Years of Potential Life Lost, and Productivity Losses—United States, 2000–2004. Atlanta, GA. 1226–1228 p.
2. CDC (2010) Vital Signs: Nonsmokers' Exposure to Secondhand Smoke --- United States, 1999--2008. Atlanta, GA. 1141-1146 p.
3. Achutan C, West C, Mueller C, Bernert JT, Bernard B (2011) Environmental tobacco smoke exposure among casino dealers. J Occup Environ Med 53: 346-351.
4. Arjomandi M, Haight T, Redberg R, Gold WM (2009) Pulmonary function abnormalities in never-smoking flight attendants exposed to secondhand tobacco smoke in the aircraft cabin. J Occup Environ Med 51: 639-646.
5. Beatty AL, Haight TJ, Redberg RF (2011) Associations between respiratory illnesses and secondhand smoke exposure in flight attendants: A cross-sectional analysis of the Flight Attendant Medical Research Institute Survey. Environ Health 10: 81.
6. Ebbert JO, Croghan IT, Schroeder DR, Murawski J, Hurt RD (2007) Association between respiratory tract diseases and secondhand smoke exposure among never smoking flight attendants: a cross-sectional survey. Environ Health 6: 28.
7. Pilkington PA, Gray S, Gilmore AB (2007) Health impacts of exposure to second hand smoke (SHS) amongst a highly exposed workforce: survey of London casino workers. BMC Public Health 7: 257.
8. CDC (2012) Current tobacco use and secondhand smoke exposure among women of reproductive age - 14 countries, 2008-2010. MMWR Morb Mortal Wkly Rep 61: 877-882.
9. He Y, Jiang B, Li LS, Li LS, Ko L, Wu L, Sun DL, He SF, Liang BQ, Hu FB, Lam TH (2012) Secondhand smoke exposure predicted chronic obstructive pulmonary disease and other tobacco related mortality in a 17-years cohort study in China. Chest.
10. Schick SF, Farraro KF, Perrino C, Sleiman M, van de Vossenberg G, Trinh MP, Hammond SK, Jenkins BM, Balmes J (2013) Thirdhand cigarette smoke in an experimental chamber: evidence of surface deposition of nicotine, nitrosamines and polycyclic aromatic hydrocarbons and de novo formation of NNK. Tob Control.
11. Becquemin MH, Bertholon JF, Bentayeb M, Attoui M, Ledur D, Roy F, Roy M, Annesi-Maesano I, Dautzenberg B (2010) Third-hand smoking: indoor measurements of concentration and sizes of cigarette smoke particles after resuspension. Tob Control 19: 347-348.
12. Hang B, Sarker AH, Havel C, Saha S, Hazra TK, Schick S, Jacob P, 3rd, Rehan VK, Chenna A, Sharan D, Sleiman M, Destaillats H, Gundel LA (2013) Thirdhand smoke causes DNA damage in human cells. Mutagenesis 28: 381-391.
13. Matt GE, Quintana PJ, Destaillats H, Gundel LA, Sleiman M, Singer BC, Jacob P, Benowitz N, Winickoff JP, Rehan V, Talbot P, Schick S, Samet J, Wang Y, Hang B, Martins-Green M, Pankow JF, Hovell MF (2011) Thirdhand tobacco smoke: emerging evidence and arguments for a multidisciplinary research agenda. Environ Health Perspect 119: 1218-1226.
14. Tillett T (2011) Thirdhand smoke in review: research needs and recommendations. Environ Health Perspect 119: a399.
15. Lee HL, Hsieh DP, Li LA (2010) Polycyclic aromatic hydrocarbons in cigarette sidestream smoke particulates from a Taiwanese brand and their carcinogenic relevance. Chemosphere 10.1016/j.chemosphere.2010.09.045.
16. Moir D, Rickert WS, Levasseur G, Larose Y, Maertens R, White P, Desjardins S (2008) A comparison of mainstream and sidestream marijuana and tobacco cigarette smoke produced under two machine smoking conditions. Chem Res Toxicol 21: 494-502.
17. Severson RF, Snook ME, Higman HC, Chortyk OT, Akin FJ (1976) Isolation, identification, and quantification of polynuclear aromatic hydrocarbons in tobacco smoke. In: Freudenthal RI, and Jones, P.W., editor. Carcinogenesis- A comprehensive survey Vol 1 Polynuclear aromatic hydrocarbons: Chemistry, metabolism, and carcinogenesis. New York, New York: Raven Press. pp. 253-270.
18. Osgood RS, Upham BL, Hill T, 3rd, Helms KL, Velmurugan K, Babica P, Bauer AK (2013) Polycyclic aromatic hydrocarbon-induced signaling events relevant to inflammation and tumorigenesis in lung cells are dependent on molecular structure. PLoS One 8: e65150.
19. Ress NB, Chou BJ, Renne RA, Dill JA, Miller RA, Roycroft JH, Hailey JR, Haseman JK, Bucher JR (2003) Carcinogenicity of inhaled vanadium pentoxide in F344/N rats and B6C3F1 mice. Toxicol Sci 74: 287-296.
20. Rondini EA, Walters DM, Bauer AK (2010) Vanadium pentoxide induces pulmonary inflammation and tumor promotion in a strain-dependent manner. Part Fibre Toxicol 7: 9.
Basic Cancer Research
The role of toll-like receptor 4 in mouse pulmonary neoplasia
More people will succumb to lung cancer this year than any other type of cancer. Lung adenocarcinoma (AC), a subtype of non-small cell lung carcinoma, is increasing at a faster rate than any other type of lung neoplasia, is the most common among nonsmokers, and is rarely detected early. Chronic inflammatory lung diseases predispose the lung to neoplasia. However, activation of certain innate immune pathways may confer protection against lung AC development. For example, several epidemiology studies observed significant decreases in lung cancer risk in those individuals exposed to endotoxin, such as farm and textile workers.[21-26]Toll-like receptor 4 (TLR4), an innate immune receptor, is the primary receptor that binds endotoxin (lipopolysaccharide; LPS), thus TLR4 is likely involved in the protective effects of exposure to endotoxin. While the observation linking lung neoplasia to endotoxin is intriguing, there is a major gap in our understanding of how this protection is elicited. Our long-term goal is to determine if TLR4 and associated molecular events are involved in the underlying mechanisms that govern this association between the innate immune system and lung carcinogenesis, which may provide novel preventive, diagnostic, and therapeutic strategies for a disease that severely lacks in identifiable biomarkers.
We previously demonstrated that TLR4-deficient mice (BALBLps-d ) were significantly more sensitive to lung tumor promotion and pulmonary inflammation at both early and advanced stages of disease than the Tlr4-wild-type mice (BALB/c) using a two stage initiation/promotion model.[28,29] Our current studies, funded by the American Cancer Society (RSG-10-162-01-LIB; AKB), focus on the importance of several innate immune receptors and pathways. More specifically, we are currently investigating the role of cell-cell communication using novel methodologies and growth factor pathways, such as epidermal growth factor (EGF).
21. Astrakianakis G, Seixas NS, Ray R, Camp JE, Gao DL, Feng Z, Li W, Wernli KJ, Fitzgibbons ED, Thomas DB, Checkoway H (2007) Lung cancer risk among female textile workers exposed to endotoxin. J Natl Cancer Inst 99: 357-364.
22. Laakkonen A, Kyyronen P, Kauppinen T, Pukkala EI (2006) Occupational exposure to eight organic dusts and respiratory cancer among Finns. Occup Environ Med 63: 726-733.
23. Lange JH, Mastrangelo G, Thomulka KW (2003) Will sewage workers with endotoxin related symptoms have the benefit of reduced lung cancer? Occup Environ Med 60: 144-145.
24. Mastrangelo G, Fedeli U, Fadda E, Milan G, Lange JH (2002) Epidemiologic evidence of cancer risk in textile industry workers: a review and update. Toxicol Ind Health 18: 171-181.
25. Mastrangelo G, Grange JM, Fadda E, Fedeli U, Buja A, Lange JH (2005) Lung cancer risk: effect of dairy farming and the consequence of removing that occupational exposure. Am J Epidemiol 161: 1037-1046.
26. Lundin JI, Checkoway H (2009) Endotoxin and cancer. Environ Health Perspect 117: 1344-1350.
27. Poltorak A, He X, Smirnova I, Liu MY, Huffel CV, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282: 2085-2088.
28. Bauer AK, Dixon D, DeGraff LM, Cho HY, Walker CR, Malkinson AM, Kleeberger SR (2005) Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis. J Natl Cancer Inst 97: 1778-1781.
29. Bauer AK, Fostel J, Degraff LM, Rondini EA, Walker C, Grissom SF, Foley J, Kleeberger SR (2009) Transcriptomic analysis of pathways regulated by toll-like receptor 4 in a murine model of chronic pulmonary inflammation and carcinogenesis. Mol Cancer 8: 107.
Dr. Brad Upham, Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI; http://cit.msu.edu/faculty/upham.html
Dr. John Volckens, Department of Radiological and Environmental Health Sciences, Colorado State University and Colorado School of Public Health, Fort Collins, CO; http://www.cvmbs.colostate.edu/erhs/faculty/volckens/index_j_volckens.htm
Dr. Charles Henry, Department of Chemistry, Colorado State University, Fort Collins, CO; http://www.chem.colostate.edu/people/chenry/
Dr. Christopher Evans, Department of Medicine, Division of Pulmonary Sciences, University of Colorado Denver, Aurora, CO; https://profiles.ucdenver.edu/display/226659
Dr. Seyed Javad Moghaddam, Department of Pulmonary Medicine, M.D. Anderson Cancer Center, Houston, TX; http://faculty.mdanderson.org/SeyedJavad_Moghaddam/
Dr. Linda Sargent, Molecular Genetics Laboratory, National Institute for Occupational Safety and Health, Morgantown, West Virginia; http://gwynethshaw.org/nb/2013/03/14/niosh-study-some-carbon-nanotubes-can-promote-cancer/
Dr. Steven Kleeberger, Laboratory of Respiratory Biology, Environmental Genetics Group, National Institute of Environmental Health Sciences, RTP, NC; http://www.niehs.nih.gov/research/atniehs/labs/lrb/enviro-gen/
Dr. Pavel Babica, Masaryk University, Research Center for Toxic Compounds in the Environment, Brno, Czech Republic; http://www.sinice.cz/index-en.php?pg=about-centre--structure--people&pid=5
Dr. Iva Sovadinova, Masaryk University, Research Center for Toxic Compounds in the Environment, Brno, Czech Republic; http://www.muni.cz/people/12052
Osgood RS, Upham BL, Hill T, Helms KL, Velmurugan K, Babica P, Bauer AK. Polycyclic aromatic hydrocarbon-induced signaling events relevant to inflammation and tumorigenesis in lung cells are dependent on molecular structure. PLoS One. 2013; 8(6):e65150.
Bauer AK, Hill T, Alexander CM. The Involvement of NRF2 in Lung Cancer. Oxid Med Cell Longev. 2013; 2013:746432.
Bauer AK, Cho HY, Miller-Degraff L, Walker C, Helms K, Fostel J, Yamamoto M, Kleeberger SR. Targeted deletion of Nrf2 reduces urethane-induced lung tumor development in mice. PLoS One. 2011; 6(10):e26590.
Bauer AK, Rondini EA, Hummel KA, Degraff LM, Walker C, Jedlicka AE, Kleeberger SR. Identification of Candidate Genes Downstream of TLR4 Signaling after Ozone Exposure in Mice: A Role for Heat-Shock Protein 70. Environ Health Perspect. 2011 Aug; 119(8):1091-7.
Backus GS, Howden R, Fostel J, Bauer AK, Cho HY, Marzec J, Peden DB, Kleeberger SR. Protective role of interleukin-10 in ozone-induced pulmonary inflammation. Environ Health Perspect. 2010 Dec; 118(12):1721-7.
Bauer AK, Kleeberger SR. Genetic mechanisms of susceptibility to ozone-induced lung disease. Ann N Y Acad Sci. 2010 Aug; 1203:113-9.
Rondini EA, Walters DM, Bauer AK. Vanadium pentoxide induces pulmonary inflammation and tumor promotion in a strain-dependent manner. Part Fibre Toxicol. 2010; 7:9.
Bauer AK, Fostel J, Degraff LM, Rondini EA, Walker C, Grissom SF, Foley J, Kleeberger SR. Transcriptomic analysis of pathways regulated by toll-like receptor 4 in a murine model of chronic pulmonary inflammation and carcinogenesis. Mol Cancer. 2009; 8:107.
Dahl M, Bauer AK, Arredouani M, Soininen R, Tryggvason K, Kleeberger SR, Kobzik L. Protection against inhaled oxidants through scavenging of oxidized lipids by macrophage receptors MARCO and SR-AI/II. J Clin Invest. 2007 Mar; 117(3):757-64.
Cho HY, Morgan DL, Bauer AK, Kleeberger SR. Signal transduction pathways of tumor necrosis factor--mediated lung injury induced by ozone in mice. Am J Respir Crit Care Med. 2007 Apr 15; 175(8):829-39.
Bauer AK, Dixon D, DeGraff LM, Cho HY, Walker CR, Malkinson AM, Kleeberger SR. Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis. J Natl Cancer Inst. 2005 Dec 7; 97(23):1778-81.
Recio L, Bauer A, Faiola B. Use of genetically modified mouse models to assess pathways of benzene-induced bone marrow cytotoxicity and genotoxicity. Chem Biol Interact. 2005 May 30; 153-154:159-64.
Dwyer-Nield LD, Srebernak MC, Barrett BS, Ahn J, Cosper P, Meyer AM, Kisley LR, Bauer AK, Thompson DC, Malkinson AM. Cytokines differentially regulate the synthesis of prostanoid and nitric oxide mediators in tumorigenic versus non-tumorigenic mouse lung epithelial cell lines. Carcinogenesis. 2005 Jul; 26(7):1196-206.
Bauer AK, Malkinson AM, Kleeberger SR. Susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: genetic similarities. Am J Physiol Lung Cell Mol Physiol. 2004 Oct; 287(4):L685-703.
Faiola B, Bauer AK, Fuller ES, Wong VA, Pluta LJ, Abernethy DJ, Mangum JB, Everitt JI, Recio L. Variations in Prkdc and susceptibility to benzene-induced toxicity in mice. Toxicol Sci. 2003 Oct; 75(2):321-32.
Bauer AK, Faiola B, Abernethy DJ, Marchan R, Pluta LJ, Wong VA, Gonzalez FJ, Butterworth BE, Borghoff SJ, Everitt JI, Recio L. Male mice deficient in microsomal epoxide hydrolase are not susceptible to benzene-induced toxicity. Toxicol Sci. 2003 Apr; 72(2):201-9.
Bauer AK, Faiola B, Abernethy DJ, Marchan R, Pluta LJ, Wong VA, Roberts K, Jaiswal AK, Gonzalez FJ, Butterworth BE, Borghoff S, Parkinson H, Everitt J, Recio L. Genetic susceptibility to benzene-induced toxicity: role of NADPH: quinone oxidoreductase-1. Cancer Res. 2003 Mar 1; 63(5):929-35.
Kisley LR, Barrett BS, Bauer AK, Dwyer-Nield LD, Barthel B, Meyer AM, Thompson DC, Malkinson AM. Genetic ablation of inducible nitric oxide synthase decreases mouse lung tumorigenesis. Cancer Res. 2002 Dec 1; 62(23):6850-6.
Kisley LR, Barrett BS, Dwyer-Nield LD, Bauer AK, Thompson DC, Malkinson AM. Celecoxib reduces pulmonary inflammation but not lung tumorigenesis in mice. Carcinogenesis. 2002 Oct; 23(10):1653-60.
Malkinson AM, Radcliffe RA, Bauer AK. Quantitative trait locus mapping of susceptibilities to butylated hydroxytoluene-induced lung tumor promotion and pulmonary inflammation in CXB mice. Carcinogenesis. 2002 Mar; 23(3):411-7.
Malkinson A, Radcliffe R, Bauer A, Dwyer-Nield L, Kleeberger S. Quantitative trait loci that regulate susceptibility to both butylated hydroxytoluene-induced pulmonary inflammation and lung tumor promotion in CXB recombinant inbred mice. Chest. 2002 Mar; 121(3 Suppl):82S.