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 research in collaboration with Dr. Upham (Michigan State University) focuses on the most abundant PAHs in 2nd 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 cell-cell communication (see Osgood et al., 2013; 2017). Recent studies focus on investigation of downstream signaling events following several "omics" studies with Drs. Pierre Bushel (NIEHS) and Dr. Nichole Reisdorph (UCD SOP).
Additional current projects:
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 et al., (2011) J Occup Environ Med 53: 346-351.
4. Arjomandi M, Haight T, Redberg R, Gold WM (2009) J Occup Environ Med 51: 639-646.
5. Beatty AL, Haight TJ, Redberg RF (2011) Environ Health 10: 81.
6. Ebbert JO et al. (2007) Environ Health 6: 28.
7. Pilkington PA, Gray S, Gilmore AB (2007) 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 et al. (2012) Chest.
10. Schick SF et al. (2013) Tob Control.
11. Becquemin MH et al. (2010) Tob Control 19: 347-348.
12. Hang B et al. (2013) Mutagenesis 28: 381-391.
13. Matt GE, et. al. (2011) Environ Health Perspect 119: 1218-1226.
14. Tillett T (2011) Environ Health Perspect 119: a399.
15. Lee HL, Hsieh DP, Li LA (2010) Chemosphere 10.1016/j.chemosphere.2010.09.045.
16. Moir D et al. (2008) Chem Res Toxicol 21: 494-502.
17. Severson RF et al. (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.
Basic Cancer Research
The role of toll-like receptors in 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 (NSCLC), 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.[18-23] Our long-term goal is to determine if TLR4, other TLR receptors, 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 (see Bauer 2005, 2009). Our recent studies, funded by the American Cancer Society (RSG-10-162-01-LIB; AKB), focused on the differential innate immune cell signatures involved in mediating the responses in mice lacking TLR4 (see Alexander et al. 2016) and downstream signaling pathways, such as cell-cell communication (see Hill et al. 2013).
In addition to these rodent studies, our most recent study (Bauer et. al., 2017) demonstrated that in humans, the mRNA expression of TLRs1-10 is associated with improved survival outcomes in NSCLC, specifically early stage adenocarcinoma. Thus, further evaluation of their predictive capacity and therapeutic utility is warranted.
Additional current projects:
- Investigation of epiregulin invovlement in the pathogenesis of NSCLC (see Bauer et al., 2016) in collaboration with Drs. Merrick, Tennis, and Nield (UCD and CO VA).
- Investigation of MUC5AC in lung carcinogenesis in collaboration with Drs. Evans (UCD SOM) and Moghaddam (MD Anderson).
18. Astrakianakis G et al. (2007) Lung cancer risk among female textile workers exposed to endotoxin. J Natl Cancer Inst 99: 357-364.
19. Laakkonen A et al. (2006) Occupational exposure to eight organic dusts and respiratory cancer among Finns. Occup Environ Med 63: 726-733.
20. Lange JH et al. (2003) Will sewage workers with endotoxin related symptoms have the benefit of reduced lung cancer? Occup Environ Med 60: 144-145.
21. Mastrangelo G et al. (2002) Epidemiologic evidence of cancer risk in textile industry workers: a review and update. Toxicol Ind Health 18: 171-181.
22. Mastrangelo G et al. (2005) Lung cancer risk: effect of dairy farming and the consequence of removing that occupational exposure. Am J Epidemiol 161: 1037-1046.
23. Lundin JI, Checkoway H (2009) Endotoxin and cancer. Environ Health Perspect 117: 1344-1350.
Current Lab Members
Kalpana Velmurugan, PhD
Katelyn Siegrist, PhD
Student Research Assistant
Student Research Assistant
Former Lab Members
Ross Osgood, PhD
Former graduate student in Toxicology
Currently a postdoctoral fellow at Harvard School of Public Health
Carla Alexander, PhD
Former post-doctoral fellow
Currently at Nexgen Pathology, Trinidad
Elizabeth Rondini, PhD
Former post-doctoral fellow
Research Scientist, Wayne State
Undergraduate students from University of Colorado Denver and Boulder
- Ka-Na Xiong
- Julie Xiong
- Rana Brooks
- Victoria Churchill-Hinton
- Zachary Leins
Undergraduates from School of Mines
Dr. Brad Upham, Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI
Dr. Christopher Evans, Department of Medicine, Division of Pulmonary Sciences, University of Colorado Denver, Aurora, CO
Dr. Seyed Javad Moghaddam, Department of Pulmonary Medicine, M.D. Anderson Cancer Center, Houston, TX
Dr. Linda Sargent, Molecular Genetics Laboratory, National Institute for Occupational Safety and Health, Morgantown, West Virginia
Drs. Steven Kleeberger and Hye Youn Cho, Laboratory of Respiratory Biology, Environmental Genetics Group, National Institute of Environmental Health Sciences, RTP, NC
Dr. Daniel Merrick, Division of Medicine, Department of Pathology, University of Colorado Denver, Aurora, CO
Dr. Heiko Käfferlein, Head for the Center for Toxicology, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute der Ruhr-Universität-Bochum (IPA)
Dr. Sabine Plöttner, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute der Ruhr-Universität-Bochum (IPA)
Dr. Pavel Babica, Masaryk University, Research Center for Toxic Compounds in the Environment, Brno, Czech Republic
Dr. Iva Sovadinova, Masaryk University, Research Center for Toxic Compounds in the Environment, Brno, Czech Republic
- Osgood, R.S., Upham, B.L., Hill, T, Helms, K.L., Velmurugan, K, Babica, P., Bauer, A.K. 2013. Polycyclic aromatic hydrocarbon-induced signaling events relevant to inflammation and tumorigenesis in lung cells are dependent on molecular structure. PLOS ONE, 3;8(6):e65150. doi:10.1371/journal.pone.0065150.
- Hill, T., Osgood, R.S., Velmurugan, K., Alexander, C.M., Upham, B.L., and Bauer., A.K. 2013 Bronchoalveolar lavage fluid utilized ex vivo to validate in vivo findings: inhibition of gap junction activity in lung tumor promotion is toll-like receptor 4-dependent. Journal of Molecular Biomarkers & Diagnosis, Dec 27;5(1). pii: 22168.
- Sargent, L.M., Porter, D.W., Staska, L., Hubbs, A.F., Lowry, D.T., Battelli, L., Siegrist, K.,Kashon, M.L., Mercer, R., Bauer, A.K., Chen, B.T., Salisbury, J.L., Frazer, D, McKinney, W., Andrew, M., Tsuruoka, S., Endo, M., Castranova, V, Reynolds, S.H. 2014 Promotion of lung adenocarcinoma and mesothelioma following inhalation exposure of multi-walled carbon nanotubes. Particle and Fiber Toxicology, Jan 9;11(1):3. doi: 10.1186/1743-8977-11-3.
- Bauer, A.K., Xiong, K., Velmurugan, K., Alexander, C.M., Xiong, J., and Brooks, R. 2016 Epiregulin is required for lung tumor promotion in a two-stage carcinogenesis model. Molecular Carcinogenesis, Feb 19. doi: 10.1002/mc.22475.
- Alexander, C.M., Xiong, K., Velmurugan, K., Osgood, R.S., Xiong, J., Bauer, A.K. 2016 Differential innate immune cell signatures and effects regulated by toll-like receptor 4 during murine lung tumor promotion. Experimental Lung Research, Apr; 42(3):154-73.
- Bayram, H., Bauer, A.K., Abdalati, W., Carlsten, C., Pinkerton, K.E., Thurston, GD, Balmes, J.R., Takaro, T.K. 2016 Environment, Global Climate Change, and Cardio-pulmonary Health American Journal of Respiratory and Critical Care Medicine 21 Sep as DOI: 1164/rccm.201604-0687PP.
- Osgood, R.S., Upham, B.L., Bushel, P., Velmurugan, K., Xiong, K., Bauer, A.K. 2017 Secondhand smoke-prevalent polycyclic aromatic hydrocarbon binary mixture- induced specific mitogenic and pro-inflammatory cell signaling events in lung epithelial cells. (Toxicological Sciences Jan 30. doi: 10.1093/toxsci/kfx027. [Epub ahead of print].
- Bauer, A.K., Upham, B.L., Rondini, E.A., Tennis, M., Velmurugan, K, and Wiese, D. 2017 Toll- like receptor expression in human non-small cell lung carcinoma: potential prognostic indicators of disease. Oncotarget, https://doi.org/10.18632/oncotarget.19463, online July 22.