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Dr. Alison Bauer
Department of Environmental and Occupational Health, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, 12850 East Montview Blvd., Rm V20-3125, Aurora, CO 80045, USA

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0 Bioactive Lipids
0 Persistent Organic Pollutants
0 polycyclic aromatic hydrocarbons
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Research article
Published: 08 February 2021 in Journal of Applied Toxicology
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Polycyclic aromatic hydrocarbons (PAHs) are generated by the incomplete combustion of carbon. Exposures correlate with systemic immune dysfunction and overall immune suppression. Real‐world exposures to PAHs are almost always encountered as mixtures; however, research overwhelmingly centers on isolated exposures to a single PAH, benzo[a]pyrene (B[a]P). Here, a human monocyte line (U937) was exposed to B[a]P, benz[a]anthracene (B[a]A), or a mixture of six PAHs (6‐MIX) to assess the differential toxicity on monocytes. Further, monocytes were exposed to PAHs with and without CYP1A1 inhibitors during macrophage differentiation to delineate PAH exposure and PAH metabolism‐driven alterations to the immune response. U937 monocytes exposed to B[a]P, B[a]A, or 6‐MIX had higher levels of cellular health and growth not observed following equimolar exposures to other individual PAHs. PAH exposures during differentiation did not alter monocyte‐derived macrophage (MDM) numbers; however, B[a]A and 6‐MIX exposures significantly altered M1/M2 polarization in a CYP1A1‐dependent manner. U937‐MDM adherence was differentially suppressed by all three PAH treatments with 6‐MIX exposed U937‐MDM having significantly more adhesion than U937‐MDM exposed to either individual PAH. Finally, 6‐MIX exposures during differentiation reduced U937‐MDM endocytic function significantly less than B[a]A exposed cells. Exposure to a unique PAH mixture during U937‐MDM differentiation resulted in mixture‐specific alterations of pro‐inflammatory markers compared to individual PAH exposures. While subtle, these differences highlight the probability that using a model PAH, B[a]P, may not accurately reflect the effects of PAH mixture exposures. Therefore, future studies should include various PAH mixtures that encompass probable real‐world PAH exposures for the endpoints under investigation.

ACS Style

Brian C. Tooker; Kevin Quinn; Michael Armstrong; Alison K. Bauer; Nichole Reisdorph. Comparing the effects of an exposure to a polycyclic aromatic hydrocarbon mixture versus individual polycyclic aromatic hydrocarbons during monocyte to macrophage differentiation: Mixture exposure results in altered immune metrics. Journal of Applied Toxicology 2021, 1 .

AMA Style

Brian C. Tooker, Kevin Quinn, Michael Armstrong, Alison K. Bauer, Nichole Reisdorph. Comparing the effects of an exposure to a polycyclic aromatic hydrocarbon mixture versus individual polycyclic aromatic hydrocarbons during monocyte to macrophage differentiation: Mixture exposure results in altered immune metrics. Journal of Applied Toxicology. 2021; ():1.

Chicago/Turabian Style

Brian C. Tooker; Kevin Quinn; Michael Armstrong; Alison K. Bauer; Nichole Reisdorph. 2021. "Comparing the effects of an exposure to a polycyclic aromatic hydrocarbon mixture versus individual polycyclic aromatic hydrocarbons during monocyte to macrophage differentiation: Mixture exposure results in altered immune metrics." Journal of Applied Toxicology , no. : 1.

Journal article
Published: 07 December 2020 in Particle and Fibre Toxicology
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Background Carbon nanotubes and nanofibers (CNT/F) have known toxicity but simultaneous comparative studies of the broad material class, especially those with a larger diameter, with computational analyses linking toxicity to their fundamental material characteristics was lacking. It was unclear if all CNT/F confer similar toxicity, in particular, genotoxicity. Nine CNT/F (MW #1–7 and CNF #1–2), commonly found in exposure assessment studies of U.S. facilities, were evaluated with reported diameters ranging from 6 to 150 nm. All materials were extensively characterized to include distributions of physical dimensions and prevalence of bundled agglomerates. Human bronchial epithelial cells were exposed to the nine CNT/F (0–24 μg/ml) to determine cell viability, inflammation, cellular oxidative stress, micronuclei formation, and DNA double-strand breakage. Computational modeling was used to understand various permutations of physicochemical characteristics and toxicity outcomes. Results Analyses of the CNT/F physicochemical characteristics illustrate that using detailed distributions of physical dimensions provided a more consistent grouping of CNT/F compared to using particle dimension means alone. In fact, analysis of binning of nominal tube physical dimensions alone produced a similar grouping as all characterization parameters together. All materials induced epithelial cell toxicity and micronuclei formation within the dose range tested. Cellular oxidative stress, DNA double strand breaks, and micronuclei formation consistently clustered together and with larger physical CNT/F dimensions and agglomerate characteristics but were distinct from inflammatory protein changes. Larger nominal tube diameters, greater lengths, and bundled agglomerate characteristics were associated with greater severity of effect. The portion of tubes with greater nominal length and larger diameters within a sample was not the majority in number, meaning a smaller percentage of tubes with these characteristics was sufficient to increase toxicity. Many of the traditional physicochemical characteristics including surface area, density, impurities, and dustiness did not cluster with the toxicity outcomes. Conclusion Distributions of physical dimensions provided more consistent grouping of CNT/F with respect to toxicity outcomes compared to means only. All CNT/F induced some level of genotoxicity in human epithelial cells. The severity of toxicity was dependent on the sample containing a proportion of tubes with greater nominal lengths and diameters.

ACS Style

Kelly Fraser; Vamsi Kodali; Naveena Yanamala; M. Eileen Birch; Lorenzo Cena; Gary Casuccio; Kristin Bunker; Traci L. Lersch; Douglas E. Evans; Aleksandr Stefaniak; Mary Ann Hammer; Michael L. Kashon; Theresa Boots; Tracy Eye; John Hubczak; Sherri A. Friend; Matthew Dahm; Mary K. Schubauer-Berigan; Katelyn Siegrist; David Lowry; Alison K. Bauer; Linda M. Sargent; Aaron Erdely. Physicochemical characterization and genotoxicity of the broad class of carbon nanotubes and nanofibers used or produced in U.S. facilities. Particle and Fibre Toxicology 2020, 17, 1 -26.

AMA Style

Kelly Fraser, Vamsi Kodali, Naveena Yanamala, M. Eileen Birch, Lorenzo Cena, Gary Casuccio, Kristin Bunker, Traci L. Lersch, Douglas E. Evans, Aleksandr Stefaniak, Mary Ann Hammer, Michael L. Kashon, Theresa Boots, Tracy Eye, John Hubczak, Sherri A. Friend, Matthew Dahm, Mary K. Schubauer-Berigan, Katelyn Siegrist, David Lowry, Alison K. Bauer, Linda M. Sargent, Aaron Erdely. Physicochemical characterization and genotoxicity of the broad class of carbon nanotubes and nanofibers used or produced in U.S. facilities. Particle and Fibre Toxicology. 2020; 17 (1):1-26.

Chicago/Turabian Style

Kelly Fraser; Vamsi Kodali; Naveena Yanamala; M. Eileen Birch; Lorenzo Cena; Gary Casuccio; Kristin Bunker; Traci L. Lersch; Douglas E. Evans; Aleksandr Stefaniak; Mary Ann Hammer; Michael L. Kashon; Theresa Boots; Tracy Eye; John Hubczak; Sherri A. Friend; Matthew Dahm; Mary K. Schubauer-Berigan; Katelyn Siegrist; David Lowry; Alison K. Bauer; Linda M. Sargent; Aaron Erdely. 2020. "Physicochemical characterization and genotoxicity of the broad class of carbon nanotubes and nanofibers used or produced in U.S. facilities." Particle and Fibre Toxicology 17, no. 1: 1-26.

Book chapter
Published: 24 August 2020 in Methods in Cell Biology
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Lung cancer is one of the deadliest types of cancer and as such requires disease models that are useful for identification of novel pathways for biomarkers as well as to test therapeutic agents. Adenocarcinoma (ADC), the most prevalent type of lung cancer, is a subtype of non-small cell lung carcinoma (NSCLC) and a disease driven mainly by smoking. However, it is also the most common subtype of lung cancer found in non-smokers with environmental exposures. Chemically driven models of lung cancer, also called primary models of lung cancer, are important because they do not overexpress or delete oncogenes or tumor suppressor genes, respectively, to increase oncogenesis. Instead these models test tumor development without forcing a specific pathway (i.e., Kras). The primary focus of this chapter is to discuss a well-established 2-stage mouse model of lung adenocarcinomas. The initiator (3-methylcholanthrene, MCA) does not elicit many, if any, tumors if not followed by exposure to the tumor promoter (butylated hydroxytoluene, BHT). In sensitive strains, such as A/J, FVB, and BALB, significantly greater numbers of tumors develop following the MCA/BHT protocol compared to MCA alone. BHT does not elicit tumors on its own; it is a non-genotoxic carcinogen and promoter. In these sensitive strains, promotion is also associated with inflammation characterized by infiltrating macrophages, lymphocytes, and neutrophils, and other inflammatory cell types in addition to increases in total protein content reflective of lung hyperpermeability. This 2-stage model is a useful tool to identify unique promotion specific events to then test in future intervention studies.

ACS Style

Alison K. Bauer; Lori D. Dwyer-Nield. Two-stage 3-methylcholanthrene and butylated hydroxytoluene-induced lung carcinogenesis in mice. Methods in Cell Biology 2020, 163, 153 -173.

AMA Style

Alison K. Bauer, Lori D. Dwyer-Nield. Two-stage 3-methylcholanthrene and butylated hydroxytoluene-induced lung carcinogenesis in mice. Methods in Cell Biology. 2020; 163 ():153-173.

Chicago/Turabian Style

Alison K. Bauer; Lori D. Dwyer-Nield. 2020. "Two-stage 3-methylcholanthrene and butylated hydroxytoluene-induced lung carcinogenesis in mice." Methods in Cell Biology 163, no. : 153-173.

Journal article
Published: 31 May 2020 in Environmental Toxicology and Pharmacology
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Inhalation exposures to polycyclic aromatic hydrocarbons (PAHs) have been associated with various adverse health effects, including chronic lung diseases and cancer. Using human bronchial epithelial cell line HBE1, we investigated the effects of structurally different PAHs on tissue homeostatic processes, namely gap junctional intercellular communication (GJIC) and MAPKs activity. Rapid (<1 h) and sustained (up to 24 h) inhibition of GJIC was induced by low/middle molecular weight (MW) PAHs, particularly by those with a bay- or bay-like region (1- and 9-methylanthracene, fluoranthene), but also by fluorene and pyrene. In contrast, linear low MW (anthracene, 2-methylanthracene) or higher MW (chrysene) PAHs did not affect GJIC. Fluoranthene, 1- and 9-methylanthracene induced strong and sustained activation of MAPK ERK1/2, whereas MAPK p38 was activated rather nonspecifically by all tested PAHs. Low/middle MW PAHs can disrupt tissue homeostasis in human airway epithelium via structure-dependent nongenotoxic mechanisms, which can contribute to their human health hazards.

ACS Style

Ondřej Brózman; Jiří Novák; Alison K. Bauer; Pavel Babica. Airborne PAHs inhibit gap junctional intercellular communication and activate MAPKs in human bronchial epithelial cell line. Environmental Toxicology and Pharmacology 2020, 79, 103422 .

AMA Style

Ondřej Brózman, Jiří Novák, Alison K. Bauer, Pavel Babica. Airborne PAHs inhibit gap junctional intercellular communication and activate MAPKs in human bronchial epithelial cell line. Environmental Toxicology and Pharmacology. 2020; 79 ():103422.

Chicago/Turabian Style

Ondřej Brózman; Jiří Novák; Alison K. Bauer; Pavel Babica. 2020. "Airborne PAHs inhibit gap junctional intercellular communication and activate MAPKs in human bronchial epithelial cell line." Environmental Toxicology and Pharmacology 79, no. : 103422.

Journal article
Published: 07 October 2019 in Particle and Fibre Toxicology
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Background The unique physicochemical properties of multi-walled carbon nanotubes (MWCNT) have led to many industrial applications. Due to their low density and small size, MWCNT are easily aerosolized in the workplace making respiratory exposures likely in workers. The International Agency for Research on Cancer designated the pristine Mitsui-7 MWCNT (MWCNT-7) as a Group 2B carcinogen, but there was insufficient data to classify all other MWCNT. Previously, MWCNT exposed to high temperature (MWCNT-HT) or synthesized with nitrogen (MWCNT-ND) have been found to elicit attenuated toxicity; however, their genotoxic and carcinogenic potential are not known. Our aim was to measure the genotoxicity of MWCNT-7 compared to these two physicochemically-altered MWCNTs in human lung epithelial cells (BEAS-2B & SAEC). Results Dose-dependent partitioning of individual nanotubes in the cell nuclei was observed for each MWCNT material and was greatest for MWCNT-7. Exposure to each MWCNT led to significantly increased mitotic aberrations with multi- and monopolar spindle morphologies and fragmented centrosomes. Quantitative analysis of the spindle pole demonstrated significantly increased centrosome fragmentation from 0.024–2.4 μg/mL of each MWCNT. Significant aneuploidy was measured in a dose-response from each MWCNT-7, HT, and ND; the highest dose of 24 μg/mL produced 67, 61, and 55%, respectively. Chromosome analysis demonstrated significantly increased centromere fragmentation and translocations from each MWCNT at each dose. Following 24 h of exposure to MWCNT-7, ND and/or HT in BEAS-2B a significant arrest in the G1/S phase in the cell cycle occurred, whereas the MWCNT-ND also induced a G2 arrest. Primary SAEC exposed for 24 h to each MWCNT elicited a significantly greater arrest in the G1 and G2 phases. However, SAEC arrested in the G1/S phase after 72 h of exposure. Lastly, a significant increase in clonal growth was observed one month after exposure to 0.024 μg/mL MWCNT-HT & ND. Conclusions Although MWCNT-HT & ND cause a lower incidence of genotoxicity, all three MWCNTs cause the same type of mitotic and chromosomal disruptions. Chromosomal fragmentation and translocations have not been observed with other nanomaterials. Because in vitro genotoxicity is correlated with in vivo genotoxic response, these studies in primary human lung cells may predict the genotoxic potency in exposed human populations.

ACS Style

Katelyn J. Siegrist; Steven H. Reynolds; Dale W. Porter; Robert R. Mercer; Alison K. Bauer; David Lowry; Lorenzo Cena; Todd A. Stueckle; Michael L. Kashon; John Wiley; Jeffrey L. Salisbury; John Mastovich; Kristin Bunker; Mark Sparrow; Jason S. Lupoi; Aleksandr B. Stefaniak; Michael J. Keane; Shuji Tsuruoka; Mauricio Terrones; Michael McCAWLEY; Linda M. Sargent. Mitsui-7, heat-treated, and nitrogen-doped multi-walled carbon nanotubes elicit genotoxicity in human lung epithelial cells. Particle and Fibre Toxicology 2019, 16, 1 -19.

AMA Style

Katelyn J. Siegrist, Steven H. Reynolds, Dale W. Porter, Robert R. Mercer, Alison K. Bauer, David Lowry, Lorenzo Cena, Todd A. Stueckle, Michael L. Kashon, John Wiley, Jeffrey L. Salisbury, John Mastovich, Kristin Bunker, Mark Sparrow, Jason S. Lupoi, Aleksandr B. Stefaniak, Michael J. Keane, Shuji Tsuruoka, Mauricio Terrones, Michael McCAWLEY, Linda M. Sargent. Mitsui-7, heat-treated, and nitrogen-doped multi-walled carbon nanotubes elicit genotoxicity in human lung epithelial cells. Particle and Fibre Toxicology. 2019; 16 (1):1-19.

Chicago/Turabian Style

Katelyn J. Siegrist; Steven H. Reynolds; Dale W. Porter; Robert R. Mercer; Alison K. Bauer; David Lowry; Lorenzo Cena; Todd A. Stueckle; Michael L. Kashon; John Wiley; Jeffrey L. Salisbury; John Mastovich; Kristin Bunker; Mark Sparrow; Jason S. Lupoi; Aleksandr B. Stefaniak; Michael J. Keane; Shuji Tsuruoka; Mauricio Terrones; Michael McCAWLEY; Linda M. Sargent. 2019. "Mitsui-7, heat-treated, and nitrogen-doped multi-walled carbon nanotubes elicit genotoxicity in human lung epithelial cells." Particle and Fibre Toxicology 16, no. 1: 1-19.

Journal article
Published: 23 April 2019 in Cancers
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Polycyclic aromatic hydrocarbons (PAHs), prevalent contaminants in our environment, in many occupations, and in first and second-hand smoke, pose significant adverse health effects. Most research focused on the genotoxic high molecular weight PAHs (e.g., benzo[a]pyrene), however, the nongenotoxic low molecular weight (LMW) PAHs are emerging as potential co-carcinogens and tumor promoters known to dysregulate gap junctional intercellular communication (GJIC), activate mitogen activated protein kinase pathways, and induce the release of inflammatory mediators. We hypothesize that inflammatory mediators resulting from LMW PAH exposure in mouse lung epithelial cell lines are involved in the dysregulation of GJIC. We used mouse lung epithelial cell lines and an alveolar macrophage cell line in the presence of a binary PAH mixture (1:1 ratio of fluoranthene and 1-methylanthracene; PAH mixture). Parthenolide, a pan-inflammation inhibitor, reversed the PAH-induced inhibition of GJIC, the decreased CX43 expression, and the induction of KC and TNF. To further determine the direct role of a cytokine in regulating GJIC, recombinant TNF (rTNF) was used to inhibit GJIC and this response was further enhanced in the presence of the PAH mixture. Collectively, these findings support a role for inflammation in regulating GJIC and the potential to target these early stage cancer pathways for therapeutics.

ACS Style

DeeDee Romo; Kalpana Velmurugan; Brad L. Upham; Lori D. Dwyer-Nield; Alison K. Bauer. Dysregulation of Gap Junction Function and Cytokine Production in Response to Non-Genotoxic Polycyclic Aromatic Hydrocarbons in an In Vitro Lung Cell Model. Cancers 2019, 11, 572 .

AMA Style

DeeDee Romo, Kalpana Velmurugan, Brad L. Upham, Lori D. Dwyer-Nield, Alison K. Bauer. Dysregulation of Gap Junction Function and Cytokine Production in Response to Non-Genotoxic Polycyclic Aromatic Hydrocarbons in an In Vitro Lung Cell Model. Cancers. 2019; 11 (4):572.

Chicago/Turabian Style

DeeDee Romo; Kalpana Velmurugan; Brad L. Upham; Lori D. Dwyer-Nield; Alison K. Bauer. 2019. "Dysregulation of Gap Junction Function and Cytokine Production in Response to Non-Genotoxic Polycyclic Aromatic Hydrocarbons in an In Vitro Lung Cell Model." Cancers 11, no. 4: 572.

Journal article
Published: 09 August 2018 in JCI Insight
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With more than 150,000 deaths per year in the US alone, lung cancer has the highest number of deaths for any cancer. These poor outcomes reflect a lack of treatment for the most common form of lung cancer, non–small cell lung carcinoma (NSCLC). Lung adenocarcinoma (ADC) is the most prevalent subtype of NSCLC, with the main oncogenic drivers being KRAS and epidermal growth factor receptor (EGFR). Whereas EGFR blockade has led to some success in lung ADC, effective KRAS inhibition is lacking. KRAS-mutant ADCs are characterized by high levels of gel-forming mucin expression, with the highest mucin levels corresponding to worse prognoses. Despite these well-recognized associations, little is known about roles for individual gel-forming mucins in ADC development causatively. We hypothesized that MUC5AC/Muc5ac, a mucin gene known to be commonly expressed in NSCLC, is crucial in KRAS/Kras-driven lung ADC. We found that MUC5AC was a significant determinant of poor prognosis, especially in patients with KRAS-mutant tumors. In addition, by using mice with lung ADC induced chemically with urethane or transgenically by mutant-Kras expression, we observed significantly reduced tumor development in animals lacking Muc5ac compared with controls. Collectively, these results provide strong support for MUC5AC as a potential therapeutic target for lung ADC, a disease with few effective treatments.

ACS Style

Alison K. Bauer; Misha Umer; Vanessa L. Richardson; Amber M. Cumpian; Anna Q. Harder; Nasim Khosravi; Zoulikha Azzegagh; Naoko M. Hara; Camille Ehre; Maedeh Mohebnasab; Mauricio S. Caetano; Daniel T. Merrick; Adrie Van Bokhoven; Ignacio I. Wistuba; Humam Kadara; Burton F. Dickey; Kalpana Velmurugan; Patrick R. Mann; Xian Lu; Anna E. Barón; Christopher M. Evans; Seyed Javad Moghaddam. Requirement for MUC5AC in KRAS-dependent lung carcinogenesis. JCI Insight 2018, 3, 1 .

AMA Style

Alison K. Bauer, Misha Umer, Vanessa L. Richardson, Amber M. Cumpian, Anna Q. Harder, Nasim Khosravi, Zoulikha Azzegagh, Naoko M. Hara, Camille Ehre, Maedeh Mohebnasab, Mauricio S. Caetano, Daniel T. Merrick, Adrie Van Bokhoven, Ignacio I. Wistuba, Humam Kadara, Burton F. Dickey, Kalpana Velmurugan, Patrick R. Mann, Xian Lu, Anna E. Barón, Christopher M. Evans, Seyed Javad Moghaddam. Requirement for MUC5AC in KRAS-dependent lung carcinogenesis. JCI Insight. 2018; 3 (15):1.

Chicago/Turabian Style

Alison K. Bauer; Misha Umer; Vanessa L. Richardson; Amber M. Cumpian; Anna Q. Harder; Nasim Khosravi; Zoulikha Azzegagh; Naoko M. Hara; Camille Ehre; Maedeh Mohebnasab; Mauricio S. Caetano; Daniel T. Merrick; Adrie Van Bokhoven; Ignacio I. Wistuba; Humam Kadara; Burton F. Dickey; Kalpana Velmurugan; Patrick R. Mann; Xian Lu; Anna E. Barón; Christopher M. Evans; Seyed Javad Moghaddam. 2018. "Requirement for MUC5AC in KRAS-dependent lung carcinogenesis." JCI Insight 3, no. 15: 1.

Genotoxicity and carcinogenicity
Published: 23 November 2017 in Archives of Toxicology
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Low molecular weight (LMW) polycyclic aromatic hydrocarbons (PAH) are the most abundant PAHs environmentally, occupationally, and are in cigarette smoke; however, little is known about their carcinogenic potential. We hypothesized that LMW PAHs act as co-carcinogens in the presence of a known carcinogen (benzo[a]pyrene (B[a]P)) in a mouse non-tumorigenic type II cell line (C10 cells). Gap junctions are commonly suppressed and inflammation induced during tumor promotion, while DNA-adduct formation is observed during the initiation stage of cancer. We used these endpoints together as markers of carcinogenicity in these lung adenocarcinoma progenitor cells. LMW PAHs (1-methylanthracene and fluoranthene, 1–10 µM total in a 1:1 ratio) were used based on previous studies as well as B[a]P (0–3 µM) as the classic carcinogen; non-cytotoxic doses were used. B[a]P-induced inhibition of gap junctional intercellular communication (GJIC) was observed at low doses and further reduced in the presence of the LMW PAH mixture (P < 0.05), supporting a role for GJIC suppression in cancer development. Benzo[a]pyrene diol-epoxide (BPDE)-DNA adduct levels were significantly induced in B[a]P-treated C10 cells and additionally increased with the LMW PAH mixture (P < 0.05). Significant increases in cyclooxygenase (Cox-2) were observed in response to the B[a]P/LMW PAH mixture combinations. DNA adduct formation coincided with the inhibition of GJIC and increase in Cox-2 mRNA expression. Significant cytochrome p4501b1 increases and connexin 43 decreases in gene expression were also observed. These studies suggest that LMW PAHs in combination with B[a]P can elicit increased carcinogenic potential. Future studies will further address the mechanisms of co-carcinogenesis driving these responses.

ACS Style

Alison K. Bauer; Kalpana Velmurugan; Sabine Plöttner; Katelyn J. Siegrist; DeeDee Romo; Peter Welge; Thomas Brüning; Ka-Na Xiong; Heiko U. Käfferlein. Environmentally prevalent polycyclic aromatic hydrocarbons can elicit co-carcinogenic properties in an in vitro murine lung epithelial cell model. Archives of Toxicology 2017, 92, 1311 -1322.

AMA Style

Alison K. Bauer, Kalpana Velmurugan, Sabine Plöttner, Katelyn J. Siegrist, DeeDee Romo, Peter Welge, Thomas Brüning, Ka-Na Xiong, Heiko U. Käfferlein. Environmentally prevalent polycyclic aromatic hydrocarbons can elicit co-carcinogenic properties in an in vitro murine lung epithelial cell model. Archives of Toxicology. 2017; 92 (3):1311-1322.

Chicago/Turabian Style

Alison K. Bauer; Kalpana Velmurugan; Sabine Plöttner; Katelyn J. Siegrist; DeeDee Romo; Peter Welge; Thomas Brüning; Ka-Na Xiong; Heiko U. Käfferlein. 2017. "Environmentally prevalent polycyclic aromatic hydrocarbons can elicit co-carcinogenic properties in an in vitro murine lung epithelial cell model." Archives of Toxicology 92, no. 3: 1311-1322.

Journal article
Published: 22 July 2017 in Oncotarget
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// Alison K. Bauer 1 , Brad L. Upham 2 , Elizabeth A. Rondini 3 , Meredith A. Tennis 4 , Kalpana Velmuragan 1 and David Wiese 5 1 Department of Environmental and Occupational Health, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 2 Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI 48824 3 Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824 4 Department of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 5 McLaren Regional Medical Center, Flint, MI, 48532 Correspondence to: Alison K. Bauer, email: [email protected] Keywords: adenocarcinoma, innate immunity, non-small cell lung carcinoma, prognostic, toll-like receptor Received: September 30, 2016 Accepted: June 02, 2017 Published: July 22, 2017 ABSTRACT Introduction . Lung cancer remains the highest cause of cancer mortality worldwide. Toll-like receptors (TLR) are innate immune receptors that have both pro- and anti-tumorigenic properties. Based on findings from epidemiological studies and in rodents, we hypothesized that elevated TLR expression would be a positive prognostic indicator of disease in non-small cell lung carcinoma patients. Results . Higher mRNA expression of TLR1-3 and 5-8 were significantly associated with increased overall survival (OS) when analyzed individually or as a group in both non-small cell lung carcinoma (NSCLC) patients and in the adenocarcinoma (ADC) subtype. Significant co-expression of many TLR combinations in ADC patients were also observed via RNA sequencing. Immunostaining demonstrated TLR4 and 8 significantly correlated in tumor tissue, similar to RNA. Methods. We used kmplot.com to perform a meta-analysis on mRNA expression of TLR1-10 to determine any significant associations with OS in NSCLC and the ADC subtype. cBioportal was also used simultaneously to assess co-expression in TLR1-10 in ADC patients via RNA sequencing and to identify any molecular alterations. Lastly, immunostaining for a subset of TLRs was conducted on ADC patients. Conclusions . Expression of innate immune receptors TLR1-10 is associated with improved survival outcomes in NSCLC. Thus, further evaluation of their predictive capacity and therapeutic utility is warranted. Alison K. Bauer1, Brad L. Upham2, Elizabeth A. Rondini3, Meredith A. Tennis4, Kalpana Velmuragan1 and David Wiese5 1Department of Environmental and Occupational Health, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 2Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI 48824 3Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824 4Department of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 5McLaren Regional Medical Center, Flint, MI, 48532 Correspondence to: Alison K. Bauer, email: [email protected] Keywords: adenocarcinoma, innate immunity, non-small cell lung carcinoma, prognostic, toll-like receptor Received: September 30, 2016 Accepted: June 02, 2017 Published: July 22, 2017 Copyright: Bauer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Introduction. Lung cancer remains the highest cause of cancer mortality worldwide. Toll-like receptors (TLR) are innate immune receptors that have both pro- and anti-tumorigenic properties. Based on findings from epidemiological studies and in rodents, we hypothesized that elevated TLR expression would be a positive prognostic indicator of disease in non-small cell lung carcinoma patients. Results. Higher mRNA expression of TLR1-3 and 5-8 were significantly associated with increased overall survival (OS) when analyzed individually or as a group in both non-small cell lung carcinoma (NSCLC) patients and in the adenocarcinoma (ADC) subtype. Significant co-expression of many TLR combinations in ADC patients were also observed via RNA sequencing. Immunostaining demonstrated TLR4 and 8 significantly correlated in tumor tissue, similar to RNA. Methods. We used kmplot.com to perform a meta-analysis on mRNA expression of TLR1-10 to determine any significant associations with OS in NSCLC and the ADC subtype. cBioportal was also used simultaneously to assess co-expression in TLR1-10 in ADC patients via RNA sequencing and to identify any molecular alterations. Lastly, immunostaining for a subset of TLRs was conducted on ADC patients. Conclusions. Expression of innate immune receptors TLR1-10 is associated with improved survival outcomes in NSCLC. Thus, further evaluation of their predictive capacity and therapeutic utility is warranted.

ACS Style

Alison K. Bauer; Brad L. Upham; Elizabeth A. Rondini; Meredith Tennis; Kalpana Velmuragan; David Wiese. Toll-like receptor expression in human non-small cell lung carcinoma: potential prognostic indicators of disease. Oncotarget 2017, 8, 91860 -91875.

AMA Style

Alison K. Bauer, Brad L. Upham, Elizabeth A. Rondini, Meredith Tennis, Kalpana Velmuragan, David Wiese. Toll-like receptor expression in human non-small cell lung carcinoma: potential prognostic indicators of disease. Oncotarget. 2017; 8 (54):91860-91875.

Chicago/Turabian Style

Alison K. Bauer; Brad L. Upham; Elizabeth A. Rondini; Meredith Tennis; Kalpana Velmuragan; David Wiese. 2017. "Toll-like receptor expression in human non-small cell lung carcinoma: potential prognostic indicators of disease." Oncotarget 8, no. 54: 91860-91875.

Journal article
Published: 30 January 2017 in Toxicological Sciences
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Low molecular weight polycyclic aromatic hydrocarbons (LMW PAHs; < 206.3 g/mol) are prevalent and ubiquitous environmental contaminants, presenting a human health concern, and have not been as thoroughly studied as the high MW PAHs. LMW PAHs exert their pulmonary effects, in part, through P38-dependent and -independent mechanisms involving cell-cell communication and the production of pro-inflammatory mediators known to contribute to lung disease. Specifically, we determined the effects of two representative LMW PAHs, 1-methylanthracene (1-MeA) and fluoranthene (Flthn), individually and as a binary PAH mixture on the dysregulation of gap junctional intercellular communication (GJIC) and connexin 43 (Cx43), activation of mitogen activated protein kinases (MAPK), and induction of inflammatory mediators in a mouse non-tumorigenic alveolar type II cell line (C10). Both 1-MeA, Flthn, and the binary PAH mixture of 1-MeA and Flthn dysregulated GJIC in a dose and time-dependent manner, reduced Cx43 protein, and activated the following MAPKs: P38, ERK1/2, and JNK. Inhibition of P38 MAPK prevented PAH-induced dysregulation of GJIC, whereas inhibiting ERK and JNK did not prevent these PAHs from dysregulating GJIC indicating a P38-dependent mechanism. A toxicogenomic approach revealed significant P38-dependent and -independent pathways involved in inflammation, steroid synthesis, metabolism, and oxidative responses. Genes in these pathways were significantly altered by the binary PAH mixture when compared with 1-MeA and Flthn alone suggesting interactive effects. Exposure to the binary PAH mixture induced the production and release of cytokines and metalloproteinases from the C10 cells. Our findings with a binary mixture of PAHs suggest that combinations of LMW PAHs may elicit synergistic or additive inflammatory responses which warrant further investigation and confirmation.

ACS Style

Ross S. Osgood; Brad L. Upham; Pierre R. Bushel; Kalpana Velmurugan; Ka-Na Xiong; Alison K. Bauer. Secondhand Smoke-Prevalent Polycyclic Aromatic Hydrocarbon Binary Mixture-Induced Specific Mitogenic and Pro-inflammatory Cell Signaling Events in Lung Epithelial Cells. Toxicological Sciences 2017, 157, 156 -171.

AMA Style

Ross S. Osgood, Brad L. Upham, Pierre R. Bushel, Kalpana Velmurugan, Ka-Na Xiong, Alison K. Bauer. Secondhand Smoke-Prevalent Polycyclic Aromatic Hydrocarbon Binary Mixture-Induced Specific Mitogenic and Pro-inflammatory Cell Signaling Events in Lung Epithelial Cells. Toxicological Sciences. 2017; 157 (1):156-171.

Chicago/Turabian Style

Ross S. Osgood; Brad L. Upham; Pierre R. Bushel; Kalpana Velmurugan; Ka-Na Xiong; Alison K. Bauer. 2017. "Secondhand Smoke-Prevalent Polycyclic Aromatic Hydrocarbon Binary Mixture-Induced Specific Mitogenic and Pro-inflammatory Cell Signaling Events in Lung Epithelial Cells." Toxicological Sciences 157, no. 1: 156-171.

Original articles
Published: 18 May 2016 in Nutritional Neuroscience
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Objectives: Ethanol (EtOH) causes oxidative stress in embryos. Because N-acetylcysteine (NAC) failures and successes in ameliorating EtOH-induced oxidative stress have been reported, the objective was to determine if exogenous NAC ameliorated EtOH-induced oxidative stress within embryonic chick brains. Methods: Control eggs were injected with approximately 25 µl of water on day 0, 1, and 2 of development (E0–2). Experimental eggs were injected with dosages of either 3.0 mmol EtOH/kg egg; 747 µmol NAC/kg egg; 3.0 mmol EtOH and 747 µmol NAC/kg egg; 1000 µmol NAC/kg egg; or 3.0 mmol EtOH and 1000 µmol NAC/kg during the first 3 days of development (E0–2). At 11 days of development (E11; late embryogenesis), brains were harvested and subsequently assayed for oxidative stress markers including the loss of long-chain membrane polyunsaturated fatty acids (PUFAs); the accumulation of lipid hydroperoxides (LPO); decreased glutathione (GSH) and glutathione/glutathione disulfide (GSSG) levels; and decreased glutathione peroxidase (GPx) activities. Results: EtOH (3 mmol/kg egg), medium NAC (747 µmol/kg egg), and EtOH and medium NAC promoted oxidative stress. These treatments caused decreased brain membrane long-chain PUFAs; increased LPO levels; decreased GSH levels and GSH/GSSG levels; and decreased Se-dependent GPx activities. High NAC dosages (1000 µmol/kg egg) attenuated EtOH-induced oxidative stress within EtOH and high NAC-treated chick brains. Discussion: Exogenous EtOH and/or medium NAC propagated oxidative stress. Meanwhile, high NAC ameliorated EtOH-induced oxidative stress.

ACS Style

Alison K. Bauer; Mary Fitzgerald; Adam T. Ladzinski; Sydney Lenhart Sherman; Benjamin H. Maddock; Zoe M. Norr; Robert R. Miller Jr. Dual behavior ofN-acetylcysteine during ethanol-induced oxidative stress in embryonic chick brains. Nutritional Neuroscience 2016, 20, 478 -488.

AMA Style

Alison K. Bauer, Mary Fitzgerald, Adam T. Ladzinski, Sydney Lenhart Sherman, Benjamin H. Maddock, Zoe M. Norr, Robert R. Miller Jr. Dual behavior ofN-acetylcysteine during ethanol-induced oxidative stress in embryonic chick brains. Nutritional Neuroscience. 2016; 20 (8):478-488.

Chicago/Turabian Style

Alison K. Bauer; Mary Fitzgerald; Adam T. Ladzinski; Sydney Lenhart Sherman; Benjamin H. Maddock; Zoe M. Norr; Robert R. Miller Jr. 2016. "Dual behavior ofN-acetylcysteine during ethanol-induced oxidative stress in embryonic chick brains." Nutritional Neuroscience 20, no. 8: 478-488.

Journal article
Published: 15 March 2016 in Experimental Lung Research
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Tumor promotion is an early and critical stage during lung adenocarcinoma (ADC). We previously demonstrated that Tlr4 mutant mice were more susceptible to butylated hydroxytoluene (BHT)-induced pulmonary inflammation and tumor promotion in comparison to Tlr4-sufficient mice. Our study objective was to elucidate the underlying differences in Tlr4 mutant mice in innate immune cell populations, their functional responses, and the influence of these cellular differences on ADC progenitor (type II) cells following BHT-treatment. BALB (Tlr4-sufficient) and C.C3-Tlr4Lps-d/J (BALBLpsd; Tlr4 mutant) mice were treated with BHT (promoter) followed by bronchoalveolar lavage (BAL) and flow cytometry processing on the lungs. ELISAs, Club cell enrichment, macrophage function, and RNA isolation were also performed. Bone marrow-derived macrophages (BMDM) co-cultured with a type II cell line were used for wound healing assays. Innate immune cells significantly increased in whole lung in BHT-treated BALBLpsd mice compared to BALB mice. BHT-treated BALBLpsd mice demonstrated enhanced macrophage functionality, increased epithelial wound closure via BMDMs, and increased Club cell number in BALBLpsd mice, all compared to BALB BHT-treated mice. Cytokine/chemokine (Kc, Mcp1) and growth factor (Igf1) levels also significantly differed among the strains and within macrophages, gene expression, and cell surface markers collectively demonstrated a more plastic phenotype in BALBLpsd mice. Therefore, these correlative studies suggest that distinct innate immune cell populations are associated with the differences observed in the Tlr4-mutant model. Future studies will investigate the macrophage origins and the utility of the pathways identified herein as indicators of immune system deficiencies and lung tumorigenesis.

ACS Style

Carla-Maria Alexander; Ka-Na Xiong; Kalpana Velmurugan; Julie Xiong; Ross S. Osgood; Alison K. Bauer. Differential innate immune cell signatures and effects regulated by toll-like receptor 4 during murine lung tumor promotion. Experimental Lung Research 2016, 42, 154 -173.

AMA Style

Carla-Maria Alexander, Ka-Na Xiong, Kalpana Velmurugan, Julie Xiong, Ross S. Osgood, Alison K. Bauer. Differential innate immune cell signatures and effects regulated by toll-like receptor 4 during murine lung tumor promotion. Experimental Lung Research. 2016; 42 (3):154-173.

Chicago/Turabian Style

Carla-Maria Alexander; Ka-Na Xiong; Kalpana Velmurugan; Julie Xiong; Ross S. Osgood; Alison K. Bauer. 2016. "Differential innate immune cell signatures and effects regulated by toll-like receptor 4 during murine lung tumor promotion." Experimental Lung Research 42, no. 3: 154-173.

Article
Published: 19 February 2016 in Molecular Carcinogenesis
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Adenocarcinoma accounts for ∼40% of lung cancer, equating to ∼88 500 new patients in 2015, most of who will succumb to this disease, thus, the public health burden is evident. Unfortunately, few early biomarkers as well as effective therapies exist, hence the need for novel targets in lung cancer treatment. We previously identified epiregulin (Ereg), an EGF‐like ligand, as a biomarker in several mouse lung cancer models. In the present investigation we used a primary two‐stage initiation/promotion model to test our hypothesis that Ereg deficiency would reduce lung tumor promotion in mice. We used 3‐methylcholanthrene (initiator) or oil vehicle followed by multiple weekly exposures to butylated hydroxytoluene (BHT; promoter) in mice lacking Ereg (Ereg−/−) and wildtype controls (BALB/ByJ; Ereg+/+) and examined multiple time points and endpoints (bronchoalveolar lavage analysis, tumor analysis, mRNA expression, ELISA, wound assay) during tumor promotion. At the early time points (4 and 12 wk), we observed significantly reduced amounts of inflammation (macrophages, PMNs) in the Ereg−/− mice compared to controls (Ereg+/+). At 20 wk, tumor multiplicity was also significantly decreased in the Ereg−/− mice versus controls (Ereg+/+). IL10 expression, an anti‐inflammatory mediator, and downstream signaling events (Stat3) were significantly increased in the Ereg−/− mice in response to BHT, supporting both reduced inflammation and tumorigenesis. Lastly, wound healing was significantly increased with recombinant Ereg in both human and mouse lung epithelial cell lines. These results indicate that Ereg has proliferative potential and may be utilized as an early cancer biomarker as well as a novel potential therapeutic target.

ACS Style

Alison K. Bauer; Kalpana Velmurugan; Ka-Na Xiong; Carla-Maria Alexander; Julie Xiong; Rana Brooks. Epiregulin is required for lung tumor promotion in a murine two-stage carcinogenesis model. Molecular Carcinogenesis 2016, 56, 94 -105.

AMA Style

Alison K. Bauer, Kalpana Velmurugan, Ka-Na Xiong, Carla-Maria Alexander, Julie Xiong, Rana Brooks. Epiregulin is required for lung tumor promotion in a murine two-stage carcinogenesis model. Molecular Carcinogenesis. 2016; 56 (1):94-105.

Chicago/Turabian Style

Alison K. Bauer; Kalpana Velmurugan; Ka-Na Xiong; Carla-Maria Alexander; Julie Xiong; Rana Brooks. 2016. "Epiregulin is required for lung tumor promotion in a murine two-stage carcinogenesis model." Molecular Carcinogenesis 56, no. 1: 94-105.

Journal article
Published: 01 January 2014 in Particle and Fibre Toxicology
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Engineered carbon nanotubes are currently used in many consumer and industrial products such as paints, sunscreens, cosmetics, toiletries, electronic processes and industrial lubricants. Carbon nanotubes are among the more widely used nanoparticles and come in two major commercial forms, single-walled carbon nanotubes (SWCNT) and the more rigid, multi-walled carbon nanotubes (MWCNT). The low density and small size of these particles makes respiratory exposures likely. Many of the potential health hazards have not been investigated, including their potential for carcinogenicity. We, therefore, utilized a two stage initiation/promotion protocol to determine whether inhaled MWCNT act as a complete carcinogen and/or promote the growth of cells with existing DNA damage. Six week old, male, B6C3F1 mice received a single intraperitoneal (ip) injection of either the initiator methylcholanthrene(MCA, 10 μg/g BW, i.p.), or vehicle (corn oil). One week after i.p. injections, mice were exposed by inhalation to MWCNT (5 mg/m3, 5 hours/day, 5 days/week) or filtered air (controls) for a total of 15 days. At 17 months post-exposure, mice were euthanized and examined for lung tumor formation.

ACS Style

Linda M Sargent; Dale W Porter; Lauren M Staska; Ann F Hubbs; David T Lowry; Lori Battelli; Katelyn J Siegrist; Michael L Kashon; Robert R Mercer; Alison K Bauer; Bean T Chen; Jeffrey L Salisbury; David Frazer; Walter McKinney; Michael Andrew; Shuji Tsuruoka; Morinobu Endo; Kara L Fluharty; Vince Castranova; Steven H Reynolds. Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes. Particle and Fibre Toxicology 2014, 11, 3 -3.

AMA Style

Linda M Sargent, Dale W Porter, Lauren M Staska, Ann F Hubbs, David T Lowry, Lori Battelli, Katelyn J Siegrist, Michael L Kashon, Robert R Mercer, Alison K Bauer, Bean T Chen, Jeffrey L Salisbury, David Frazer, Walter McKinney, Michael Andrew, Shuji Tsuruoka, Morinobu Endo, Kara L Fluharty, Vince Castranova, Steven H Reynolds. Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes. Particle and Fibre Toxicology. 2014; 11 (1):3-3.

Chicago/Turabian Style

Linda M Sargent; Dale W Porter; Lauren M Staska; Ann F Hubbs; David T Lowry; Lori Battelli; Katelyn J Siegrist; Michael L Kashon; Robert R Mercer; Alison K Bauer; Bean T Chen; Jeffrey L Salisbury; David Frazer; Walter McKinney; Michael Andrew; Shuji Tsuruoka; Morinobu Endo; Kara L Fluharty; Vince Castranova; Steven H Reynolds. 2014. "Promotion of lung adenocarcinoma following inhalation exposure to multi-walled carbon nanotubes." Particle and Fibre Toxicology 11, no. 1: 3-3.

Research article
Published: 03 June 2013 in PLOS ONE
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Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and occupational toxicants, which are a major human health concern in the U.S. and abroad. Previous research has focused on the genotoxic events caused by high molecular weight PAHs, but not on non-genotoxic events elicited by low molecular weight PAHs. We used an isomeric pair of low molecular weight PAHs, namely 1-Methylanthracene (1-MeA) and 2-Methylanthracene (2-MeA), in which only 1-MeA possessed a bay-like region, and hypothesized that 1-MeA, but not 2-MeA, would affect non-genotoxic endpoints relevant to tumor promotion in murine C10 lung cells, a non-tumorigenic type II alveolar pneumocyte and progenitor cell type of lung adenocarcinoma. The non-genotoxic endpoints assessed were dysregulation of gap junction intercellular communication function and changes in the major pulmonary connexin protein, connexin 43, using fluorescent redistribution and immunoblots, activation of mitogen activated protein kinases (MAPK) using phosphospecific MAPK antibodies for immunoblots, and induction of inflammatory genes using quantitative RT-PCR. 2-MeA had no effect on any of the endpoints, but 1-MeA dysregulated gap junctional communication in a dose and time dependent manner, reduced connexin 43 protein expression, and altered membrane localization. 1-MeA also activated ERK1/2 and p38 MAP kinases. Inflammatory genes, such as cyclooxygenase 2, and chemokine ligand 2 (macrophage chemoattractant 2), were also upregulated in response to 1-MeA only. These results indicate a possible structure-activity relationship of these low molecular weight PAHs relevant to non-genotoxic endpoints of the promoting aspects of cancer. Therefore, our novel findings may improve the ability to predict outcomes for future studies with additional toxicants and mixtures, identify novel targets for biomarkers and chemotherapeutics, and have possible implications for future risk assessment for these PAHs.

ACS Style

Ross S. Osgood; Brad L. Upham; Thomas Hill; Katherine L. Helms; Kalpana Velmurugan; Pavel Babica; Alison K. Bauer. Polycyclic Aromatic Hydrocarbon-Induced Signaling Events Relevant to Inflammation and Tumorigenesis in Lung Cells Are Dependent on Molecular Structure. PLOS ONE 2013, 8, e65150 .

AMA Style

Ross S. Osgood, Brad L. Upham, Thomas Hill, Katherine L. Helms, Kalpana Velmurugan, Pavel Babica, Alison K. Bauer. 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.

Chicago/Turabian Style

Ross S. Osgood; Brad L. Upham; Thomas Hill; Katherine L. Helms; Kalpana Velmurugan; Pavel Babica; Alison K. Bauer. 2013. "Polycyclic Aromatic Hydrocarbon-Induced Signaling Events Relevant to Inflammation and Tumorigenesis in Lung Cells Are Dependent on Molecular Structure." PLOS ONE 8, no. 6: e65150.

Conference paper
Published: 15 April 2013 in Carcinogenesis
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Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants as well as major components of tobacco smoke. Exposure to PAHs represents a significant health concern due to their association with a variety of cancer endpoints. While a majority of research has focused on the ability of the high molecular weight PAHs to act as carcinogens through their ability to bind and adduct DNA, recent evidence suggests that the low molecular weight PAHs, two to four ring compounds, may act through distinct mechanisms to promote, rather than initiate, neoplasia. We evaluated five sidestream smoke PAHs, 1-Methylanthracene (1-MeA) and 2 Methlyanthracene (2-MeA), Phenanthrene (Phe) and Anthracene (A) and Fluoranthene (Flthn) for their ability to (1) inhibit gap junction intercellular communication (GJIC), (2) with a concomitant effect on the gap junction protein Connexin 43 (Cxn43) and (3) to activate mitogen activated protein kinases (MAPK) in murine lung cells. Since both dysregulation of GJIC and activation of MAPK have been previously reported to contribute to tumor promotion, these pathways represent potential mechanistic targets for PAH perturbation. Murine C10 cells (a non-tumorigenic type II alveolar pneumocyte, and progenitor cell type of lung adenocarcinoma) were used to assess the effects of these low molecular weight PAHs on GJIC and MAPKs over a time course of 15 minutes to 4 hours. Detection of MAPKs and Connexin 43 protein was determined by immunoblot, and GJIC was assessed by a scrap-load dye transfer assay. Pathway specific antagonists were used to further elucidate the mechanism by which 1-MeA 2-MeA, Phe, A, and Flthn inhibited GJIC in a dose and time dependent manner while the isomers, 2-MeA and A, did not. With 1-MeA, this inhibition was prevented by blocking either the phosphotidylcholine-phospholipase or p38 pathway, while inhibiting the MAP kinase kinase (MEK) pathway had no effect. Treatment with 1-MeA also activated ERK1/2 and p38 MAP kinases and also decreased the overall amount of Connexin 43, the major lung connexin, in a time-dependent manner. The ability of 1-MeA to both inhibit GJIC as well as activate MAPKs supports a role for low molecular weight tobacco-smoke PAHs to act as tumor promoters in lung cells, and is consistent with previous studies that suggest these compounds may act as tumor promoters in liver cells. The differences observed between 1-MeA and 2-MeA and Phe and A suggests that the ability of low molecular weight PAHs to inhibit GJIC and activate MAPKs is highly dependent on chemical structure. Such structure-activity relationships are often indicative of discrete toxicological mechanisms.

ACS Style

Ross S. Osgood; Thomas Hill; Katherine L. Helms; Pavel Babica; Brad L. Upham; Alison K. Bauer. Abstract 3587: Polycyclic aromatic hydrocarbons exhibit differential tumor promoting properties through mitogen activated protein kinases and inhibition of gap junctions in murine lung cells. Carcinogenesis 2013, 73, 3587 -3587.

AMA Style

Ross S. Osgood, Thomas Hill, Katherine L. Helms, Pavel Babica, Brad L. Upham, Alison K. Bauer. Abstract 3587: Polycyclic aromatic hydrocarbons exhibit differential tumor promoting properties through mitogen activated protein kinases and inhibition of gap junctions in murine lung cells. Carcinogenesis. 2013; 73 ():3587-3587.

Chicago/Turabian Style

Ross S. Osgood; Thomas Hill; Katherine L. Helms; Pavel Babica; Brad L. Upham; Alison K. Bauer. 2013. "Abstract 3587: Polycyclic aromatic hydrocarbons exhibit differential tumor promoting properties through mitogen activated protein kinases and inhibition of gap junctions in murine lung cells." Carcinogenesis 73, no. : 3587-3587.

Conference paper
Published: 15 April 2013 in Carcinogenesis
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ACS Style

Carla-Maria Alexander; Thomas Hill; Ross Osgood; Alison K. Bauer. Abstract 3607: Toll-like receptor (TLR) 4 and innate immune cells are involved in the early stages of murine lung tumor promotion. Carcinogenesis 2013, 1 .

AMA Style

Carla-Maria Alexander, Thomas Hill, Ross Osgood, Alison K. Bauer. Abstract 3607: Toll-like receptor (TLR) 4 and innate immune cells are involved in the early stages of murine lung tumor promotion. Carcinogenesis. 2013; ():1.

Chicago/Turabian Style

Carla-Maria Alexander; Thomas Hill; Ross Osgood; Alison K. Bauer. 2013. "Abstract 3607: Toll-like receptor (TLR) 4 and innate immune cells are involved in the early stages of murine lung tumor promotion." Carcinogenesis , no. : 1.

Conference paper
Published: 15 April 2013 in Carcinogenesis
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ACS Style

Thomas Hill; Carla-Maria Alexander; Alison K. Bauer. Abstract 4801: Bronchoalveolar lavage fluid (BALF) from subchronic exposure to butylated-hydroxytoluene (BHT) inhibits gap junctional communication in a toll-like receptor 4-dependent manner. Carcinogenesis 2013, 1 .

AMA Style

Thomas Hill, Carla-Maria Alexander, Alison K. Bauer. Abstract 4801: Bronchoalveolar lavage fluid (BALF) from subchronic exposure to butylated-hydroxytoluene (BHT) inhibits gap junctional communication in a toll-like receptor 4-dependent manner. Carcinogenesis. 2013; ():1.

Chicago/Turabian Style

Thomas Hill; Carla-Maria Alexander; Alison K. Bauer. 2013. "Abstract 4801: Bronchoalveolar lavage fluid (BALF) from subchronic exposure to butylated-hydroxytoluene (BHT) inhibits gap junctional communication in a toll-like receptor 4-dependent manner." Carcinogenesis , no. : 1.

Review article
Published: 18 March 2013 in Oxidative Medicine and Cellular Longevity
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Nuclear factor, erythroid-derived 2, like 2 (NRF2) is a key regulator of antioxidants and cellular stress responses. The role ofNRF2in pulmonary neoplasia, a diverse disease for which few biomarkers exist, is complicated and appears to depend on several main factors including the existence of activating mutations inNRF2and/or loss of function mutations inKEAP1and the stage of carcinogenesis studied, particularly in the mouse models tested. Therapeutic strategies for lung cancer targetingNRF2have observed mixed results, both anti- and protumorigenic effects; however, these differences seem to reflect the mutation status ofNRF2orKEAP1. In this paper, we will discuss the studies on humanNRF2and the mechanisms proposed, several mouse models using various mice deficient inNRF2, as well as xenograft models, and the chemotherapeutic strategies using theNRF2pathway.

ACS Style

Alison K. Bauer; Thomas Hill; Carla-Maria Alexander. The Involvement ofNRF2in Lung Cancer. Oxidative Medicine and Cellular Longevity 2013, 2013, 1 -10.

AMA Style

Alison K. Bauer, Thomas Hill, Carla-Maria Alexander. The Involvement ofNRF2in Lung Cancer. Oxidative Medicine and Cellular Longevity. 2013; 2013 ():1-10.

Chicago/Turabian Style

Alison K. Bauer; Thomas Hill; Carla-Maria Alexander. 2013. "The Involvement ofNRF2in Lung Cancer." Oxidative Medicine and Cellular Longevity 2013, no. : 1-10.

Validation study
Published: 21 October 2011 in PLOS ONE
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Nrf2 is a key transcription factor that regulates cellular redox and defense responses. However, permanent Nrf2 activation in human lung carcinomas promotes pulmonary malignancy and chemoresistance. We tested the hypothesis that Nrf2 has cell survival properties and lack of Nrf2 suppresses chemically-induced pulmonary neoplasia by treating Nrf2+/+ and Nrf2-/- mice with urethane. Airway inflammation and injury were assessed by bronchoalveolar lavage analyses and histopathology, and lung tumors were analyzed by gross and histologic analysis. We used transcriptomics to assess Nrf2-dependent changes in pulmonary gene transcripts at multiple stages of neoplasia. Lung hyperpermeability, cell death and apoptosis, and inflammatory cell infiltration were significantly higher in Nrf2-/- mice compared to Nrf2+/+ mice 9 and 11 wk after urethane. Significantly fewer lung adenomas were found in Nrf2-/- mice than in Nrf2+/+ mice at 12 and 22 wk. Nrf2 modulated expression of genes involved cell-cell signaling, glutathione metabolism and oxidative stress response, and immune responses during early stage neoplasia. In lung tumors, Nrf2-altered genes had roles in transcriptional regulation of cell cycle and proliferation, carcinogenesis, organismal injury and abnormalities, xenobiotic metabolism, and cell-cell signaling genes. Collectively, Nrf2 deficiency decreased susceptibility to urethane-induced lung tumorigenesis in mice. Cell survival properties of Nrf2 were supported, at least in part, by reduced early death of initiated cells and heightened advantage for tumor cell expansion in Nrf2+/+ mice relative to Nrf2-/- mice. Our results were consistent with the concept that Nrf2 over-activation is an adaptive response of cancer conferring resistance to anti-cancer drugs and promoting malignancy.

ACS Style

Alison K. Bauer; Hye-Youn Cho; Laura Miller-DeGraff; Christopher Walker; Katherine Helms; Jennifer Fostel; Masayuki Yamamoto; Steven R. Kleeberger. Targeted Deletion of Nrf2 Reduces Urethane-Induced Lung Tumor Development in Mice. PLOS ONE 2011, 6, e26590 .

AMA Style

Alison K. Bauer, Hye-Youn Cho, Laura Miller-DeGraff, Christopher Walker, Katherine Helms, Jennifer Fostel, Masayuki Yamamoto, Steven R. Kleeberger. Targeted Deletion of Nrf2 Reduces Urethane-Induced Lung Tumor Development in Mice. PLOS ONE. 2011; 6 (10):e26590.

Chicago/Turabian Style

Alison K. Bauer; Hye-Youn Cho; Laura Miller-DeGraff; Christopher Walker; Katherine Helms; Jennifer Fostel; Masayuki Yamamoto; Steven R. Kleeberger. 2011. "Targeted Deletion of Nrf2 Reduces Urethane-Induced Lung Tumor Development in Mice." PLOS ONE 6, no. 10: e26590.