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Effects of E-Cigarette Aerosols with Varying Levels of Nicotine on Biomarkers of Oxidative Stress and Inflammation in Mice

Sun, Yuan-Wan; Chen, Kun-Ming; Atkins, Hannah; Aliaga, Cesar; Gordon, Terry; Guttenplan, Joseph B; El-Bayoumy, Karam
To provide insights into the cause of e-cigarette (e-cig) associated lung injury, we examined the effects of propylene glycol (PG) and glycerol (G), two common solvent carriers used to deliver nicotine/flavor, on markers of oxidative stress and inflammation in female B6C3F1 mice which had been used successfully in tobacco smoke (TS)-induced lung carcinogenesis. Mice exposed to air and TS were used as negative and positive controls, respectively. Using LC-MS/MS, we showed that PG/G alone, in the absence of nicotine, significantly increased the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG or its tautomer 8-oxodG), a biomarker of DNA oxidative damage, in lung and plasma of mice; moreover, addition of nicotine (12 and 24 mg/mL) in e-cig liquid appears to suppress the levels of 8-oxodG. Exposure to e-cig aerosols or TS induced nonsignificant increases of plasma C-reactive protein (CRP), a biomarker of inflammation; nonetheless, the levels of fibronectin (FN), a biomarker of tissue injury, were significantly increased by e-cig aerosols or TS. Although preliminary, our data showed that exposure to e-cig aerosols induced a higher score of lung injury than did control air or TS exposure. Our results indicate that the B6C3F1 mouse model may be suitable for an in-depth examination of the impact of e-cig on lung injury associated with oxidative stress and inflammation and this study adds to the growing evidence that the use of e-cig can lead to lung damage.
PMID: 33761748
ISSN: 1520-5010
CID: 4855532

Effects of the Tobacco Carcinogens N'-Nitrosonornicotine and Dibenzo[a,l]pyrene Individually and in Combination on DNA Damage in Human Oral Leukoplakia and on Mutagenicity and Mutation Profiles in lacI Mouse Tongue

Guttenplan, Joseph B; Chen, Kun-Ming; Sun, Yuan-Wan; Shalaby, Nora A E; Kosinska, Wieslawa; Desai, Dhimant; Gowda, Krishne; Amin, Shantu; El-Bayoumy, Karam
In previous studies, we showed that the topical application of dibenzo[a,l]pyrene (DB[a,l]P), also known as dibenzo[def,p]chrysene, to the oral cavity of mice induced oral squamous cell carcinoma. We also showed that dA and dG adducts likely account for most of the mutagenic activity of DB[a,l]P in the oral tissues in vivo. Here we report for the first time that the oral treatment of lacI mice with a combination of tobacco smoke carcinogens, DB[a,l]P and N'-nitrosonornicotine (NNN), induces a higher fraction of mutations than expected from a simple sum of their induced individual mutation fractions, and a change in the mutational profile compared with that expected from the sum of the individual agents. The mutational profile of the combination of agents resembled that of the P53 gene in human head and neck cancers more than that of either of the individual agents, in that the percentage of the major class of mutations (GC > AT transitions) is similar to that seen in the P53 gene. A preliminary study was performed to understand the origin of the unexpected mutagenesis observations by measuring specific DNA adducts produced by both NNN and DB[a,l]P in human oral leukoplakia cells. No significant differences in the expected and observed major adduct levels from either agent were observed between individual or combined treatments, suggesting that additional adducts are important in mutagenesis induced by the mixture. Taken together, the above observations support the use of this animal model not only to investigate tobacco smoke-induced oral cancer but also to study chemoprevention.
PMID: 31433626
ISSN: 1520-5010
CID: 4104292

E-cigarette Aerosol Condensate Enhances Metabolism of Benzo(a)pyrene to Genotoxic Products, and Induces CYP1A1 and CYP1B1, Likely by Activation of the Aryl Hydrocarbon Receptor

Sun, Yuan-Wan; Kosinska, Wieslawa; Guttenplan, Joseph B
E-cigarette aerosol contains lower levels of most known carcinogens than tobacco smoke, but many users of e-cigarettes are also smokers, and these individuals may be vulnerable to possible promoting and/or cocarcinogenic effects of e-cigarettes. We investigated the possibility that a condensate of e-cigarette aerosol (EAC) enhances the metabolism of the tobacco carcinogen, benzo(a)pyrene (BaP), to genotoxic products in a human oral keratinocyte cell line. Cells were pretreated with EAC from two popular e-cigs and then with BaP. Metabolism to its ultimate carcinogenic metabolite, anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro B[a]P (BPDE), was assayed by measuring isomers of its spontaneous hydrolysis products, BaP tetrols. The pretreatment of cells with EAC enhanced the rate of BaP tetrol formation several fold. Pretreatment with the e-liquid resulted in a smaller enhancement. The treatment of cells with EAC induced CYP1A1/1B1 mRNA and protein. The enhancement of BaP tetrol formation was inhibited by the aryl hydrocarbon receptor (AhR) inhibitor, α-napthoflavone, indicating EAC likely induces CYP1A1/1B1 and enhances BaP metabolism by activating the AhR. To our knowledge, this is first report demonstrating that e-cigarettes can potentiate the genotoxic effects of a tobacco smoke carcinogen.
PMID: 31373329
ISSN: 1660-4601
CID: 4014822

Effects of Black Raspberry on Dibenzo[a,l]Pyrene Diol Epoxide Induced DNA Adducts, Mutagenesis and Tumorigenesis in the Mouse Oral Cavity

Chen, Kun-Ming; Guttenplan, Joseph B; Sun, Yuan-Wan; Cooper, Timothy; Shalaby, Nora Ae; Kosinska, Wieslawa; Benitez, Gabrielle; Aliaga, Cesar; Zhu, Junjia; Liao, Jason; Gowda, Krishne; Amin, Shantu; Stoner, Gary; El-Bayoumy, Karam
We previously showed that metabolic activation of the environmental and tobacco smoke constituent dibenzo[a,l]pyrene (DB[a,l]P) to its active fjord region diol epoxide (DB[a,l]PDE) is required to induce DNA damage, mutagenesis and squamous cell carcinoma (SCC) in the mouse oral cavity. In contrast to procarcinogens which were employed previously to induce SCC, DB[a,l]PDE does not require metabolic activation to exert its biological effects and thus, this study was initiated to examine, for the first time, whether black raspberry powder (BRB) inhibits post-metabolic processes such as DNA damage, mutagenesis and tumorigenesis. Prior to long-term chemoprevention studies we initially examined the effect of BRB (5% added to AIN-93M diet) on DNA damage in B6C3F1 mice using LC-MS/MS and on mutagenesis in the lacI gene in the mouse oral cavity. We showed that BRB inhibited DB[a,l]PDE-induced DNA damage (p<0.05) and mutagenesis (p=0.053) in the oral cavity. Tumor incidence in the oral cavity (oral mucosa and tongue) of mice fed diet containing 5% BRB was significantly (p<0.05) reduced from 93% to 66%. Specifically the incidence of benign tumor was significantly (p<0.001) reduced from 90% to 31% (62% to 28% in the oral cavity and 28% to 2% in the tongue); a non-significant reduction of malignant tumors from 52% to 45%. Our preclinical findings demonstrate for the first time that the chemopreventive efficacy of BRB can be extended to direct-acting carcinogens that do not require phase I enzymes and is not just limited to procarcinogens.
PMID: 29158340
ISSN: 1940-6215
CID: 2792102

Effects of Black Raspberry Extract and Berry Compounds on Repair of DNA Damage and Mutagenesis Induced by Chemical and Physical Agents in Human Oral Leukoplakia and Rat Oral Fibroblasts

Guttenplan, Joseph B; Chen, Kun-Ming; Sun, Yuan-Wan; Lajara, Braulio; Shalaby, Nora A E; Kosinska, Wieslawa; Benitez, Gabrielle; Gowda, Krishne; Amin, Shantu; Stoner, Gary; El-Bayoumy, Karam
Black raspberries (BRB) have been shown to inhibit carcinogenesis in a number of systems, with most studies focusing on progression. Previously we reported that an anthocyanin-enriched black raspberry extract (BE) enhanced repair of dibenzo-[a,l]-pyrene dihydrodiol (DBP-diol)-induced DNA adducts and inhibited DBP-diol and DBP-diolepoxide (DBPDE)-induced mutagenesis in a lacI rat oral fibroblast cell line, suggesting a role for BRB in the inhibition of initiation of carcinogenesis. Here we extend this work to protection by BE against DNA adduct formation induced by dibenzo-[a,l]-pyrene (DBP) in a human oral leukoplakia cell line (MSK) and to a second carcinogen, UV light. Treatment of MSK cells with DBP and DBPDE led to a dose-dependent increase in DBP-DNA adducts. Treatment of MSK cells with BE after addition of DBP reduced levels of adducts relative to cells treated with DBP alone, and treatment of rat oral fibroblasts with BE after addition of DBPDE inhibited mutagenesis. These observations showed that BE affected repair of DNA adducts and not metabolism of DBP. As a proof of principle we also tested aglycones of two anthocyanins commonly found in berries, delphinidin chloride and pelargonidin chloride. Delphinidin chloride reduced DBP-DNA adduct levels in MSK cells, while PGA did not. These results suggested that certain anthocyanins can enhance repair of bulky DNA adducts. As DBP and its metabolites induced formation of bulky DNA adducts, we investigated the effects of BE on genotoxic effects of a second carcinogen that induces bulky DNA damage, UV light. UV irradiation produced a dose-dependent increase in cyclobutanepyrimidine dimer levels in MSK cells, and post-UV treatment with BE resulted in lower cyclobutanepyrimidine dimer levels. Post-UV treatment of the rat lacI cells with BE reduced UV-induced mutagenesis. Taken together, the results demonstrate that BE extract reduces bulky DNA damage and mutagenesis and support a role for BRB in the inhibition of initiation of carcinogenesis.
PMID: 29068672
ISSN: 1520-5010
CID: 2891202

Carcinogenesis of the Oral Cavity: Environmental Causes and Potential Prevention by Black Raspberry

El-Bayoumy, Karam; Chen, Kun-Ming; Zhang, Shang-Min; Sun, Yuan-Wan; Amin, Shantu; Stoner, Gary; Guttenplan, Joseph B
Worldwide, cancers of the oral cavity and pharynx comprise the sixth most common malignancies. Histologically, more than 90% of oral cancers are squamous cell carcinoma (SCC). Epidemiologic data strongly support the role of exogenous factors such as tobacco, alcohol, and human papilloma virus infection as major causative agents. Avoidance of risk factors has only been partially successful, and survival rates have not improved despite advances in therapeutic approaches. Therefore, new or improved approaches to prevention and/or early detection are critical. Better understanding of the mechanisms of oral carcinogenesis can assist in the development of novel biomarkers for early detection and strategies for disease prevention. Toward this goal, several animal models for carcinogenesis in the oral cavity have been developed. Among these are xenograft, and transgenic animal models, and others employing the synthetic carcinogens such as 7,12-dimethylbenz[a]anthracene in hamster cheek pouch and 4-nitroquinoline-N-oxide in rats and mice. Additional animal models employing environmental carcinogens such as benzo[a]pyrene and N'-nitrosonornicotine have been reported. Each model has certain advantages and disadvantages. Models that (1) utilize environmental carcinogens, (2) reflect tumor heterogeneity, and (3) accurately represent the cellular and molecular changes involved in the initiation and progression of oral cancer in humans could provide a realistic platform. To achieve this goal, we introduced a novel nonsurgical mouse model to study oral carcinogenesis induced by dibenzo[a,l]pyrene (DB[a,l]P), an environmental pollutant and tobacco smoke constituent, and its diol epoxide metabolite (+/-)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene [(+/-)-anti-DB[a,l]PDE]. On the basis of a detailed comparison of oral cancer induced by DB[a,l]P with that induced by the other above-mentioned oral carcinogens with respect to dose, duration, species and strain, cellular and molecular targets, and relative carcinogenic potency, our animal model may offer a more realistic platform to study oral carcinogenesis. In this perspective, we also discuss our preclinical studies to demonstrate the potential of black raspberry extracts on the prevention of OSCC. Specifically, we were the first to demonstrate that black raspberry inhibited DB[a,l]P-DNA binding and of particular importance its capacity to enhance the repair of DB[a,l]P-induced bulky lesions in DNA. We believe that the information presented in this perspective will stimulate further research on the impact of environmental carcinogens in the development of oral cancer and may lead to novel strategies toward the control and prevention of this disease.
PMID: 28092946
ISSN: 1520-5010
CID: 2412142

Effects of black raspberry extract and protocatechuic acid on carcinogen-DNA adducts and mutagenesis, and oxidative stress in rat and human oral cells

Guttenplan, Joseph; Chen, Kun-Ming; Sun, Yuan Wan; Kosinska, Wieslawa; Zhou, Ying; Kim, Seungjin Agatha; Sung, Youngjae; Gowda, Krishne; Amin, Shantu; Stoner, Gary; El-Bayoumy, Karam
Effects of black raspberry (BRB) extract and protocatechuic acid (PCA) on DNA adduct formation and mutagenesis induced by metabolites of dibenzo[,a,l]pyrene (DBP) were investigated in rat oral fibroblasts (OFB). The DBP metabolites, (+)-anti-11,12-dihydroxy -11,12,-dihydrodibenzo[a,l]pyrene (DBP-diol) and 11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DBPDE) induced dose-dependent DNA adducts and mutations. DBPDE was considerably more potent, while the parent compound had no significant effect. Treatment with BRB extract (BRBE) and PCA resulted in reduced DBP-derived DNA adduct levels and reduced mutagenesis induced by DBP-diol, but only BRBE was similarly effective against (DBPDE). BRBE did not directly inactivate DBPDE, but rather induced a cellular response - enhanced DNA repair. When BRBE was added to cells one day after the DBP-diol, the BRBE greatly enhanced removal of DBP-derived DNA adducts. As oxidative stress can contribute to several stages of carcinogenesis, BRBE and PCA were investigated for their abilities to reduce oxidative stress in a human leukoplakia cell line by monitoring the. BRBE effectively inhibited the oxidation of the redox indicator, 2',7'-dichlorodihydrofluorescein diacetate (H2DCF) in cellular and acellular systems. PCA was only minimally effective against H2DCF. These results taken together provide evidence that BRBE and PCA can inhibit initiation of carcinogenesis by polycyclic aromatic hydrocarbons; and in addition, BRBE reduces oxidative stress.
PMID: 27267891
ISSN: 1940-6215
CID: 2136722

Effects of black raspberry extract (BRB) and related compounds on mutagenesis induced by metabolites of the tobacco carcinogen, dibenzo(a,l) pyrene in cultured rat oral fibroblasts; and on oxidative stress in human oral cancer cells [Meeting Abstract]

Guttenplan, Joseph B; Kim, Seungjin; Zhou, Ying; Kosinska, Wieslawa; Golgotiu, Ana-Vera; Amin, Shantu; Stoner, Gary D; Sun, Yuan-Wan; Chen, Kun-Ming; EI-Bayoumy, Karam
ISSN: 1538-7445
CID: 2057022

Comparative transforming effects of ultra low tar (ULT) and full flavor low tar (FFLT) cigarette smoke particulate extracts on human oral epithelial cells [Meeting Abstract]

Han, Tianzhen; Sacks, Peter; Guttenplan, Joseph B
ISSN: 1538-7445
CID: 1598312

Effects of black raspberry extract (BRB) and related compounds on mutagenesis induced by the tobacco carcinogen, dibenzo(a,l)pyrene and its metabolites in cultured rat oral fibroblasts [Meeting Abstract]

Guttenplan, Joseph B; Kosinska, Wieslawa; Han, Tianzhen; Chen, Kun-Ming; Zhang, Shangmin; Gowdahalli, Krishnegowda; Shantu, Amin; Stoner, Gary; El-Bayoumy, Karam
ISSN: 1538-7445
CID: 1598322