TOXICOLOGICAL SCIENCES 111(2), 247–253 (2009)doi:10.1093/toxsci/kfp151Advance Access publication July 13, 2009Effect of Dietary Selenium and Cigarette Smoke on Pulmonary CellProliferation in MiceJun Li,*,† Job C. Tharappel,* Sung Gu Han,‡,§ Austin H. Cantor,§ Eun Y. Lee,{ C. Gary Gairola,‡ and Howard P. Glauert*,‡,1*Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40506; †Health Supervision Institute of Chongqing Municipal HealthBureau, Chongqing, China; ‡Graduate Center for Toxicology; §Department of Animal and Food Sciences; and {Department of Pathology and LaboratoryMedicine, University of Kentucky, Lexington, Kentucky 40506Received May 8, 2009; accepted July 8, 2009The objective of this study was to determine if dietary seleniumcould inhibit pulmonary cell proliferation in control and cigarettesmoke-exposed female A/J mice. Selenium in the form of sodiumselenite was supplemented to purified diets similar to the AIN-93Mdiet to yield 0.15, 0.5, or 2.0 mg selenium/kg diet. After 3 weeks,mice in each dietary group were divided into two subgroups; oneused as control, whereas the other was exposed to cigarette smokefor five consecutive days. Mice from both groups were euthanized3 days later. Mice were administered bromodeoxyuridine in thedrinking water starting 5 days before the initiation of the smokeexposure and continuing until they were euthanized. After eutha-nasia, the left lung lobe was processed for histology and cellproliferation analysis. Cigarette smoke increased cell proliferationin the terminal bronchioles and large airways, but not in alveoli.High-selenium diets inhibited cell proliferation in the alveoli,terminal bronchioles and large airways areas in both control andsmoke-exposed mice. Increasing the dietary selenium level led toincreased selenium levels in the blood and lung, and increasedglutathione peroxidase (GPx) activity in the lung. CytochromeP-450 1A1 protein levels in the lung were increased by cigarettesmoke but were not affected by dietary selenium. It is concludedthat dietary selenium inhibits pulmonary cell proliferation inboth control and cigarette smoke-exposed mice, indicating thatselenium is inhibiting cell proliferation independently of smokeexposure, and that this inhibition may be related to seleniumconcentration and GPx activity in the lung.Key Words: selenium; cigarette; smoke; cell proliferation; lung.Lung cancer is the leading cause of death from cancer inthe United States. The major risk factor for lung cancerdevelopment is cigarette smoking. Tobacco smoke is a complexchemical mixture which has been found to contain approx-imately 4800 different compounds (Hoffmann et al., 2001);approximately 100 of them are known carcinogens, co-carcinogens and/or mutagens. Polycyclic aromatic hydrocar-bons (PAHs) and N-nitrosamines have received most attentionin relation to tobacco carcinogenesis. Many other smokeconstituents like free radicals, aromatic amines, catechols,aldehydes, and inorganics like nickel, chromium, and cadmiummay be equally important, however, because some of these arepresent in smoke at substantially high levels. The presence ofhigh levels of pro-oxidants like free radicals in smoke is welldocumented, and a puff of cigarette smoke is estimated tocontain over 1015free radicals, which are detectable in bothmainstream and sidestream cigarette smoke (Pryor et al., 1983).Steady state reactions in smoke can prolong the half-lives ofmany radicals that continue to generate superoxide anions andother free radicals (Pryor, 1997), thus increasing the oxidativepotential and possibly tumorigenic activity of cigarette smoke.Although the tumorigenicity of cigarette smoke condensateson mouse skin was demonstrated long ago, it has beengenerally difficult to induce respiratory cancers in animals byinhalation exposure to cigarette smoke (Coggins, 1998, 2007).However, Witschi and coworkers (Witschi et al., 1997a, b,2000, 2002) have conclusively demonstrated the carcinoge-nicity of inhaled cigarette smoke in the A/J strain of mice. TheA/J mouse strain used in the smoking model is relatively moresensitive to carcinogens and has been extensively employed toexamine the carcinogenicity of many structurally diversechemicals and to develop chemopreventive interventions forlung tumorigenesis (Stoner, 1991; Stoner et al., 1993).Treatment of these mice with single carcinogens, some knownto be present in tobacco smoke, for example, PAH andN-nitrosamines, has been found to significantly increase thenumber of lung tumors in this strain. These observations andothers have led to the widely held belief that PAH metaboliteslike diolepoxides and tobacco specific N-nitrosamine meta-bolites like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK) are the primary tobacco carcinogens (Hecht, 1999).However, studies of Witschi and coworkers (Witschi et al.,1997a, 1998, 2000) suggest that other smoke constituents mayalso be involved in tobacco carcinogenesis. Two observationsin particular support this contention. First, chemopreventiveagents which inhibited PAH- and NNK-induced lung tumorsin this mouse model were found to be ineffective against1To whom correspondence should be addressed at Graduate Center forNutritional Sciences, 222 Funkhouser Building, University of Kentucky,Lexington, KY 40506-0054. Fax: (859) 323-0061. E-mail: [email protected].Ó The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.For permissions, please email: [email protected] lung tumors (Witschi et al., 1998, 2000).Second, exposure to gas phase of smoke alone, which is largelydevoid of the particulate carcinogens, increased lung tumors inA/J mice to the same extent as whole smoke (Witschi et al.,1997a). More recent studies have implicated a role of othertobacco smoke constituents such as 1,3-butadiene in smoke-induced lung tumorigenesis (Witschi, 2005). Free radicals andother pro-oxidants of tobacco smoke, which induce oxidativestress, can also be expected to play a role in lung tumorigenesis.Overall, these studies demonstrate the utility of Witschi modelfor testing complex mixture like cigarette smoke and forexamining the effects of putative chemopreventive agents.Dietary selenium (Se) has been found to inhibit thedevelopment of several types of cancer in epidemiologicaland experimental studies. The beneficial effect of Se in cancerchemoprevention has
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