title: Synergism between 2,3,7,8-tetrachlorodibenzo-p-dioxin and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone on lung tumor incidence in mice.
abstract: Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is classified as a human carcinogen, TCDD only induced oxidative DNA damages. In our present study, we combined TCDD with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to investigate their tumorigenic effects on lung tumor formation in A/J mice. Application of NNK at a tumorigenic dose (2 mg/mouse) induced lung adenoma in both male and female A/J mice. Neither application of NNK at a non-tumorigenic dose (1 mg/mouse) nor repeated application of TCDD alone increased tumor incidence. Following the single injection of NNK at a non-tumorigenic dose (1 mg/mouse), repeated application of TCDD significantly increased the lung tumor incidence in female, but not in male, A/J mice 24 weeks later. Utilizing the real-time RT-PCR array, we found that P16 mRNA was significantly reduced in female lung, but not male lung, of NNK/TCDD co-treated A/J mice. With immunohistochemical staining, we confirmed that nuclear P16 protein was reduced in the lungs of NNK/TCDD co-treated female mice. These data suggest that P16 reduction at least partially contributed to synergistic effects of TCDD in lung tumorigenesis.
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Medical College, Tainan, Taiwan.
authors.forename: Ying-Jan
authors.initials: YJ
authors.lastname: Wang
authors.forename: Han
authors.initials: H
authors.lastname: Chang
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Kuo
authors.forename: Chien-Kai
authors.initials: CK
authors.lastname: Wang
authors.forename: Shih-He
authors.initials: SH
authors.lastname: Siao
authors.forename: Louis W
authors.initials: LW
authors.lastname: Chang
authors.forename: Pinpin
authors.initials: P
authors.lastname: Lin
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D005260:Female; D019942:Genes, p16; D007150:Immunohistochemistry; D015994:Incidence; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D051379:Mice; D009602:Nitrosamines / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002273:Carcinogens; D009602:Nitrosamines; D000072317:Polychlorinated Dibenzodioxins; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone