title: Aryl hydrocarbon receptor polymorphism modulates DMBA-induced inflammation and carcinogenesis in phenotypically selected mice.
abstract: We tested the role of aryl hydrocarbon receptor (Ahr) gene polymorphism in the inflammatory response and in skin and lung tumorigenesis in 2 lines of mice phenotypically selected for maximum or minimum acute inflammatory reaction (AIRmax and AIRmin, respectively). Following 7,12-dimethylbenz[a]anthracene (DMBA) treatment, AIRmin but not AIRmax mice showed early skin reactions and eventually developed malignant skin tumors and lung adenocarcinomas. In skin tissue, transcript levels of IL1beta, Tnf, Il6, Tgfbeta1 and Cyp1b1 genes were upregulated in AIRmin but not AIRmax mice, consistent with the inflammatory responses to the carcinogen. These findings appeared to be related to the homozygosity status of the Ahr functional A375V polymorphism, which influences the binding capability of the receptor for DMBA: the 375A allele, encoding the high-affinity ligand-binding receptor (Ahr(b1)), segregated in AIRmin mice, whereas AIRmax mice carried the 375V, corresponding to the low-affinity binding receptor (Ahr(d)), to DMBA. The differential segregation of Ahr functional Ahr(d)versus Ahr(b1) alleles in AIRmax and AIRmin suggests a role for the Ahr gene in the control of inflammatory responsiveness and tumor development of these mouse lines.
authors.affiliation: Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.
authors.forename: Vinicius R C
authors.initials: VR
authors.lastname: De Souza
authors.forename: Wafa K
authors.initials: WK
authors.lastname: Cabrera
authors.forename: Antonella
authors.initials: A
authors.lastname: Galvan
authors.forename: Orlando G
authors.initials: OG
authors.lastname: Ribeiro
authors.forename: Marcelo
authors.initials: M
authors.lastname: De Franco
authors.forename: Francisca
authors.initials: F
authors.lastname: Vorraro
authors.forename: Nancy
authors.initials: N
authors.lastname: Starobinas
authors.forename: Solange
authors.initials: S
authors.lastname: Massa
authors.forename: Tommaso A
authors.initials: TA
authors.lastname: Dragani
authors.forename: Olga M
authors.initials: OM
authors.lastname: Ibañez
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D017931:DNA Primers; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics*; D007371:Interferon-gamma / Q000235:genetics; D020382:Interleukin-18 / Q000235:genetics; D007378:Interleukins / Q000235:genetics; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D010641:Phenotype; D011110:Polymorphism, Genetic; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics; D015854:Up-Regulation
chemical_list: D002273:Carcinogens; D017931:DNA Primers; D020382:Interleukin-18; D007378:Interleukins; D018336:Receptors, Aryl Hydrocarbon; D015127:9,10-Dimethyl-1,2-benzanthracene; D007371:Interferon-gamma; D019363:Cytochrome P-450 CYP1A1