title: Gene expression analysis in the lung of the rasH2 transgenic mouse at week 4 prior to induction of malignant tumor formation by urethane and N-methylolacrylamide.
abstract: The rasH2 transgenic (Tg) mice are susceptible to genotoxic and some non-genotoxic carcinogens. In carcinogenicity studies carried out using rasH2 Tg mice, the carcinogenic potential of chemicals are evaluated over a 26-week experimental period. In the present study, we examined the comprehensive gene expressions in the lungs of Tg and non-Tg mice prior to the induction of malignant tumors. Urethane (UR), a mutagenic carcinogen, was administered for 4 weeks, and thereafter withdrawn for 22 weeks. N-methylolacrylamide (NMA), a non-mutagenic carcinogen, was administered for 26 weeks. At week 4, gene expression analysis of non-neoplastic part of the lungs demonstrated changes in the expressions of the cell-cycle and inflammation related genes following UR and NMA treatment, respectively, in both the Tg and non-Tg mice. The gene expressions of epireguline, aurora kinase B, and cyclin B1 increased in the UR-treated Tg mice. We also found an increase in the plasma carcinoembryonic antigen level in the UR-treated Tg mice. Although UR treatment induced the formation of adenomas or adenocarcinomas in the lungs in all mice, earlier induction was apparent in the Tg mice. NMA treatment was found to induce the formation of adenomas and adenocarcinomas at week 26 in the Tg mice, but not in the non-Tg mice, and no expressions of specific genes were apparent in either genotype of mice. Our results indicate that analysis of cancer-related gene expressions in the lungs and plasma biomarkers at week 4 in rasH2 Tg mice could be a screening tool for carcinogenicity, especially of mutagenic carcinogens.
authors.affiliation: Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tsuji
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kuwahara
authors.forename: Hironori
authors.initials: H
authors.lastname: Takagi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sugiura
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakanishi
authors.forename: Masaki
authors.initials: M
authors.lastname: Wakamatsu
authors.forename: Katsuki
authors.initials: K
authors.lastname: Tsuritani
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sato
mesh_terms: D000178:Acrylamides / Q000633:toxicity*; D000230:Adenocarcinoma / Q000139:chemically induced* / Q000235:genetics*; D000236:Adenoma / Q000139:chemically induced* / Q000235:genetics*; D000818:Animals; D064107:Aurora Kinase B / Q000235:genetics; D014408:Biomarkers, Tumor / Q000097:blood; D002272:Carcinoembryonic Antigen / Q000097:blood; D002273:Carcinogens / Q000633:toxicity*; D002453:Cell Cycle / Q000235:genetics; D056744:Cyclin B1 / Q000235:genetics; D015870:Gene Expression / Q000235:genetics*; D007249:Inflammation / Q000235:genetics; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D014520:Urethane
chemical_list: D000178:Acrylamides; D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen; D002273:Carcinogens; C534700:Ccnb1 protein, mouse; D056744:Cyclin B1; D014520:Urethane; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; C066443:N-methylolacrylamide