title: Comparison of the mutational spectra of the lacZ transgene in four organs of the MutaMouse treated with benzo[a]pyrene: target organ specificity.
abstract: We recently demonstrated that not all organs with a high rate of induction of mutation in the lacZ transgene develop tumors in the lambdalacZ transgenic mice (MutaMouse) used for a long-term carcinogenicity study with benzo[a]pyrene (BP). To better understand the role of chemical-induced in vivo mutations in carcinogenesis, we compared the mutational spectra of the lacZ transgene in four organs of the MutaMouse obtained 2 weeks after five daily consecutive oral treatments with 125 mg/kg/day BP. lacZ transgenes were analyzed in two target organs (forestomach and spleen) and two non-target organs (colon and glandular stomach) for BP-induced carcinogenesis in MutaMouse, and all of these organs were highly mutated in the lacZ transgene. The sequence data showed similar mutational spectra of the lacZ transgene between the two target organs; the predominant mutations were G:C-->T:A transversions (55% and 50% for forestomach and spleen, respectively), followed by deletions (20% and 21% for forestomach and spleen, respectively) mainly at G:C site. The frequent G:C-->T:A transversions are consistent with reports of the mutational spectra produced in the p53 gene in tumors generated in rats and mice exposed to BP. In contrast, the mutational spectra of the lacZ transgene in the two non-target organs are different from those in the target organs, and are also suggested to differ from one another. These findings suggest an organ/tissue-specific mechanism of mutagenesis.
authors.affiliation: Drug Safety Research Laboratories, Eisai, 1, Takehaya-machi, Kawashima-cho, Hashima-gun, Gifu, Japan. a1-hakura@eisai.co.jp
authors.forename: A
authors.initials: A
authors.lastname: Hakura
authors.forename: Y
authors.initials: Y
authors.lastname: Tsutsui
authors.forename: J
authors.initials: J
authors.lastname: Sonoda
authors.forename: K
authors.initials: K
authors.lastname: Tsukidate
authors.forename: T
authors.initials: T
authors.lastname: Mikami
authors.forename: F
authors.initials: F
authors.lastname: Sagami
mesh_terms: D000284:Administration, Oral; D019943:Amino Acid Substitution; D000818:Animals; D001435:Bacteriophages / Q000235:genetics; D001483:Base Sequence; D001564:Benzo(a)pyrene / Q000008:administration & dosage / Q000633:toxicity*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005753:Gastric Mucosa / Q000378:metabolism; D007763:Lac Operon / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D009152:Mutagenicity Tests; D009153:Mutagens / Q000008:administration & dosage / Q000633:toxicity; D009154:Mutation; D017354:Point Mutation; D017384:Sequence Deletion; D013154:Spleen / Q000187:drug effects* / Q000378:metabolism; D013270:Stomach / Q000187:drug effects*; D019076:Transgenes / Q000235:genetics
chemical_list: D009153:Mutagens; D001564:Benzo(a)pyrene; D004247:DNA