Proceedings of the Korean Society of Toxicology Conference (한국독성학회:학술대회논문집)

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Tumorigenicity of benzo(a)pyrene and benzo(a)pyrene diol epoxides in v-Ha-ras transgenic TG-AC mice

  • Lee Byung Mu (Division of Toxicology, College of Pharmacy, Sungkyunkwan University) ;
  • Germolec Dori (National Institute of Environmental Health Sciences, Lab. of Immunology(D.G.), Lab, of Pharmmacology(K.H.J), Lab. of Environmental Carcinogenesis and Mutagenesis,(R.W.T)) ;
  • Jeohn Kwang-Ho (National Institute of Environmental Health Sciences, Lab. of Immunology(D.G.), Lab, of Pharmmacology(K.H.J), Lab. of Environmental Carcinogenesis and Mutagenesis,(R.W.T)) ;
  • Tennant Raymond W, (National Institute of Environmental Health Sciences, Lab. of Immunology(D.G.), Lab, of Pharmmacology(K.H.J), Lab. of Environmental Carcinogenesis and Mutagenesis,(R.W.T))
  • Published : 1998.10.01
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Abstract

Tumorigenicity of benzo(a)pyrene (BP) and benzo(a)pyrene diol epoxides ((+)BPDE-1, (-)BPDE-1) was investigated in transgenic TG-AC mice carrying v-Ha-ras oncogene fused to the promoter of the mouse embryonic a-like, z-globin gene. Animals were topically treated twice per week for 25weeks with BPDE (10$\mu$g/mouse) and BP (10, 20, 40$\mu$g/mouse). In addition, animals were treated with BPDE or BP (initiated) followed by TPA (2$\times$2.5$\mu$g/week, for 4 weeks) for promotion study. In the continuous treatment of BPDE or BP, animals treated with 40$\mu$g BP showed $100\%$ tumor response after 20 weeks, $40\%$ of mice for 20$\mu$g BP, and $20\%$ for (+)BPDE-1, but (-)BPDE-1 and 10$\mu$g BP did not show any tumor response. After 25 weeks, most tumors turned out to be carcinomas in animals treated with 40$\mu$g BP. In BPDE or BP/TPA Initiation-promotion study, papilloma response occurred earlier (6 weeks after TPA treatment) than in continuously treated animals with BPDE or BP. RT-PCR assay for transgene expression showed that BP or BPOE was not transgene dependent in its tumorigenicity, but TPA was. Several Cytokine genes(TGF-a, TNF-a) and c-myc gene expressions were monitored in skin tissues during BP carcinogenesis. In early stage of BP treatment, the gene expressions were elevated(c-myc,TGF-a) or unchanged(TNF-a) compared to control, but the levels were gradually decreased during both middle and late stages of cacinogenesis, Gene expression levels of skin papillomas in acetone initiated-TPA promoted animals were close to those of middle stage or between middle and late stages. i-NOS was also highly expressed in carcinoma and papilloma, These data suggest that transgene expressions of TG-AC mice were not dependent on BP carcinogenesis and that TG-AC mice were more sensitive to TPA regardless of types of initiators. In addition, genes(TGF-a, c-myc, TNF-a, i-NOS) were modulated in the skin during BP cacinogenesis or TPA promotion.

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