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High Frequency of Ras Mutations in Forestomach and Lung Tumors of B6C3F1 Mice Exposed to 1-Amino-2,4-dibromoanthraquinone for 2 Years
Shim-Mo Hayashi
Laboratory of Experimental Pathology National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709, USA
Hue-Hua L. Hong
Laboratory of Experimental Pathology National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709, USA
Kazuhiro Toyoda
Laboratory of Experimental Pathology National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709, USA
Thai-Vu T. Ton
Laboratory of Experimental Pathology National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709, USA
Theodora R. Devereux
Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709, USA
Robert R. Maronpot
Laboratory of Experimental Pathology National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709, USA
James Huff
Laboratory of Experimental Pathology National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709, USA
Robert C. Sills
Laboratory of Experimental Pathology National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709, USA, sills{at}niehs.nih.gov
1-Amino-2,4-dibromoanthraquinone (ADBAQ) is an anthraquinone-derived vat dye, and a potent carcinogen in laboratory animals. In a 2-year study with dietary exposure to 10,000 or 20,000 ppm ADBAQ, increased incidence of forestomach and lung tumors were observed in B6C3F1 mice. The present study indentified genetic alterations in H-ras and K-ras proto-oncogenes in ADBAQ-induced tumors. Point mutations in ras proto-oncogenes were identified by restriction fragment length polymorphism, single-stranded conformational polymorphis m analysis and cycle sequencing of polymerase chain reaction-amplified DNA isolated from paraffin-embedded squamous cell papillomas and carcinomas in the forestomach, and alveolar/bronchiolar adenomas and carcinomas in the lung. A higher frequency of ras mutations was identified in ADBAQ-induced forestomach (23/32, 72%) and lung tumors (16/23, 70%) than in spontaneous forestomach (4/11, 36%) and lung tumors (26/86, 30%). H-ras codon 61 CTA mutations were detected in (4/8, 50%) ADBAQ-induced forestomach squamous cell papillomas and (10/24, 42%) squamous cell carcinomas, but not in the spontaneous forestomach tumors examined. H-ras codon 61 CGA mutation (6/24, 25%) was also detected in ADBAQ-induced forestomach squamous cell carcinomas. K-ras codon 61 A to T transversions and A to G transitions were prominent in ADBAQ-induced lung alveolar/bronchiolar adenomas and alveolar/bronchiolar carcinomas. The major finding of A to T transversions or A to G transitions in forestomach and lung tumors suggests that ADBAQ or its metabolites target adenine bases in the ras proto-oncogene s and that these mutations play a dominant role in multi-organ carcinogenesi s in the B6C3F1 mouse.
Key Words: 1-Amino-2,4-dibromoanthraquinone • forestomach tumor • lung tumor • squamous cell papilloma and carcinoma • alveolar/bronchiolar adenoma and carcinoma • H-ras • K-ras • polymerase chain reaction • restriction fragment length polymorphism • single-stranded conformational polymorphism analysis.
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Toxicologic Pathology, Vol. 29, No. 4,
422-429 (2001)
DOI: 10.1080/01926230152499908
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