The overall objective of this project is the development and application of analytical methods for the detection of human pulmonary exposure to active metabolites of mutagenic and carcinogenic polycyclic aromatic hydrocarbons, including benzo[a]pyrene, cyclopental[cd]pyrene, fluoranthene, and other prominent mutagens discovered by this program project. DNA and histone adducts of the PAH will be determined in three types of human lung tissue:surgically derived bulk tissue, bronchial epithelial cells obtained by brush biopsy, and anatomically dissected whole lungs. Histone adducts will be assayed by cryogenic fluorescence line narrowing spectrometry and gas chromatography-mass spectrometry. DNA adducts will be assayed by a newly developed 35S-post labelling technique. The results will be compared with enzyme activities, mutational spectra, and localization of specific mutations determined by the other projects to develop an understanding of the role that chemical carcinogen adducts play in the development of human lung cancer.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Program Projects (P01)
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Zheng, Weiming; Khrapko, Konstantin; Coller, Hilary A et al. (2006) Origins of human mitochondrial point mutations as DNA polymerase gamma-mediated errors. Mutat Res 599:11-20
Coller, Hilary A; Khrapko, Konstantin; Herrero-Jimenez, Pablo et al. (2005) Clustering of mutant mitochondrial DNA copies suggests stem cells are common in human bronchial epithelium. Mutat Res 578:256-71
Pedersen, Daniel U; Durant, John L; Taghizadeh, Koli et al. (2005) Human cell mutagens in respirable airborne particles from the northeastern United States. 2. Quantification of mutagens and other organic compounds. Environ Sci Technol 39:9547-60
Pedersen, Daniel U; Durant, John L; Penman, Bruce W et al. (2004) Human-cell mutagens in respirable airborne particles in the northeastern United States. 1. Mutagenicity of fractionated samples. Environ Sci Technol 38:682-9
Tomita-Mitchell, Aoy; Ling, Losee Lucy; Glover, Curtis L et al. (2003) The mutational spectrum of the HPRT gene from human T cells in vivo shares a significant concordant set of hot spots with MNNG-treated human cells. Cancer Res 63:5793-8
Luo, Wen; Gurjuar, Rajan; Ozbal, Can et al. (2003) Quantitative detection of benzo[alpha]pyrene diolepoxide-DNA adducts by cryogenic laser induced fluorescence. Chem Res Toxicol 16:74-80
Kim, Andrea S; Thilly, William G (2003) Ligation of high-melting-temperature 'clamp' sequence extends the scanning range of rare point-mutational analysis by constant denaturant capillary electrophoresis (CDCE) to most of the human genome. Nucleic Acids Res 31:e97
Muniappan, Brindha P; Thilly, William G (2002) The DNA polymerase beta replication error spectrum in the adenomatous polyposis coli gene contains human colon tumor mutational hotspots. Cancer Res 62:3271-5
Kim, Andrea S; Holmquist, Gerald P; Thilly, William G (2002) High-efficiency DNA ligation for clamp attachment without polymerase chain reaction. Anal Biochem 310:179-85
Zheng, Weiming; Marcelino, Luisa A; Thilly, William G (2002) Scanning low-frequency point mutants in the mitochondrial genome using constant denaturant capillary electrophoresis. Methods Mol Biol 197:93-106

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