Accelerator Mass Spectrometry in Biomedical Dosimetry: Relationship Between Low-Level Exposure and Covalent Binding of Heterocyclic Amine Carcinogens to DNA

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 87; no. 14; pp. 5288 - 5292
• Main Authors: Turteltaub, K. W., Felton, J. S., Gledhill, B. L., Vogel, J. S., Southon, J. R., Caffee, M. W., Finkel, R. C., Nelson, D. E., Proctor, I. D., Davis, J. C.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.07.1990; National Acad Sciences
• Subjects: 550201 - Biochemistry- Tracer Techniques; ADDUCTS; AMINES; Analytical biochemistry: general aspects, technics, instrumentation; Analytical, structural and metabolic biochemistry; ANIMALS; BACTERIA; BASIC BIOLOGICAL SCIENCES; Biological and medical sciences; BODY; Body weight; CARBON 14 COMPOUNDS; Carbon Radioisotopes; CARCINOGENS; Carcinogens - metabolism; CHRONIC EXPOSURE; DIGESTIVE SYSTEM; Dioxins - metabolism; DNA; DNA - isolation & purification; DNA - metabolism; DNA ADDUCTS; Dosage; Dose-Response Relationship, Drug; DOSE-RESPONSE RELATIONSHIPS; Fundamental and applied biological sciences. Psychology; GLANDS; Isotopes; Kinetics; LABELLED COMPOUNDS; LIVER; Liver - metabolism; Male; MAMMALS; MAN; MASS SPECTROMETERS; Mass Spectrometry - methods; MASS SPECTROSCOPY; MEASURING INSTRUMENTS; MICE; Mice, Inbred C57BL; MICROORGANISMS; Nucleotides; ORGANIC COMPOUNDS; ORGANS; Phosphorus Radioisotopes; Polychlorinated Dibenzodioxins - metabolism; POLYCYCLIC AROMATIC AMINES; PRIMATES; Quinoxalines - metabolism; Radiocarbon; RODENTS; SENSITIVITY; SPECTROMETERS; SPECTROSCOPY; VERTEBRATES; Quinoxaline derivatives; Radiolabelling; Liver; Rodentia; Cytotoxicity; Carcinogen; Vertebrata; Mammalia; Methylosinus trichosporium; Mouse; DNA; Molecular association; Covalent bond; Bacteria; Mass spectrometry; Molecular adduct; Physicochemical properties; Quantitative analysis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.87.14.5288

Accelerator mass spectrometry (AMS) is used to determine the amount of carcinogen covalently bound to mouse liver DNA (DNA adduct) following very low-level exposure to a14C-labeled carcinogen. AMS is a highly sensitive method for counting long-lived but rare cosmogenic isotopes. While AMS is a tool of importance in the earth sciences, it has not been applied in biomedical research. The ability of AMS to assay rare isotope concentrations (10Be,14C,26Al,41Ca, and129I) in microgram amounts suggests that extension to the biomedical sciences is a natural and potentially powerful application of the technology. In this study, the relationship between exposure to low levels of 2-amino-3,8-dimethyl[2-14C]imidazo[4,5-f]quinoxaline and formation of DNA adducts is examined to establish the dynamic range of the technique and the potential sensitivity for biological measurements, as well as to evaluate the relationship between DNA adducts and low-dose carcinogen exposure. Instrument reproducibility in this study is 2%; sensitivity is 1 adduct per 1011nucleotides. Formation of adducts is linearly dependent on dose down to an exposure of 500 ng per kg of body weight. With the present measurements, we demonstrate at least 1 order of magnitude improvement over the best adduct detection sensitivity reported to date and 3-5 orders of magnitude improvement over other methods used for adduct measurement. An additional improvement of 2 orders of magnitude in sensitivity is suggested by preliminary experiments to develop bacterial hosts depleted in radiocarbon. Expanded applications involving human subjects, including clinical applications, are now expected because of the great detection sensitivity and small sample size requirements of AMS.