Aflatoxin-Guanine DNA Adducts and Oxidatively Induced DNA Damage in Aflatoxin-Treated Mice in Vivo as Measured by Liquid Chromatography-Tandem Mass Spectrometry with Isotope Dilution

Erdem Coskun, Pawel Jaruga, Vladimir Vartanian, Onur Erdem, Patricia A. Egner, John D. Groopman, R. Stephen Lloyd, Miral Dizdaroglu

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Dietary exposure to aflatoxin B 1 (AFB 1 ) is a significant contributor to the incidence of hepatocellular carcinomas globally. AFB 1 exposure leads to the formation of AFB 1 -N 7 -guanine (AFB 1 -N 7 -Gua) and two diastereomers of the imidazole ring-opened 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B 1 (AFB 1 -FapyGua) in DNA. These adducts lead to G → T transversion mutations with the ring-opened adduct being more mutagenic than the cationic species. Accurate measurement of these three adducts as biomarkers in DNA and urine will help identify dietary exposure to AFB 1 as a risk factor in the development of hepatocellular carcinoma worldwide. Herein, we report an improved methodology for the measurement of AFB 1 -N 7 -Gua and the two diastereomers of AFB 1 -FapyGua using liquid chromatography-tandem mass spectrometry with isotope dilution. We measured the levels of these compounds in liver DNA of six control mice and six AFB 1 -treated mice. Levels varying from 1.5 to 45 lesions/10 6 DNA bases in AFB 1 -treated mice were detected depending on the compound and animal. No background levels of these adducts were detected in control mice. We also tested whether the AFB 1 treatment caused oxidatively induced DNA base damage using gas chromatography-tandem mass spectrometry with isotope dilution. Although background levels of several pyrimidine- and purine-derived lesions were detected, no increases in these levels were found upon AFB 1 treatment of mice. On the other hand, significantly increased levels of (5′R)- and (5′S)-8,5′-cyclo-2′-deoxyadenosines were observed in liver DNA of AFB 1 -treated mice. The impact of this work is expected to achieve the accurate measurement of three AFB 1 -DNA adducts and oxidatively induced DNA lesions as biomarkers of AFB 1 exposure as germane to investigations designed for the prevention of aflatoxin-related hepatocellular carcinomas and for determining the effects of genetic deficiencies in human populations.

Original languageEnglish (US)
Pages (from-to)80-89
Number of pages10
JournalChemical Research in Toxicology
Volume32
Issue number1
DOIs
StatePublished - Jan 22 2019

ASJC Scopus subject areas

  • Toxicology

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