Comparison of the metabolic activation of environmental carcinogens in mouse embryonic stem cells and mouse embryonic fibroblasts.

TitleComparison of the metabolic activation of environmental carcinogens in mouse embryonic stem cells and mouse embryonic fibroblasts.
Publication TypeJournal Article
Year of Publication2015
AuthorsKrais AM, Mühlbauer K-R, Kucab JE, Chinbuah H, Cornelius MG, Wei Q-X, Hollstein M, Phillips DH, Arlt VM, Schmeiser HH
JournalToxicol In Vitro
Volume29
Issue1
Pagination34-43
Date Published02/2015
ISSN1879-3177
KeywordsAnimals, Aristolochic Acids, Benz(a)Anthracenes, Benzo(a)pyrene, Blotting, Western, Carcinogens, Environmental, DNA Adducts, DNA Methylation, Embryonic Stem Cells, Fibroblasts, Gene Expression Profiling, Mice, Mice, Inbred C57BL, Real-Time Polymerase Chain Reaction
Abstract

We compared mouse embryonic stem (ES) cells and fibroblasts (MEFs) for their ability to metabolically activate the environmental carcinogens benzo[a]pyrene (BaP), 3-nitrobenzanthrone (3-NBA) and aristolochic acid I (AAI), measuring DNA adduct formation by (32)P-postlabelling and expression of xenobiotic-metabolism genes by quantitative real-time PCR. At 2 μM, BaP induced Cyp1a1 expression in MEFs to a much greater extent than in ES cells and formed 45 times more adducts. Nqo1 mRNA expression was increased by 3-NBA in both cell types but induction was higher in MEFs, as was adduct formation. For AAI, DNA binding was over 450 times higher in MEFs than in ES cells, although Nqo1 and Cyp1a1 transcriptional levels did not explain this difference. We found higher global methylation of DNA in ES cells than in MEFs, which suggests higher chromatin density and lower accessibility of the DNA to DNA damaging agents in ES cells. However, AAI treatment did not alter DNA methylation. Thus mouse ES cells and MEFs have the metabolic competence to activate a number of environmental carcinogens, but MEFs have lower global DNA methylation and higher metabolic capacity than mouse ES cells.

DOI10.1016/j.tiv.2014.09.004
Alternate JournalToxicol In Vitro
PubMed ID25230394
PubMed Central IDPMC4258613
Grant ListC313/A14329 / / Cancer Research UK / United Kingdom
WT101126MA / / Wellcome Trust / United Kingdom