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 32P-postlabelling and expression of xenobiotic-metabolism genes by quantitative real-time PCR. At 2μM, 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.
Highlights
The protein p53, encoded by TP53, is a transcription factor that induces cell cycle arrest, apoptosis and DNA repair in response to cellular stress and DNA damage in order to protect the cell from oncogenic transformation, which has led to its description as ‘the guardian of the genome’ (Lane, 1992)
In this study we showed that embryonic stem (ES) cells and mouse embryonic fibroblasts (MEFs) derived from mice on a C57Bl/6 genetic background carrying wild-type Trp53 have the metabolic competence to activate a number of environmental carcinogens
Our results clearly indicate that MEFs have a higher metabolic capacity than ES cells and that the metabolic capacity depends on the carcinogen studied
Summary
The protein p53, encoded by TP53, is a transcription factor that induces cell cycle arrest, apoptosis and DNA repair in response to cellular stress and DNA damage in order to protect the cell from oncogenic transformation, which has led to its description as ‘the guardian of the genome’ (Lane, 1992). Disruption of the normal p53 response by TP53 mutation leads to the development of tumours and as 50% of human tumours contain a mutation in TP53 it is arguably the most important cancer gene (Olivier et al, 2010). ⇑ Corresponding author at: Analytical and Environmental Sciences Division, MRC-. Present address: Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Heidelberg, Germany. Present address: Max-Eder-Junior Research Group Translational Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
