AHR- and DNA-damage-mediated gene expression responses induced by benzo(a)pyrene in human cell lines

Hockley, Sarah L, Arlt, Volker M, Brewer, Daniel, Te Poele, Robert, Workman, Paul, Giddings, Ian and Phillips, David H (2007) AHR- and DNA-damage-mediated gene expression responses induced by benzo(a)pyrene in human cell lines. Chemical Research in Toxicology, 20 (12). pp. 1797-810. ISSN 0893-228X

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Abstract

Carcinogens induce complex transcriptional responses in cells that may hold key mechanistic information. Benzo(a)pyrene (BaP) modulation of transcription may occur through the activation of the aryl hydrocarbon receptor (AHR) or through responses to DNA damage. To characterize further the expression profiles induced by BaP in HepG2 and MCF-7 cells obtained in our previous study, they were compared to those induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which activates AHR but does not bind to DNA, and anti-benzo(a)pyrene- trans-7,8-dihydrodiol-9,10-epoxide (BPDE), which binds directly to DNA but does not activate AHR. A total of 22 genes had altered expression in MCF-7 cells after both BaP and TCDD exposure, and a total of 29 genes had altered expression in HepG2 cells. In both cell lines, xenobiotic metabolism was upregulated through induction of NQO1, MGST1, and CYP1B1. A total of 78 expression changes were induced by both BaP and BPDE in MCF-7 cells, and a total of 29 expression changes were induced by both BaP and BPDE in HepG2 cells. These genes were predominantly involved in cell cycle regulation, apoptosis, and DNA repair. BaP and BPDE caused the repression of histone genes in both cell lines, suggesting that regulation of these genes is an important component of the DNA damage response. Interestingly, overlap of the BPDE and TCDD gene expression profiles was also observed. Furthermore, some genes were modulated by BaP but not by TCDD or BPDE, including induction of CRY1 and MAK, which may represent novel signaling pathways that are independent of both AHR activation and DNA damage. Promoter analysis identified candidate genes for direct transcriptional regulation by either AHR or p53. These analyses have further dissected and characterized the complex cellular response to BaP.

Item Type: Article
Uncontrolled Keywords: benzo(a)pyrene,binding sites,carcinogens, environmental,cell line, tumor,cell survival,cytochrome p-450 cyp1a1,dna adducts,dna damage,gene expression profiling,gene expression regulation,humans,oligonucleotide array sequence analysis,receptors, aryl hydrocarbon,reverse transcriptase polymerase chain reaction,tetrachlorodibenzodioxin,tumor suppressor protein p53
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Pure Connector
Date Deposited: 06 Jan 2014 14:10
Last Modified: 21 Apr 2020 22:43
URI: https://ueaeprints.uea.ac.uk/id/eprint/47042
DOI: 10.1021/tx700252n

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