Time- and concentration-dependent changes in gene expression induced by benzo(a)pyrene in two human cell lines, MCF-7 and HepG2.

2.50
Hdl Handle:
http://hdl.handle.net/10146/25115
Title:
Time- and concentration-dependent changes in gene expression induced by benzo(a)pyrene in two human cell lines, MCF-7 and HepG2.
Authors:
Hockley, Sarah L.; Arlt, Volker M.; Brewer, Daniel; Giddings, Ian; Phillips, David H.
Abstract:
BACKGROUND: The multi-step process of carcinogenesis can be more fully understood by characterizing gene expression changes induced in cells by carcinogens. In this study, expression microarrays were used to monitor the activity of 18,224 cDNA clones in MCF-7 and HepG2 cells exposed to the carcinogen benzo(a)pyrene (BaP) or its non-carcinogenic isomer benzo(e)pyrene (BeP). Time and concentration gene expression effects of BaP exposure have been assessed and linked to other measures of cellular stress to aid in the identification of novel genes/pathways involved in the cellular response to genotoxic carcinogens. RESULTS: BaP (0.25-5.0 muM; 6-48 h exposure) modulated 202 clones in MCF-7 cells and 127 in HepG2 cells, including 27 that were altered in both. In contrast, BeP did not induce consistent gene expression changes at the same concentrations. Significant time- and concentration-dependent responses to BaP were seen in both cell lines. Expression changes observed in both cell lines included genes involved in xenobiotic metabolism (e.g., CYP1B1, NQO1, MGST1, AKR1C1, AKR1C3,CPM), cell cycle regulation (e.g., CDKN1A), apoptosis/anti-apoptosis (e.g., BAX, IER3), chromatin assembly (e.g., histone genes), and oxidative stress response (e.g., TXNRD1). RTqPCR was used to validate microarray data. Phenotypic anchoring of the expression data to DNA adduct levels detected by 32P-postlabelling, cell cycle data and p53 protein expression identified a number of genes that are linked to these biological outcomes, thereby strengthening the identification of target genes. The overall response to BaP consisted of up-regulation of tumour suppressor genes and down-regulation of oncogenes promoting cell cycle arrest and apoptosis. Anti-apoptotic signalling that may increase cell survival and promote tumourigenesis was also evident. CONCLUSION: This study has further characterised the gene expression response of human cells after genotoxic insult, induced after exposure to concentrations of BaP that result in minimal cytotoxicity. We have demonstrated that investigating the time and concentration effect of a carcinogen on gene expression related to other biological end-points gives greater insight into cellular responses to such compounds and strengthens the identification of target genes.
Citation:
BMC Genomics 2006, 7:260
Journal:
BMC Genomics
Issue Date:
2006
URI:
http://hdl.handle.net/10146/25115
DOI:
10.1186/1471-2164-7-260
PubMed ID:
17042939
Additional Links:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17042939; http://www.biomedcentral.com/1471-2164/7/260
Type:
Article
Language:
en
ISSN:
1471-2164
Sponsors:
The authors (SH, VA, DP) are partners of ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5:"Food Quality and Safety" (Contract No. 513943).
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorHockley, Sarah L.-
dc.contributor.authorArlt, Volker M.-
dc.contributor.authorBrewer, Daniel-
dc.contributor.authorGiddings, Ian-
dc.contributor.authorPhillips, David H.-
dc.date.accessioned2008-05-08T11:56:16Z-
dc.date.available2008-05-08T11:56:16Z-
dc.date.issued2006-
dc.identifier.citationBMC Genomics 2006, 7:260en
dc.identifier.issn1471-2164-
dc.identifier.pmid17042939-
dc.identifier.doi10.1186/1471-2164-7-260-
dc.identifier.urihttp://hdl.handle.net/10146/25115-
dc.description.abstractBACKGROUND: The multi-step process of carcinogenesis can be more fully understood by characterizing gene expression changes induced in cells by carcinogens. In this study, expression microarrays were used to monitor the activity of 18,224 cDNA clones in MCF-7 and HepG2 cells exposed to the carcinogen benzo(a)pyrene (BaP) or its non-carcinogenic isomer benzo(e)pyrene (BeP). Time and concentration gene expression effects of BaP exposure have been assessed and linked to other measures of cellular stress to aid in the identification of novel genes/pathways involved in the cellular response to genotoxic carcinogens. RESULTS: BaP (0.25-5.0 muM; 6-48 h exposure) modulated 202 clones in MCF-7 cells and 127 in HepG2 cells, including 27 that were altered in both. In contrast, BeP did not induce consistent gene expression changes at the same concentrations. Significant time- and concentration-dependent responses to BaP were seen in both cell lines. Expression changes observed in both cell lines included genes involved in xenobiotic metabolism (e.g., CYP1B1, NQO1, MGST1, AKR1C1, AKR1C3,CPM), cell cycle regulation (e.g., CDKN1A), apoptosis/anti-apoptosis (e.g., BAX, IER3), chromatin assembly (e.g., histone genes), and oxidative stress response (e.g., TXNRD1). RTqPCR was used to validate microarray data. Phenotypic anchoring of the expression data to DNA adduct levels detected by 32P-postlabelling, cell cycle data and p53 protein expression identified a number of genes that are linked to these biological outcomes, thereby strengthening the identification of target genes. The overall response to BaP consisted of up-regulation of tumour suppressor genes and down-regulation of oncogenes promoting cell cycle arrest and apoptosis. Anti-apoptotic signalling that may increase cell survival and promote tumourigenesis was also evident. CONCLUSION: This study has further characterised the gene expression response of human cells after genotoxic insult, induced after exposure to concentrations of BaP that result in minimal cytotoxicity. We have demonstrated that investigating the time and concentration effect of a carcinogen on gene expression related to other biological end-points gives greater insight into cellular responses to such compounds and strengthens the identification of target genes.en
dc.description.sponsorshipThe authors (SH, VA, DP) are partners of ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5:"Food Quality and Safety" (Contract No. 513943).en
dc.language.isoenen
dc.relation.urlhttp://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17042939en
dc.relation.urlhttp://www.biomedcentral.com/1471-2164/7/260en
dc.subject.meshBenzo(a)pyrene-
dc.subject.meshCell Cycle-
dc.subject.meshCell Line-
dc.subject.meshCell Survival-
dc.subject.meshDNA Adducts-
dc.subject.meshGene Expression-
dc.subject.meshGene Expression Profiling-
dc.subject.meshHumans-
dc.subject.meshPrincipal Component Analysis-
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction-
dc.subject.meshTime Factors-
dc.subject.meshTumor Suppressor Protein p53-
dc.titleTime- and concentration-dependent changes in gene expression induced by benzo(a)pyrene in two human cell lines, MCF-7 and HepG2.en
dc.typeArticleen
dc.identifier.journalBMC Genomicsen

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