10.1021/tx700252n.s003
Sarah L. Hockley
Sarah L.
Hockley
Volker M. Arlt
Volker M.
Arlt
Daniel Brewer
Daniel
Brewer
Robert te Poele
Robert te
Poele
Paul Workman
Paul
Workman
Ian Giddings
Ian
Giddings
David H. Phillips
David H.
Phillips
AHR- and DNA-Damage-Mediated Gene Expression Responses Induced by Benzo(<i>a</i>)pyrene in Human Cell Lines
American Chemical Society
2007
Human Cell LinesCarcinogens
NQO
aryl hydrocarbon receptor
BPDE
BaP
AHR
MAK
cell lines
cell cycle regulation
TCDD gene expression profiles
29 expression changes
1B
HepG 2 cells
DNA damage
DNA damage response
CYP
78 expression changes
MGST
MCF
2007-12-17 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/AHR_and_DNA_Damage_Mediated_Gene_Expression_Responses_Induced_by_Benzo_i_a_i_pyrene_in_Human_Cell_Lines/2968684
Carcinogens induce complex transcriptional responses in cells that may hold key mechanistic information. Benzo(<i>a</i>)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-<i>p</i>-dioxin (TCDD), which activates AHR but does not bind to DNA, and <i>anti</i>-benzo(<i>a</i>)pyrene-<i>trans</i>-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 <i>NQO1</i>, <i>MGST1</i>, and <i>CYP1B1</i>. 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 <i>CRY1</i> and <i>MAK</i>, 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.