Microarray analysis of gene regulation in the Hepa1c1c7 cell line following exposure to the DNA methylation inhibitor 5-aza-2′-deoxycytidine and 2,3,7,8-tetrachlorodibenzo-p-dioxin

Jin, Bum Ja; Kim, Gyongsun; Park, Duk Woong; Ryu, Doug-Young

doi:10.1016/j.tiv.2004.02.006

Cited by 15 publications

(7 citation statements)

References 22 publications

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“…In vivo and in vitro studies examining TCDD-elicited global gene expression have demonstrated that AhR targets a limited portion of the genome [10-12,19-23]. In addition, PWM-based computational searches identified a low percentage of orthologs with conserved putative functional DREs within their regulatory regions (10kb upstream of the TSS and the 5'UTR) [17,18].…”

Section: Discussionmentioning

confidence: 99%

Differences in TCDD-elicited gene expression profiles in human HepG2, mouse Hepa1c1c7 and rat H4IIE hepatoma cells

et al. 2011

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Background2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant that elicits a broad spectrum of toxic effects in a species-specific manner. Current risk assessment practices routinely extrapolate results from in vivo and in vitro rodent models to assess human risk. In order to further investigate the species-specific responses elicited by TCDD, temporal gene expression responses in human HepG2, mouse Hepa1c1c7 and rat H4IIE cells were compared.ResultsMicroarray analysis identified a core set of conserved gene expression responses across species consistent with the role of AhR in mediating adaptive metabolic responses. However, significant species-specific as well as species-divergent responses were identified. Computational analysis of the regulatory regions of species-specific and -divergent responses suggests that dioxin response elements (DREs) are involved. These results are consistent with in vivo rat vs. mouse species-specific differential gene expression, and more comprehensive comparative DRE searches.ConclusionsComparative analysis of human HepG2, mouse Hepa1c1c7 and rat H4IIE TCDD-elicited gene expression responses is consistent with in vivo rat-mouse comparative gene expression studies, and more comprehensive comparative DRE searches, suggesting that AhR-mediated gene expression is species-specific.

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Section: Discussionmentioning

confidence: 99%

Differences in TCDD-elicited gene expression profiles in human HepG2, mouse Hepa1c1c7 and rat H4IIE hepatoma cells

et al. 2011

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“…Microarrays have been used to identify global gene expression changes induced by TCDD in a variety of vertebrate cell types (Puga et al, 2000b;Frueh et al, 2001;Martinez et al, 2002;Fisher et al, 2004;Jin et al, 2004;Vezina et al, 2004;Hanlon et al, 2005). A recent study identified TCDD-induced gene expression changes in whole zebrafish embryos after a 3-day exposure to TCDD, a point at which cardiac toxicity is strongly manifested (Handley-Goldstone et al, 2005).…”

mentioning

confidence: 99%

Aryl Hydrocarbon Receptor Activation Produces Heart-Specific Transcriptional and Toxic Responses in Developing Zebrafish

Carney¹,

Chen²,

Burns³

et al. 2006

Mol Pharmacol

154

166

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Proper regulation of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, is required for normal vertebrate cardiovascular development. AHR hyperactivation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during zebrafish (Danio rerio) development results in altered heart morphology and function, culminating in death. To identify genes that may cause cardiac toxicity, we analyzed the transcriptional response to TCDD in zebrafish hearts. Zebrafish larvae were exposed to TCDD for 1 h at 72 h after fertilization (hpf), and the hearts were extracted for microarray analysis at 1, 2, 4, and 12 h after exposure (73, 74, 76, and 84 h postfertilization). The remaining body tissue was also collected at each time for comparison. TCDD rapidly induced expression in 42 genes within 1 to 2 h of exposure. These genes function in xenobiotic metabolism, proliferation, heart contractility, and pathways that regulate heart development. Furthermore, these expression changes preceded signs of cardiovascular toxicity, characterized by decreased stroke volume, peripheral blood flow, and a halt in heart growth. This identifies strong candidates for important AHR target genes. It is noteworthy that the TCDDinduced transcriptional response in the hearts of zebrafish larvae was substantially different from that induced in the rest of the body tissues. One of the biggest differences included a cluster of genes that were down-regulated 12 h after exposure in heart tissue, but not in the body samples. More than 70% of the transcripts in this heart-specific cluster promote cellular growth and proliferation. Thus, the developing heart stands out as being responsive to TCDD at both the level of toxicity and gene expression.

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“…We previously provided evidence that the AhR is partially activated by ligands present in the medium in Hepa-1 cells cultured in the absence of added ligand (Wang et al 2004). To our knowledge, the other genes we identified have not been reported to be induced by TCDD (Jin et al 2004, Boverhof et al 2005, Boverhof et al 2006, Dere E et al 2006, Yoon et al 2006). They therefore may represent novel target genes of unliganded AhR.…”

Section: Discussionmentioning

confidence: 89%

The Effect of Aromatic Hydrocarbon Receptor on the Phenotype of the Hepa 1c1c7 Murine Hepatoma Cells in the Absence of Dioxin

Wang

Zhang

Shi

et al. 2007

Gene�Regul Syst Bio

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Abstract:The aromatic hydrocarbon receptor (AhR) mediates biological responses to certain exogenous ligands, such as the environmental contaminant 2, 3,7,, and has also been demonstrated to modulate the cell cycle and differentiated state of several cell lines independently of exogenous ligands. In this study, we used DNA micorarray analysis to elucidate the profi le of genes responsive to the expression of unliganded AhR by re-introducing AhR into an AhR-defi cient mouse derivative (c19) of the mouse hepatoma cell line Hepa1c1c7. 22 gene products were up-regulated and 8 were down-regulated two-fold or more in c19 cells infected with a retroviral vector expressing mouse AhR. Surprisingly, expression of genes involved in cell proliferation or differentiation were not affected by introduction of AhR. AhR also did not restore expression of the albumin gene in c19 cells. Introduction of AhR into c12, a similar AhRdefective mouse hepatoma cell line, also did not restore albumin expression, and furthermore, did not lead to changes in cellular morphology or cell cycle parameters. These observations fail to support the notion that unliganded AhR regulates proliferation and differentiation of liver-derived cells.

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Microarray analysis of gene regulation in the Hepa1c1c7 cell line following exposure to the DNA methylation inhibitor 5-aza-2′-deoxycytidine and 2,3,7,8-tetrachlorodibenzo-p-dioxin

Cited by 15 publications

References 22 publications

Differences in TCDD-elicited gene expression profiles in human HepG2, mouse Hepa1c1c7 and rat H4IIE hepatoma cells

Differences in TCDD-elicited gene expression profiles in human HepG2, mouse Hepa1c1c7 and rat H4IIE hepatoma cells

Aryl Hydrocarbon Receptor Activation Produces Heart-Specific Transcriptional and Toxic Responses in Developing Zebrafish

The Effect of Aromatic Hydrocarbon Receptor on the Phenotype of the Hepa 1c1c7 Murine Hepatoma Cells in the Absence of Dioxin

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