title: Comparisons of differential gene expression elicited by TCDD, PCB126, βNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver.
abstract: The aryl hydrocarbon receptor (AhR) is a promiscuous receptor activated by structurally diverse synthetic and natural compounds. AhR activation may lead to ligand-specific changes in gene expression despite similarities in mode of action. Therefore, differential gene expression elicited by four structurally diverse, high affinity AhR ligands (2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 10nM, 30 μg/kg), 3,3',4,4',5-pentachlorobiphenyl (PCB126; 100nM, 300μg/kg), β-naphthoflavone (βNF; 10 μM, 90 mg/kg), and indolo[3,2-b]carbazole (ICZ; 1μM)) in mouse Hepa1c1c7 hepatoma cells and C57BL/6 mouse liver samples were compared. A total of 288, 183, 119, and 131 Hepa1c1c7 genes were differentially expressed (|fold-change|≥ 1.5, P1(t)≥ 0.9999) by TCDD, βNF, PCB126, and ICZ, respectively. Only ∼35% were differentially expressed by all 4 ligands in Hepa1c1c7 cells. In vivo, 661, 479, and 265 hepatic genes were differentially expressed following treatment with TCDD, βNF, and PCB126, respectively. Similar to Hepa1c1c7 cells, ≤ 34% of gene expression changes were common across all ligands. Principal components analysis identified time-dependent gene expression divergence. Comparisons of ligand-elicited expression between Hepa1c1c7 cells and mouse liver identified only 11 common gene expression changes across all ligands. Although metabolism may explain some ligand-specific gene expression changes, PCB126, βNF, and ICZ also elicited divergent expression compared to TCDD, suggestive of selective AhR modulation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA; Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Rance
authors.initials: R
authors.lastname: Nault
authors.forename: Agnes L
authors.initials: AL
authors.lastname: Forgacs
authors.forename: Edward
authors.initials: E
authors.lastname: Dere
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Zacharewski
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000633:toxicity*; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis* / Q000235:genetics; D019324:beta-Naphthoflavone / Q000633:toxicity*
chemical_list: D002227:Carbazoles; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C075954:indolo(3,2-b)carbazole; D019324:beta-Naphthoflavone; D011078:Polychlorinated Biphenyls; C023035:3,4,5,3',4'-pentachlorobiphenyl
keywords: Cross-ligand comparison; Microarray; Mouse; Selective AhR modulation