title: Aryl hydrocarbon receptor-dependence of dioxin's effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components.
abstract: The aryl hydrocarbon receptor (AHR) has physiological roles in the absence of exposure to exogenous ligands, and mediates adaptive and toxic responses to the environmental pollutant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD). A readily metabolized AHR agonist, 3-methylcholanthrene, disrupts the expression of mouse hepatic growth hormone (GH) signaling components and suppresses cytochrome P450 2D9 (Cyp2d9), a male-specific gene controlled by pulsatile GH via signal transducer and activator of transcription 5b (STAT5b). Using TCDD as an essentially nonmetabolized AHR agonist, and Ahr (-/-) mice as the preferred model to determine the AHR-dependence of biological responses, we now show that 2 mouse hepatic STAT5b target genes, Cyp2d9, and major urinary protein 2 (Mup2), are suppressed by TCDD in an AHR-dependent manner. TCDD also decreased hepatic mRNA levels for GH receptor, Janus kinase 2, and STAT5a/b with AHR-dependence. Without inducing selected hepatic inflammatory markers, TCDD caused AHR-dependent induction of Cyp1a1 and NADPH-cytochrome P450 oxidoreductase (Por) and suppression of Cyp3a11. In vehicle-treated mice, basal mRNA levels for CYP2D9, CYP3A11, POR, serum amyloid protein P, and MUP2 were influenced by Ahr genetic status. We conclude that AHR activation per se leads to dysregulation of hepatic GH signaling components and suppression of some, but not all, STAT5b target genes.
authors.affiliation: Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Chunja
authors.initials: C
authors.lastname: Lee
authors.forename: David S
authors.initials: DS
authors.lastname: Riddick
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D015536:Down-Regulation / Q000187:drug effects; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009251:NADPH-Ferrihemoprotein Reductase / Q000096:biosynthesis / Q000235:genetics; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000072467:Cytochrome P450 Family 2; D004785:Environmental Pollutants; D053614:Janus Kinase 2; D008565:Membrane Proteins; D009251:NADPH-Ferrihemoprotein Reductase; D000072317:Polychlorinated Dibenzodioxins; D011506:Proteins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; C484722:Ahr protein, mouse; C494096:Stat5b protein, mouse; C035737:major urinary proteins; C504575:CYP2D9 protein, mouse; C496508:Cyp3a11 protein, mouse; C507926:Jak2 protein, mouse