title: The constitutively active Ah receptor (CA-Ahr) mouse as a potential model for dioxin exposure--effects in vital organs.
abstract: The dioxin/aryl hydrocarbon receptor (AhR) mediates most, if not all, toxic effects of dioxins and functions as a ligand-activated transcription factor regulating transcription of a battery of genes. In order to study the mechanisms behind the toxicity of ligands of the Ah receptor we have created a transgenic mouse model expressing a constitutively active Ah receptor (CA-AhR). The mutant Ah receptor is expressed and functionally active in all organs studied. The purpose of the present study was to characterize histopathologically, the phenotype of the CA-AhR with regard to the liver, kidney, lung, heart, spleen and thymus of male and female transgenic CA-AhR mice. Moreover, cell-specific activity of the CA-AhR using up-regulation of the AhR target gene CYP1A1 as a marker, was also examined. The relative weight of liver, kidney and heart were increased while relative thymus weight was decreased. Furthermore, slight morphological lesions of the liver, kidney and spleen was seen. Expression of CYP1A1 was found in cells corresponding to endothelial cells in all of the organs studied. In some tissues additional cell types, such as hepatocytes, renal tubuli cell and Clara cells expressed CYP1A1. Both the effects on organ weights and the cellular expression of CYP1A1 in CA-AhR mice correspond well to observations in TCDD-exposed mice. In conclusion, this characterization further support that the CA-AhR mouse is a useful model for life-long continuous low-level activity of the AhR, i.e. the dioxin exposure situation of humans of the general population.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Nobels väg 13, Solna, Stockholm, Sweden. sara.brunnberg@ki.se
authors.forename: Sara
authors.initials: S
authors.lastname: Brunnberg
authors.forename: Patrik
authors.initials: P
authors.lastname: Andersson
authors.forename: Maria
authors.initials: M
authors.lastname: Lindstam
authors.forename: Ivar
authors.initials: I
authors.lastname: Paulson
authors.forename: Lorenz
authors.initials: L
authors.lastname: Poellinger
authors.forename: Annika
authors.initials: A
authors.lastname: Hanberg
mesh_terms: D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D004147:Dioxins / Q000633:toxicity*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D006321:Heart / Q000187:drug effects; D006529:Hepatomegaly / Q000235:genetics / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015431:Weight Loss / Q000187:drug effects
chemical_list: D004147:Dioxins; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1