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Knockout of the aryl hydrocarbon receptor results in distinct hepatic and renal phenotypes in rats and mice.
- Source :
-
Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2013 Oct 15; Vol. 272 (2), pp. 503-18. Date of Electronic Publication: 2013 Jul 13. - Publication Year :
- 2013
-
Abstract
- The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor which plays a role in the development of multiple tissues and is activated by a large number of ligands, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In order to examine the roles of the AHR in both normal biological development and response to environmental chemicals, an AHR knockout (AHR-KO) rat model was created and compared with an existing AHR-KO mouse. AHR-KO rats harboring either 2-bp or 29-bp deletion mutation in exon 2 of the AHR were created on the Sprague-Dawley genetic background using zinc-finger nuclease (ZFN) technology. Rats harboring either mutation type lacked expression of AHR protein in the liver. AHR-KO rats were also insensitive to thymic involution, increased hepatic weight and the induction of AHR-responsive genes (Cyp1a1, Cyp1a2, Cyp1b1, Ahrr) following acute exposure to 25 μg/kg TCDD. AHR-KO rats had lower basal expression of transcripts for these genes and also accumulated ~30-45-fold less TCDD in the liver at 7 days post-exposure. In untreated animals, AHR-KO mice, but not AHR-KO rats, had alterations in serum analytes indicative of compromised hepatic function, patent ductus venosus of the liver and persistent hyaloid arteries in the eye. AHR-KO rats, but not AHR-KO mice, displayed pathological alterations to the urinary tract: bilateral renal dilation (hydronephrosis), secondary medullary tubular and uroepithelial degenerative changes and bilateral ureter dilation (hydroureter). The present data indicate that the AHR may play significantly different roles in tissue development and homeostasis and toxicity across rodent species.<br /> (© 2013 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Gene Knockdown Techniques
Kidney metabolism
Kidney pathology
Liver metabolism
Liver pathology
Mice
Mice, Knockout
Organ Size genetics
Phenotype
Rats
Rats, Sprague-Dawley
Species Specificity
Gene Deletion
Kidney drug effects
Liver drug effects
Polychlorinated Dibenzodioxins toxicity
Receptors, Aryl Hydrocarbon genetics
Receptors, Aryl Hydrocarbon metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0333
- Volume :
- 272
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Toxicology and applied pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 23859880
- Full Text :
- https://doi.org/10.1016/j.taap.2013.06.024