RGD Reference Report - Knockout of the aryl hydrocarbon receptor results in distinct hepatic and renal phenotypes in rats and mice. - Rat Genome Database

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Knockout of the aryl hydrocarbon receptor results in distinct hepatic and renal phenotypes in rats and mice.

Authors: Harrill, Joshua A  Hukkanen, Renee R  Lawson, Marie  Martin, Greg  Gilger, Brian  Soldatow, Valerie  Lecluyse, Edward L  Budinsky, Robert A  Rowlands, J Craig  Thomas, Russell S 
Citation: Harrill JA, etal., Toxicol Appl Pharmacol. 2013 Oct 15;272(2):503-18. doi: 10.1016/j.taap.2013.06.024. Epub 2013 Jul 13.
RGD ID: 13204753
Pubmed: (View Article at PubMed) PMID:23859880
DOI: Full-text: DOI:10.1016/j.taap.2013.06.024

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.




Phenotype Values via PhenoMiner     Click to see Annotation Detail View
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Strains with Phenominer Data Strains with phenominer data
Hsd:SD SD-Ahrem2Sage

Objects Annotated

Genes (Rattus norvegicus)
Ahr  (aryl hydrocarbon receptor)
Ahrem2Sage  (aryl hydrocarbon receptor; ZFN induced mutant2, Sage)

Strains
Hsd:SD  (Sprague Dawley)
SD-Ahrem2Sage  (NA)


Additional Information