Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5846677 | Toxicology and Applied Pharmacology | 2013 | 16 Pages |
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.
Keywords
DREHCTRBCALTHBSSTCDDCYP1A1EPIMCHARNTKETCBCPLTphosCREAMCHCMCVCYP1B1LyMTBILCaOxCYP1A2cytochrome P450, family 1, subfamily A, polypeptide 1cytochrome P450, family 1, subfamily B, polypeptide 1ZFNURBCAIPTBACHOLALBAHRGGTAHRRLD50HSP90Red blood cellsBAsγ-glutamyl transpeptidaseASTAspartate aminotransferaseAlanine aminotransferaseSerum albuminALPAlkaline phosphataseEosinophilsaryl hydrocarbon receptor nuclear translocatorbasophilsCalcium oxalate crystalsBILItrigTriglyceridesneuMean corpuscular volumeBUNSodiumcomplete blood countEOsPhosphorusLymphocytesLeukocytesmean corpuscular hemoglobinHank's balanced salt solutionComparisonMONMonocytesmedian lethal doseMean corpuscular hemoglobin concentrationNeutrophilswild-typeblood urea nitrogenzinc finger nucleasehematocritHemoglobinUrine specific gravityPotassiumurine protein90-kDa heat shock proteinPlateletsLivercreatinineglobtotal bile acidtotal bilirubinTotal serum proteinChloridecholesterolCalciumKidneyGlucUrine glucoseSerum glucosearyl hydrocarbon receptoraryl hydrocarbon receptor repressor
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Authors
Joshua A. Harrill, Renee R. Hukkanen, Marie Lawson, Greg Martin, Brian Gilger, Valerie Soldatow, Edward L. LeCluyse, Robert A. Budinsky, J. Craig Rowlands, Russell S. Thomas,