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

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: 2,3,7,8-tetracholorodibenzo-p-dioxin; 90-kDa heat shock protein; AHR; AHR-KO; AIP; ALB; ALP; ALT; ARNT; AST; Ahrr; Aryl hydrocarbon receptor knockout mouse; Aryl hydrocarbon receptor knockout rat; BAS; BILI; BLO; BUN; CA; CAOX; CBC; CHOL; CL; CREA; CYP1A1; CYP1A2; CYP1B1; Comparison; DRE; EOS; EPI; GGT; GLOB; GLUC; HB; HBSS; HCT; HSP90; Hank's Balanced Salt Solution; K; KET; Kidney; LD(50); LEUC; LYM; Liver; MCH; MCHC; MCV; MON; NA; NEU; PHOS; PLT; RBC; SG; TBA; TBIL; TCDD; TP; TPHO; TRIG; Tissue phenotypes; UBIL; UGLU; ULEUC; UPRO; URBC; UWBC; WT; ZFN; alanine aminotransferase; alkaline phosphatase; aryl hydrocarbon receptor; aryl hydrocarbon receptor interacting protein; aryl hydrocarbon receptor knockout; aryl hydrocarbon receptor nuclear translocator; aryl hydrocarbon receptor repressor; aspartate aminotransferase; basophils; blood urea nitrogen; calcium; calcium oxalate crystals; chloride; cholesterol; complete blood count; creatinine; cytochrome P450, family 1, subfamily A, polypeptide 1; cytochrome P450, family 1, subfamily A, polypeptide 2; cytochrome P450, family 1, subfamily B, polypeptide 1; dioxin-response element; eosinophils; hematocrit; hemoglobin; leukocytes; lymphocytes; mean corpuscular hemoglobin; mean corpuscular hemoglobin concentration; mean corpuscular volume; median lethal dose; monocytes; neutrophils; phosphorus; platelets; potassium; red blood cells; serum albumin; serum globulin; serum glucose; sodium; total bile acid; total bilirubin; total serum protein; total white blood cells; triglycerides; triple phosphate crystals; urine bilinogen; urine bilirubin; urine epithelial cells; urine glucose; urine ketones; urine leukocytes; urine occult blood; urine protein; urine red blood cells; urine specific gravity; wild-type; zinc finger nuclease; γ-glutamyl transpeptidase.