title: Generation of a New Model Rat: Nrf2 Knockout Rats Are Sensitive to Aflatoxin B1 Toxicity.
abstract: THE TRANSCRIPTION FACTOR NRF2: (NF-E2-related-factor 2) REGULATES A BATTERY OF ANTIOXIDATIVE STRESS-RESPONSE GENES AND DETOXICATION GENES, AND NRF2 KNOCKOUT LINES OF MICE HAVE BEEN CONTRIBUTING CRITICALLY TO THE CLARIFICATION OF ROLES THAT NRF2 PLAYS FOR CELL PROTECTION HOWEVER, THERE ARE APPARENT LIMITATIONS IN USE OF THE MOUSE MODELS FOR INSTANCE, RATS EXHIBIT MORE SUITABLE FEATURES FOR TOXICOLOGICAL OR PHYSIOLOGICAL EXAMINATIONS THAN MICE IN THIS STUDY, WE GENERATED 2 LINES OF NRF2 KNOCKOUT RATS BY USING A GENOME EDITING TECHNOLOGY; 1 LINE HARBORS A 7-BP DELETION Δ7 AND THE OTHER LINE HARBORS A 1-BP INSERTION +1 IN THE NRF2 GENE IN THE LIVERS OF RATS HOMOZYGOUSLY DELETING THE NRF2 GENE, AN ACTIVATOR OF NRF2 SIGNALING, CDDO-IM, COULD NOT INDUCE EXPRESSION OF REPRESENTATIVE NRF2 TARGET GENES TO EXAMINE ALTERED TOXICOLOGICAL RESPONSE, WE TREATED THE NRF2 KNOCKOUT RATS WITH AFLATOXIN B1 AFB1, A CARCINOGENIC MYCOTOXIN THAT ELICITS GENE MUTATIONS THROUGH BINDING OF ITS METABOLITES TO DNA AND FOR WHICH THE RAT HAS BEEN PROPOSED AS A REASONABLE SURROGATE FOR HUMAN TOXICITY INDEED, IN THE NRF2 KNOCKOUT RAT LIVERS THE ENZYMES OF THE AFB1 DETOXICATION PATHWAY WERE SIGNIFICANTLY DOWNREGULATED SINGLE DOSE ADMINISTRATION OF AFB1 INCREASED HEPATOTOXICITY AND BINDING OF AFB1-N7-GUANINE TO HEPATIC DNA IN NRF2 KNOCKOUT RATS COMPARED WITH WILD-TYPE NRF2 KNOCKOUT RATS REPEATEDLY TREATED WITH AFB1 WERE PRONE TO LETHALITY AND CDDO-IM WAS NO LONGER PROTECTIVE THESE RESULTS DEMONSTRATE THAT NRF2 KNOCKOUT RATS ARE QUITE SENSITIVE TO AFB1 TOXICITIES AND THIS RAT GENOTYPE EMERGES AS A NEW MODEL ANIMAL IN TOXICOLOGY.
authors.affiliation: *Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Aoba, Sendai 980-8575, Japan;
authors.forename: Keiko
authors.initials: K
authors.lastname: Taguchi
authors.affiliation: *Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Aoba, Sendai 980-8575, Japan;
authors.forename: Misaki
authors.initials: M
authors.lastname: Takaku
authors.affiliation: Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland 21205;
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Egner
authors.affiliation: *Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Aoba, Sendai 980-8575, Japan;
authors.forename: Masanobu
authors.initials: M
authors.lastname: Morita
authors.affiliation: Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Takehito
authors.initials: T
authors.lastname: Kaneko
authors.affiliation: Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Tomoji
authors.initials: T
authors.lastname: Mashimo
authors.affiliation: Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland 21205; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.affiliation: *Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Aoba, Sendai 980-8575, Japan; masiyamamoto@med.tohoku.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D016604:Aflatoxin B1; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D018736:DNA Adducts / Q000378:metabolism; D004195:Disease Models, Animal; D000072669:Gene Editing / Q000379:methods; D020869:Gene Expression Profiling / Q000379:methods; D020022:Genetic Predisposition to Disease; D007093:Imidazoles / Q000494:pharmacology; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011916:Rats, Inbred F344; D055647:Rats, Transgenic
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D018736:DNA Adducts; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C495637:Nfe2l2 protein, rat; D009828:Oleanolic Acid; D016604:Aflatoxin B1
keywords: Nrf2; aflatoxin; hepatotoxicity.; knockout rat