Generation of a New Model Rat: Nrf2 Knockout Rats Are Sensitive to Aflatoxin B1 Toxicity

Area of Science:

• Toxicology
• Genetics
• Molecular Biology

Background:

• The transcription factor NRF2 (NF-E2-related-factor 2) is crucial for regulating antioxidant and detoxification genes.
• NRF2 knockout mouse models have aided in understanding its cell-protective roles, but limitations exist for toxicological applications.
• Rats offer potentially more suitable physiological and toxicological examination features compared to mice.

Purpose of the Study:

• To generate and characterize NRF2 knockout rat models using genome editing technology.
• To investigate the toxicological response of these NRF2 knockout rats to aflatoxin B1 (AFB1).
• To establish a novel rat model for toxicology research.

Main Methods:

• Generated two lines of NRF2 knockout rats (a 7-bp deletion (Δ7) and a 1-bp insertion (+1)) via genome editing.
• Administered the NRF2 activator CDDO-IM to confirm the absence of target gene induction in knockout rats.
• Treated NRF2 knockout and wild-type rats with aflatoxin B1 (AFB1) to assess toxicity and DNA adduct formation.

Main Results:

• Homozygous NRF2 knockout rats showed no induction of NRF2 target genes upon CDDO-IM administration.
• AFB1 detoxification pathway enzymes were significantly downregulated in NRF2 knockout rat livers.
• Single-dose AFB1 increased hepatotoxicity and DNA adducts in NRF2 knockout rats compared to wild-type.
• Repeated AFB1 treatment led to increased lethality and loss of CDDO-IM protection in knockout rats.

Conclusions:

• NRF2 knockout rats exhibit heightened sensitivity to AFB1 toxicity.
• The generated NRF2 knockout rat genotype serves as a valuable new animal model in toxicology.
• This model provides enhanced insights into NRF2-mediated protection against mycotoxin-induced toxicity.