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

In this study, we generated 2 lines of Nrf2 knockout rats by using a genome editing technology; 1 line harbors a 7-bp deletion (7) 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.
Source: Toxicological Sciences - Category: Toxicology Authors: Tags: Nrf2 Knockout Rats and Aflatoxin Toxicity Source Type: research