LAUSR

Resistance to anticoagulant rodenticides in Norway rats has been primarily explained by selection on the mutations in the vitamin K epoxide reductase complex subunit 1 (Vkorc1) gene. Whether warfarin resistance can be induced independent of Vkorc1 mutations and its role in the acquirement of warfarin resistance is unclear. In this study, we screened susceptible Norway rats with a sublethal dose of warfarin from the generation F0–F5 and found the warfarin tolerance level of the screened rats was significantly improved. Further, lethal feeding period (LFP) tests indicated 5.7–7.1% of screened rats were resistant, while all unscreened rats were susceptible. Analysis of the Vkorc1 polymorphisms suggested none of the screened F5 rats carried any potential warfarin resistance Vkorc1 mutations. As a fitness cost, the litter size of the screened rats tended to be smaller over generations, implicating the reproductive success could be impacted by warfarin induction. Our findings reveal that susceptible Norway rats can actively acquire inheritable warfarin resistance under constant warfarin induction without changing the Vkorc1 genotype. Further exploration of epigenetic and cryptic genetic mechanisms of warfarin resistance in those resistant rats is essential to fully understand the 'missing' heritability of warfarin resistance.