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.

挪威大鼠对抗凝血灭鼠剂的耐药性主要是通过选择维生素K环氧还原酶复合物亚基1（Vkorc1）基因的突变来解释的。目前尚不清楚是否可以独立于Vkorc1突变诱导华法林耐药性及其在获得华法林耐药性中的作用。在这项研究中，我们用F0至F5代亚致命剂量的华法林筛选了易感的挪威大鼠，发现所筛选大鼠的华法林耐受性水平得到了显着改善。此外，致命喂养期（LFP）测试表明，有5.7–7.1％的经筛选大鼠具有耐药性，而所有未经筛选的大鼠均易感。Vkorc1的分析多态性提示筛选的F5大鼠均未携带任何潜在的华法林耐药性Vkorc1突变。作为健身费用，被筛选大鼠的产仔数世代趋于变小，暗示华法林的诱导可能影响繁殖成功。我们的发现表明，易感的挪威大鼠在恒定的华法令诱导下可以主动获得可遗传的华法令抗性，而无需改变Vkorc1基因型。对那些抗药性大鼠进一步研究华法林抗性的表观遗传和隐秘遗传机制，对于充分了解华法林抗性的“缺失”遗传力至关重要。