Adaptative evolution of theVkorc1gene inMus musculus domesticusis influenced by the selective pressure of anticoagulant rodenticides

Abstract

Anticoagulant rodenticides are commonly used to control rodent pests worldwide. They specifically inhibit the vitamin K epoxide reductase (VKORC1), which is an enzyme encoded by the Vkorc1 gene, involved in the recycling of vitamin K. Therefore, they prevent blood clotting. Numerous mutations of Vkorc1 gene were reported in rodents, and some are involved in the resistant to rodenticides phenotype. Two hundred and sixty‐six mice tails were received from 65 different locations in France. Coding sequences of Vkorc1 gene were sequenced in order to detect mutations. Consequences of the observed mutations were evaluated by the use of recombinant VKORC1. More than 70% of mice presented Vkorc1 mutations. Among these mice, 80% were homozygous. Contrary to brown rats for which only one predominant Vkorc1 genotype was found in France, nine missense single mutations and four double mutations were observed in house mice. The single mutations lead to resistance to first‐generation antivitamin K (AVKs) only and are certainly associated with the use of these first‐generation molecules by nonprofessionals for the control of mice populations. The double mutations, probably obtained by genetic recombination, lead to in vitro resistance to all AVKs. They must be regarded as an adaptive evolution to the current use of second‐generation AVKs. The intensive use of first‐generation anticoagulants probably allowed the selection of a high diversity of mutations, which makes possible the genetic recombination and consequently provokes the emergence of the more resistant mutated Vkorc1 described to date.

Low warfarin resistance frequency in Norway rats in two cities in China after 30 years of usage of anticoagulant rodenticides

“…In Europe, SGARs were introduced after about 30 years of FGAR use when FGAR‐associated resistance was well established. This resistance included that conferred by the Tyr139Cys/Phe and Leu128Ser mutations, which are known to provide resistance to both FGARs and bromadiolone . There was a rapid spreading of resistance to some SGAR compounds after the introduction of SGARs in the 1980s .…”

“…This resistance included that conferred by the Tyr139Cys/Phe and Leu128Ser mutations, which are known to provide resistance to both FGARs and bromadiolone. 4,5,9,19,45 There was a rapid spreading of resistance to some SGAR compounds after the introduction of SGARs in the 1980s. 1,46,47 In China, SGARs were widely used with FGARs from the 1990s, although FGAR resistance in Norway rats was not a problem at that time.…”

“…18 In Norway rats, at least 10 Vkorc1 mutations were suggested to be associated with anticoagulant resistance based on in vivo, in vitro and in silico studies. 9,14,15,[19][20][21][22][23][24][25][26] Some Vkorc1 mutations, for example Tyr139Cys/Phe/Ser, have been widely used as genetic markers for screening or monitoring resistant commensal rodent species in Europe. 2,14 However, those genetic markers may not be applicable to rodents in other regions as other resistance Vkorc1 mutations may be present in different local populations.…”

The stereoisomerism of second generation anticoagulant rodenticides: a way to improve this class of molecules to meet the requirements of society?

“…Why were they identified as such? Two major problems are associated with their use, the phenomenon of widespread resistance to some of these molecules in some rodent populations and their ecotoxicity …”

“…It seems therefore necessary to continue this evaluation for the four stereoisomers considered individually and no longer 2 by 2, in rats but also in other rodents whose populations must be controlled, and especially in AR‐resistant rodents. Indeed, mutations of VKORC1 supporting resistance are numerous and very varied between rodent species Systematically, regardless of the SGAR considered, a diastereomeric pair has a half‐life lower than that of the other pair in rats (Table ) .…”