Oral ivermectin as an unexpected initiator of CreT2-mediated deletion in T cells

Hidden away in plain sight in Nature Immunology is a disturbing little correspondence that anyone who is using tamoxifen-inducible Cre transgenes in mice should be aware of. It is a report of an unintended and as yet unexplained consequence of treating mice for pinworm or fur mites with the common, broad-spectrum anti-helmintic drug, ivermectin. The consequence is no less than the mimicry of the effect of tamoxifen on the excision of floxed alleles in the complete absence of tamoxifen. To make matters worse, mice treated with ivermectin continue to wreak experimental havoc by producing offspring with excised floxed alleles long after treatment has been stopped (>15 weeks!).

The work reported raises many questions, but what has been demonstrated is that 1) the excision of floxed alleles occurs in preweaning mice whose mothers are treated with ivermectin; 2) the mothers continue to have affected offspring for up to 15 weeks after treatment is stopped; 3) excision takes place in preweaned mice carrying both a floxed allele and a ubiquitin CreT2 transgene although adult mice of the same genotype are not affected; 4) different floxed alleles behave the same way; 5) not all mice are affected and not all tissues are affected.

There are major outstanding questions about mechanism and some missing experimental details that could be important. It should be noted that only the UBC-CreT2 transgene was tested, although independent colonies of mice with this transgene (presumably independent insertion sites) behaved the same way. The effect is somewhat sporadic, although there is not enough information to determine whether there is tissue specificity or varying tissue susceptibility. Even with this uncertainty, what is abundantly clear is that standard procedures for dealing with pinworm and fur mites can cause serious disruptions to research using floxed alleles. Learning about this phenomenon may result in more than one “Ah ha!” moment by explaining previously mysterious excision of conditional alleles.