PLACENTAL P-GLYCOPROTEIN DEFICIENCY ENHANCES SUSCEPTIBILITY TO CHEMICALLY-INDUCED BIRTH-DEFECTS IN MICE

A subpopulation of the CF-1 mouse strain contains a spontaneous mutati on in the P-glycoprotein (Pgp) mdrla gene, which leads to a lack of md rla expression in the placenta as well as brain and intestine. Individ ual CF-1 mice can be identified according to their Pgp status by a res triction fragment length polymorphism. Male and female mice selected o n the basis of Pgp genotype were mated and the pregnant dams exposed d uring gestation to the known Pgp substrate, L-652,280, the 8,9 Z photo isomer of the naturally occurring avermectin Bla, which is known to pr oduce cleft palate in mice, Fetal examination demonstrated that within individual litters, fetuses deficient in Pgp (-/-) were 100% suscepti ble to cleft palate, whereas their +/- heterozygote littermates were l ess sensitive. The homozygous +/+ fetuses with abundant Pgp were total ly insensitive at the doses tested. The degree of chemical exposure of fetuses within each litter was inversely related to expression of pla cental Pgp, which was determined by the fetal genotype. These results demonstrate the importance of placental Pgp in protecting the fetus fr om potential teratogens and suggest that Pgp inhibitors should be care fully evaluated for their potential to increase susceptibility to chem ical-induced teratogenesis. (C) 1998 Elsevier Science Inc.