Lankas G R, Wise L D, Cartwright M E, Pippert T, Umbenhauer D R
Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Reprod Toxicol. 1998 Jul-Aug;12(4):457-63. doi: 10.1016/s0890-6238(98)00027-6.
A subpopulation of the CF-1 mouse strain contains a spontaneous mutation in the P-glycoprotein (Pgp) mdr1a gene, which leads to a lack of mdr1a expression in the placenta as well as brain and intestine. Individual CF-1 mice can be identified according to their Pgp status by a restriction fragment length polymorphism. Male and female mice selected on the basis of Pgp genotype were mated and the pregnant dams exposed during gestation to the known Pgp substrate, L-652,280, the 8,9 Z photoisomer of the naturally occurring avermectin Bla, which is known to produce cleft palate in mice. Fetal examination demonstrated that within individual litters, fetuses deficient in Pgp (-/-) were 100% susceptible to cleft palate, whereas their +/- heterozygote littermates were less sensitive. The homozygous +/+ fetuses with abundant Pgp were totally insensitive at the doses tested. The degree of chemical exposure of fetuses within each litter was inversely related to expression of placental Pgp, which was determined by the fetal genotype. These results demonstrate the importance of placental Pgp in protecting the fetus from potential teratogens and suggest that Pgp inhibitors should be carefully evaluated for their potential to increase susceptibility to chemical-induced teratogenesis.
CF-1小鼠品系的一个亚群在P-糖蛋白（Pgp）mdr1a基因中存在自发突变，这导致胎盘、脑和肠道中缺乏mdr1a表达。可以通过限制性片段长度多态性根据其Pgp状态鉴定个体CF-1小鼠。根据Pgp基因型选择的雄性和雌性小鼠进行交配，怀孕的母鼠在妊娠期暴露于已知的Pgp底物L-652,280，即天然存在的阿维菌素B1a的8,9 Z光异构体，已知其可在小鼠中产生腭裂。胎儿检查表明，在单个窝中，缺乏Pgp（-/-）的胎儿对腭裂100%敏感，而其+/-杂合子同窝仔鼠敏感性较低。具有丰富Pgp的纯合子+/+胎儿在测试剂量下完全不敏感。每个窝中胎儿的化学暴露程度与胎盘Pgp的表达呈负相关，胎盘Pgp的表达由胎儿基因型决定。这些结果证明了胎盘Pgp在保护胎儿免受潜在致畸剂影响方面的重要性，并表明应仔细评估Pgp抑制剂增加化学诱导致畸易感性的潜力。
