Kalabis G M, Petropoulos S, Gibb W, Matthews S G
Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
Placenta. 2007 Oct;28(10):1073-81. doi: 10.1016/j.placenta.2007.03.010. Epub 2007 May 24.
Breast Cancer Resistance Protein (BCRP), a recently-discovered transporter belonging to ABC superfamily, is highly expressed within the labyrinth of the placenta, the primary site of exchange between the maternal and fetal circulation. It has been proposed to function as an efflux pump protecting the fetus from a wide range of xenobiotics. It has also been recently shown that the yolk sac, in addition to the placenta, may be involved in transport of certain substances to and from the fetus. We hypothesised that there are changes in placental Bcrp1 (the mouse orthologue of human BCRP) expression during pregnancy and that these correlate with changes in progesterone production that occur in late gestation. We also hypothesised that Bcrp1 is expressed in the yolk sac, and that levels change with advancing gestation. Either whole concepti, or placenta and yolk sac, were collected from pregnant mice and analysed at embryonic (E) day 9.5, 12.5, 15.5 and 18.5 (term approximately E19.5). Peak expression of Bcrp1 mRNA was detected using in situ hybridisation within the placenta at E9.5 and the yolk sac at E12.5. There was a significant decrease thereafter in both tissues (p<0.001). In contrast, expression of Bcrp1 protein as assessed by immunohistochemistry and Western immunoblots did not change significantly during gestation either in the placenta nor the yolk sac, and no sex difference in Bcrp1 protein expression in either tissue was observed at E12.5. Daily progesterone treatment starting at E14.5 and continuing until E18.5 significantly increased maternal progesterone levels, but did not elicit any changes in the Bcrp1 mRNA or Bcrp1 protein expression either in the placenta or the yolk sac. Significant expression of Bcrp1 protein in fetal tissue was evident at the end of gestation, while expression in the fetal brain endothelium was evident as early as E12.5. We suggest that the placenta and the yolk sac, both of which express Bcrp1, may limit fetal exposure to the potentially adverse effects of xenobiotics including therapeutic drugs which the mother may be exposed to during pregnancy. The significant decrease in Bcrp1 mRNA expression in both the yolk sac and the placenta from mid to late gestation may be counter-balanced by an increase in Bcrp1 expression in fetal organs involved in absorption, excretion and protection.
乳腺癌耐药蛋白（BCRP）是最近发现的一种属于ABC超家族的转运蛋白，在胎盘的迷路中高度表达，胎盘是母胎循环之间进行物质交换的主要部位。有人提出它作为一种外排泵，可保护胎儿免受多种外源性物质的影响。最近还发现，除胎盘外，卵黄囊也可能参与某些物质在胎儿与母体之间的运输。我们推测，孕期胎盘Bcrp1（人类BCRP的小鼠同源物）表达会发生变化，且这些变化与妊娠后期孕酮分泌的变化相关。我们还推测，Bcrp1在卵黄囊中表达，且其水平会随着妊娠进展而变化。从怀孕小鼠收集整个胚胎，或胎盘和卵黄囊，在胚胎（E）第9.5、12.5、15.5和18.5天（足月约为E19.5）进行分析。通过原位杂交在E9.5的胎盘和E12.5的卵黄囊中检测到Bcrp1 mRNA的峰值表达。此后，两个组织中的表达均显著下降（p<0.001）。相比之下，通过免疫组织化学和Western免疫印迹评估的Bcrp1蛋白表达在孕期胎盘和卵黄囊中均未发生显著变化，在E12.5时，两个组织中均未观察到Bcrp1蛋白表达的性别差异。从E14.5开始并持续至E18.5的每日孕酮治疗显著提高了母体孕酮水平，但未引起胎盘或卵黄囊中Bcrp1 mRNA或Bcrp1蛋白表达的任何变化。妊娠末期胎儿组织中Bcrp1蛋白有明显表达，而在胎儿脑内皮中早在E12.5时就有明显表达。我们认为，胎盘和卵黄囊均表达Bcrp1，可能会限制胎儿接触外源性物质（包括母亲在孕期可能接触到的治疗药物）的潜在不利影响。从妊娠中期到晚期，卵黄囊和胎盘中Bcrp1 mRNA表达的显著下降可能会被参与吸收、排泄和保护的胎儿器官中Bcrp1表达的增加所抵消。
