Breast cancer resistance protein (Bcrp1/Abcg2) in mouse placenta and yolk sac: ontogeny and its regulation by progesterone.
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.
Kalabis
G M
GM
Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
Petropoulos
S
S
Gibb
W
W
Matthews
S G
SG
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D005260:Female; D051379:Mice; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011374:Progesterone / Q000097:blood / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D015017:Yolk Sac / Q000187:drug effects / Q000378:metabolism*
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D012333:RNA, Messenger; D011374:Progesterone