Open AccessGlucocorticoids modulate multidrug resistance transporters in the first trimester human placenta
Author(s) -
Lye Phetcharawan,
Bloise Enrrico,
Nadeem Lubna,
Gibb William,
Lye Stephen J.,
Matthews Stephen G.
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13646
Subject(s) - syncytiotrophoblast , syncytiotrophoblasts , abcg2 , cytotrophoblast , placenta , biology , endocrinology , trophoblast , medicine , glucocorticoid , fetal membrane , atp binding cassette transporter , transporter , fetus , pregnancy , biochemistry , gene , genetics
Abstract The placental multidrug transporters, P‐glycoprotein (P‐gp, encoded by ABCB 1 ) and breast cancer resistance protein ( BCRP , ABCG 2 ) protect the foetus from exposure to maternally derived glucocorticoids, toxins and xenobiotics. During pregnancy, maternal glucocorticoid levels can be elevated by stress or exogenous administration. We hypothesized that glucocorticoids modulate the expression of ABCB 1 /P‐gp and ABCG 2 / BCRP in the first trimester human placenta. Our objective was to examine whether dexamethasone ( DEX ) or cortisol modulate first trimester placental expression of multidrug transporters and determine whether cytotrophoblasts or the syncytiotrophoblast are/is responsible for mediating these effects. Three models were examined: (i) an ex‐vivo model of placental villous explants (7‐10 weeks), (ii) a model of isolated first trimester syncytiotrophoblast and cytotrophoblast cells and (iii) the BeWo immortalized trophoblast cell line model. These cells/tissues were treated with DEX or cortisol for 24 hour to 72 hour. In first trimester placental explants, DEX (48 hour) increased ABCB 1 ( P < .001) and ABCG 2 ( P < .05) mRNA levels, whereas cortisol (48 hour) only increased ABCB 1 mRNA levels ( P < .01). Dexamethasone ( P < .05) and cortisol ( P < .01) increased BCRP but did not affect P‐gp protein levels. Breast cancer resistance protein expression was primarily confined to syncytiotrophoblasts. BeWo cells, when syncytialized with forskolin, increased expression of BCRP protein, and this was further augmented by DEX ( P < .05). Our data suggest that the protective barrier provided by BCRP increases as cytotrophoblasts fuse to form the syncytiotrophoblast. Increase in glucocorticoid levels during the first trimester may reduce embryo/foetal exposure to clinically relevant BCRP substrates, because of an increase in placental BCRP.