title: Glucocorticoid regulation of placental breast cancer resistance protein (Bcrp1) in the mouse.
abstract: Placental breast cancer resistance protein (Bcrp1; encoded by the Abcg2 gene) limits maternal-fetal transplacental transfer of numerous endogenous and exogenous substrates; however, the regulation of placental Abcg2 and Bcrp1 and is not well understood. Placental Abcg2 messenger RNA (mRNA) levels decrease with advancing gestation in the mouse, and this corresponds to increasing levels of maternal and fetal plasma glucocorticoid. Glucocorticoids, including dexamethasone (DEX), downregulate Bcrp1 expression and function in both breast cancer cell lines and the blood-brain barrier in vitro; whether this occurs in the placenta is not known. The potential regulatory role of synthetic glucocorticoids on placental Bcrp1 is of interest, given that approximately 10% of pregnant women are treated with synthetic glucocorticoid for threatened preterm labor. We hypothesized that (1) exposure of pregnant mice to DEX will downregulate placental Abcg2 mRNA and Bcrp1 protein, and (2) results in increased fetal accumulation of [(3)H]mitoxantrone. Pregnant mice were treated with DEX (low-dose: 0.1 mg/kg or high-dose: 1 mg/kg) or vehicle (saline) from embryonic day (E) E9.5 to E15.5 or E12.5 to E18.5. In placentae derived from female fetuses, high-dose DEX significantly downregulated Abcg2 mRNA expression on E15.5 (P < .05) and significantly inhibited Bcrp1 function (P < .05). Similarly, high-dose DEX significantly inhibited Bcrp1 function in the placentae derived from male fetuses (P < .05). In conclusion, there is a dose-dependent regulatory effect of synthetic glucocorticoid on placental Abcg2 mRNA and Bcrp1 function in vivo. Further, it appears that, at the level of Abcg2 gene expression, the female-derived placentae are more susceptible to the effects of DEX than male placentae.
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Sophie
authors: S
authors: Petropoulos
authors: William
authors: W
authors: Gibb
authors: Stephen G
authors: SG
authors: Matthews