Breast cancer-resistance protein (BCRP1), encoded by Abcg2 mRNA, limits the penetration of a spectrum of compounds into the brain. The fetal brain is a primary target for many BCRP1 substrates; however, the developmental expression, function, and regulation of Abcg2/BCRP1 in the mouse fetal brain are unknown. Synthetic glucocorticoids (e.g., dexamethasone [DEX]) increase Abcg2/BCRP1 expression and function in vitro in endothelial cells derived from brain microvessels. A regulatory role of glucocorticoids on Abcg2/BCRP1 in the fetal brain is of importance given that approximately 10% of pregnant women are treated with synthetic glucocorticoid for threatened preterm labor. We hypothesized the following: 1) Abcg2 mRNA and BCRP1 protein expression increases with development (from Embryonic Day [E] 15.5 to E18.5), corresponding to decreased accumulation of BCRP1 substrate in the fetal brain. 2) Maternal treatment with DEX will up-regulate Abcg2 mRNA and BCRP1 protein expression in the fetal brain, resulting in decreased BCRP1 substrate accumulation. Pregnant FVB dams were euthanized on E15.5 or E18.5, and fetal brains were collected and analyzed for [3H]mitoxantrone (BCRP1-specific substrate) accumulation and Abcg2/BCRP1 expression. In another six groups (n = 4–5/group), pregnant mice were treated with DEX (0.1 or 1 mg/kg) or vehicle (saline) from either E9.5 to E15.5 (midgestation) or E12.5 to E18.5 (late gestation) and then injected with [3H]mitoxantrone. In conclusion, Abcg2 mRNA expression significantly decreases with advancing gestation, while BCRP1-mediated neuroprotection increases. Furthermore, there is a dose-, sex-, and age-dependent effect of DEX on Abcg2 mRNA in the fetal brain in vivo, indicating a complex regulatory role of glucocorticoid during development.
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Vol. 84 • No. 4