Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Brazil.
FASEB J. 2022 Apr;36(4):e22245. doi: 10.1096/fj.202101552RR.
Antenatal synthetic glucocorticoids (sGCs) are a life-saving treatment in managing pre-term birth. However, off-target effects of sGCs can impact blood-brain barrier (BBB) drug transporters essential for fetal brain protection, including P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (BCRP/Abcg2). We hypothesized that maternal antenatal sGC treatment modifies BBB function in juvenile offspring in a sex-dependent manner. Thus, the objective of this study was to determine the long-term impact of a single or multiple courses of betamethasone on P-gp/Abcb1 and BCRP/Abcg2 expression and function at the BBB. Pregnant guinea pigs (N = 42) received 3 courses (gestation days (GDs) 40, 50, and 60) or a single course (GD50) of betamethasone (1 mg/kg) or vehicle (saline). Cerebral microvessels and brain endothelial cells (BEC) were collected from the post-natal day (PND) 14 offspring to measure protein, gene expression, and function of the drug transporters P-gp/Abcb1 and BCRP/Abcg2. P-gp protein expression was decreased (p < .05) in microvessels from male offspring that had been exposed to multiple courses and a single course of sGC, in utero. Multiple courses of sGC resulted in a significant decrease in P-gp function in BECs from males (p < .05), but not females. There was a very strong trend for increased P-gp function in males compared to females (p = .055). Reduced P-gp expression and function at the BBB of young male offspring following multiple prenatal sGC exposures, is clinically relevant as many drugs administered postnatally are P-gp substrates. These novel sex differences in drug transporter function may underlie potential sexual dimorphism in drug sensitivity and toxicity in the newborn and juvenile brain.
产前合成糖皮质激素（sGCs）是治疗早产的救命治疗方法。然而，sGCs 的脱靶效应会影响血脑屏障（BBB）中对胎儿大脑保护至关重要的药物转运体，包括 P-糖蛋白（P-gp/Abcb1）和乳腺癌耐药蛋白（BCRP/Abcg2）。我们假设，母体产前 sGC 治疗以性别依赖的方式改变幼仔的 BBB 功能。因此，本研究的目的是确定单次或多次倍他米松治疗对 BBB 中 P-gp/Abcb1 和 BCRP/Abcg2 表达和功能的长期影响。将怀孕的豚鼠（N=42）分为 3 组（妊娠第 40、50 和 60 天）或单次组（妊娠第 50 天）接受倍他米松（1mg/kg）或载体（生理盐水）处理。从产后第 14 天（PND14）的后代中收集脑微血管和脑内皮细胞（BEC），以测量药物转运体 P-gp/Abcb1 和 BCRP/Abcg2 的蛋白、基因表达和功能。暴露于单次和多次 sGC 宫内的雄性后代的微血管中 P-gp 蛋白表达降低（p<0.05）。多次 sGC 导致雄性 BEC 中 P-gp 功能显著降低（p<0.05），但雌性则没有。与雌性相比，雄性的 P-gp 功能明显增强（p=0.055），这是一个很强的趋势。与多次产前 sGC 暴露后年轻雄性后代的 BBB 中 P-gp 表达和功能降低相关，这在临床上是相关的，因为许多新生儿期后给予的药物都是 P-gp 底物。这些药物转运体功能的新的性别差异可能是新生儿和幼仔大脑中药物敏感性和毒性潜在性别二态性的基础。
