Fetal glucocorticoid exposure leads to sex‐specific changes in drug‐transporter function at the blood‐brain barrier in juvenile guinea pigs

Abstract

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.