Bile acids and ursodeoxycholic acid alter gene expression in primary myometrial cells

Abstract

Abstract Intrahepatic cholestasis of pregnancy (ICP), characterised by elevated maternal serum bile acids (BAs), increases risk of preterm labour that may be mitigated by ursodeoxycholic acid (UDCA) treatment. How different BA species, including UDCA, affect myometrial function remains imperfectly understood. Primary human myometrial cells were isolated from women with uncomplicated pregnancy and treated with taurocholic acid (TCA, 150µmol/l), tauro-UDCA (TUDCA, 150µmol/l) or both TCA and TUDCA (75µmol/l each); some were stimulated oxytocin (10nmol/l, 6 h). Gene expression was determined using real-time quantitative PCR, and IL-6 protein in supernatant using ELISA. TCA increased OXTR mRNA expression after 4, 10, 18 and 24 h. Following overnight BA pre-treatment, 6-hour combined treatment with TCA and TUDCA led to highest OXTR ( p < 0.01 vs. control) and increased oxytocin-induced COX-2 ( p < 0.05) and IL-6 mRNA ( p = 0.06) expression. IL-6 protein was increased by TCA but not TUDCA. This indicates elevated BAs in maternal serum may alter expression of oxytocin-responsive genes by upregulating OXTR expression. Combined exposure to high TCA and TUDCA increased expression of OXTR , COX-2 and IL-6 , but not IL-6 protein, while TUDCA alone had no effect. Altered OXTR expression and downstream gene expression changes may contribute to ICP-associated myometrial contractility and preterm birth risk, meriting further study.