Date of Award

2016

Degree Type

Thesis

Degree Name

Master of Science in Pharmaceutical Sciences

Specialization

Pharmacology and Toxicology

Department

Biomedical and Pharmaceutical Sciences

First Advisor

Ruitang Deng

Abstract

The association between serum bile acid levels and preterm birth has been reported. Clinical studies have shown that significant increase of serum bile acids during intrahepatic cholestasis of pregnancy (ICP) is associated with higher rate of preterm birth. However, the role of bile acids in preterm birth has not been established. In this study, we found that preterm birth was induced in mice by increasing plasma bile acids with cholic acid (CA) or carbon tetrachloride (CCl4) treatment. CCl4 treatment increased plasma bile acids by causing acute liver injury which down-regulated bile salt export pump (BSEP) in the liver. The data demonstrated that increased bile acid levels served as trigger for preterm birth. Consistent with the findings, reducing plasma bile acids by cholestyramine (CTM) was able to reverse the preterm birth induced by CA by decreasing plasma bile acid levels.

Mechanistic investigation revealed that preterm delivery induced by elevated bile acids was mediated by prostaglandins and prostaglandin receptor expressions. An increase in prostaglandin F2α receptor (PTGFR) and a decrease in 15-hydroxyprostaglandin dehydrogenase (HPGD) and prostaglandin E2 receptor (PTGER2), all of which participate in normal parturition, was observed. More importantly, the expression change in PTGFR was reversed with CTM treatment, suggesting that prostaglandin F (PGF)/PTGFR signaling pathways are involved in mediating preterm birth induced by bile acids. Further studies showed an inverse correlation between plasma progesterone (P4) levels and PTGFR expression, which is consistent with significant P4 withdrawal and elevation of PTGFR before delivery in human.

In conclusion, we established the causative relationship of maternal bile acid levels and preterm delivery. The results from this study provide a molecular basis for new strategies to prevent preterm birth in pregnant women with ICP or other liver diseases by modulating bile acid homeostasis as well as the PGF/PTGFR signaling pathways.

Available for download on Saturday, June 02, 2018

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