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Title page for ETD etd-07152010-141308


Type of Document Dissertation
Author Sun, Xiaofei
URN etd-07152010-141308
Title Studying the role of endocannabinoid signaling in reproduction
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Richard M. Breyer Committee Chair
David L. Hachey Committee Member
Lawrence J. Marnett Committee Member
Sanjoy K. Das Committee Member
Sudhansu K. Dey Committee Member
Keywords
  • Placentation
  • Uterus
  • Endocannabinoids
  • Testis
  • Reproduction
Date of Defense 2010-07-12
Availability unrestricted
Abstract
Marijuana is the most commonly used illicit drug, and its major active component, Δ9-tetrahydrocannabinol (Δ9-THC) exert its functions by targeting cannabinoid receptors, CNR1 and CNR2. There receptors are also targeted by endocannabinoids, including anandamide.

In this dissertation, we show that genetic loss of Faah, which encodes fatty acid amide hydrolase (FAAH), results in elevated levels of anandamide, an endocannabinoid, in the male reproductive system, leading to compromised fertilizing capacity of sperm. This defect is rescued by superimposing deletion of cannabinoid receptor 1 (Cnr1). Retention of Faah-/- sperm on the egg zona-pellucida provides evidence that sperm’s capacity to penetrate the zona barrier is dampened by elevated anandamide levels. Collectively, the results show that aberrant endocannabinoid signaling via CNR1 impairs normal sperm function. Besides unveiling a new regulatory mechanism of sperm function, this study has clinical significance in male fertility.

Exposure to marijuana during pregnancy has adverse effects on placentation. Using mice as a model, we found that the endocannabinoid system is also present on the ectoplacental cone and spongiotrophoblast cells in placentas. We also observed that aberrant endocannabinoid signaling confers premature trophoblast stem cell differentiation, and defective trophoblast development and invasion. These defects are reflected in retarded fetal development and elevated spontaneous pregnancy loss. Because the endocannabinoid system is conserved across species, including humans, our study suggests that endocannabinoid signaling is critical to placentation and pregnancy success in humans.

Collectively, my work demonstrated that appropriate endocannabinoid signaling is critical for both male and female reproductive functions.

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