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 sperms 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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07152010-141308 |
| Date | 16 July 2010 |
| Creators | Sun, Xiaofei |
| Contributors | Sudhansu K. Dey, Sanjoy K. Das, Lawrence J. Marnett, David L. Hachey, Richard M. Breyer |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu//available/etd-07152010-141308/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.0017 seconds