Fatty acid amide hydrolase deficiency limits early pregnancy events
Haibin Wang, … , Benjamin F. Cravatt, Sudhansu K. Dey
Haibin Wang, … , Benjamin F. Cravatt, Sudhansu K. Dey
Published August 1, 2006
Citation Information: J Clin Invest. 2006;116(8):2122-2131. https://doi.org/10.1172/JCI28621.
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Research Article Reproductive biology

Fatty acid amide hydrolase deficiency limits early pregnancy events

Abstract

Synchronized preimplantation embryo development and passage through the oviduct into the uterus are prerequisites for implantation, dysregulation of which often leads to pregnancy failure in women. Cannabinoid/endocannabinoid signaling via cannabinoid receptor CB1 is known to influence early pregnancy. Here we provide evidence that a critical balance between anandamide synthesis by N-acylphosphatidylethanolamine–selective phospholipase D (NAPE-PLD) and its degradation by fatty acid amide hydrolase (FAAH) in mouse embryos and oviducts creates locally an appropriate “anandamide tone” for normal development of embryos and their oviductal transport. FAAH inactivation yielding higher anandamide or experimentally induced higher cannabinoid [(-)-Δ9-tetrahydrocannabinol] levels constrain preimplantation embryo development with aberrant expression of Cdx2, Nanog, and Oct3/4, genes known to direct lineage specification. Defective oviductal embryo transport arising from aberrant endocannabinoid signaling also led to deferred on-time implantation and poor pregnancy outcome. Intercrossing between wild-type and Faah–/– mice rescued developmental defects, not oviductal transport, implying that embryonic and maternal FAAH plays differential roles in these processes. The results suggest that FAAH is a key metabolic gatekeeper, regulating on-site anandamide tone to direct preimplantation events that determine the fate of pregnancy. This study uncovers what we believe to be a novel regulation of preimplantation processes, which could be clinically relevant for fertility regulation in women.

Authors

Haibin Wang, Huirong Xie, Yong Guo, Hao Zhang, Toshifumi Takahashi, Philip J. Kingsley, Lawrence J. Marnett, Sanjoy K. Das, Benjamin F. Cravatt, Sudhansu K. Dey

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Figure 4

Elevated anandamide signaling by pharmacological inhibition of FAAH causes impaired oviductal embryo transport in wild-type mice.

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Elevated anandamide signaling by pharmacological inhibition of FAAH caus...
(A) FAAH inhibition by its selective inhibitor URB597 (URB) increased oviductal levels of anandamide in pregnant wild-type females. Pregnant wild-type females received subcutaneous injection of URB597 at a dose of 1 mg/kg BW on days 1–3, and oviductal tissues were collected after treated females were sacrificed 3 hours after the last drug administration. (B) Number of mice with embryos retained in the oviduct per total number of mice examined. (C) Percentage of embryos recovered from oviducts or uteri of mice with different treatments. (D) Differential distribution of morulae and blastocysts among the drug-treated groups. Oviductal retention of embryos with impaired growth was noted in wild-type mice via silencing of FAAH activity by the selective inhibitor URB597, which was substantially restored when mice were cotreated with URB597 and SR141716. Statistical significance between treatment groups was evaluated using unpaired 1-tailed Student’s t test (*P < 0.05).