Fatty acid amide hydrolase deficiency limits early pregnancy events
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
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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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 1

Impact of marijuana exposure on oviductal transport, early embryo development, and implantation in wild-type mice.

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Impact of marijuana exposure on oviductal transport, early embryo develo...
(A) Number of mice with oviductal embryo retention per total number of mice examined on day 4 of pregnancy. (B) Percentage of embryos recovered from oviducts or uteri. (C) Differential distribution of morulae and blastocysts among drug-treated groups. Statistical significance between treatment groups was evaluated using unpaired 1-tailed Student’s t test (*P < 0.01). (D) TUNEL analysis in blastocysts upon maternal exposure to THC in vivo. Images shown depict FITC-labeled apoptotic cells as green, propidium iodide–labeled nuclei as red, and merge as yellow (scale bar: 20 μm). (E and F) Implantation in mice receiving different drug treatments. Implantation sites (IS) were visualized by the blue-dye method on day 5 mid-morning. Numbers within the bars in E indicate the number of mice with implantation sites per total number of mice examined. The results show that while THC, the most psychoactive component of marijuana, but not the inactive CBD and CBN, derails oviductal embryo transport, retards preimplantation embryo development, induces apoptosis in blastocysts, and blocks implantation in wild-type mice, SR141716 (SR1, a selective CB1 antagonist) largely reduces the detrimental effects of THC exposure. Veh, vehicle.