The uterus is a potential site for anandamide synthesis and hydrolysis: Differential profiles of anandamide synthase and hydrolase activities in the mouse uterus during the periimplantation period

Paria, Bibhash C.; Deutsch, Dale D.; Dey, Sudhansu K.

doi:10.1002/(sici)1098-2795(199610)45:2<183::aid-mrd11>3.0.co;2-2

Cited by 136 publications

(82 citation statements)

References 33 publications

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“…This is consistent with higher levels of amidohydrolase activity and of PGE 2 in implantation sites (14,41). Increases in uterine anandamide synthase activity with concomitant decreases in amidohydrolase activity by indomethacin in vivo and in vitro (14) also support this assumption. It should be noted that inhibition of PG synthesis by indomethacin interferes with implantation (40,41).…”

Section: Resultssupporting

confidence: 91%

“…Also, activation of CB1-R by cannabinoid ligands including anandamide interferes with preimplantation embryo development, and this effect is completely reversed by a specific CB1-R antagonist (13). These results and anandamide synthetic capacity of the periimplantation mouse uterus (11,12,14) suggested that cannabinoid-ligand receptor signaling during implantation could be physiologically and pharmacologically important.…”

supporting

confidence: 76%

“…Therefore, direct N-acylation of ethanolamine must be considered as a possible alternative pathway of anandamide synthesis in this tissue. This is consistent with our findings of a relatively low substrate requirement (K m of 3.8 M and 1.2 mM for arachidonic acid and ethanolamine, respectively) for the uterine anandamide synthase activity that was also shown to be active in the presence of phenylmethylsulfonyl fluoride, an inhibitor of the amidohydrolase (14). It is interesting to note that the changing uterine levels of anandamide with pregnancy status are reflected in changing patterns of uterine anandamide synthase and amidohydrolase activity (14).…”

Section: Resultsmentioning

confidence: 99%

“…Another possibility is that anandamide serves as a reservoir of arachidonic acid for the generation of prostaglandins (PGs) which are important for embryo development and implantation (39)(40)(41). This is consistent with higher levels of amidohydrolase activity and of PGE 2 in implantation sites (14,41). Increases in uterine anandamide synthase activity with concomitant decreases in amidohydrolase activity by indomethacin in vivo and in vitro (14) also support this assumption.…”

Section: Resultsmentioning

confidence: 99%

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Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation

Schmid

Paria

Krebsbach

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

240

166

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Anandamide (N-arachidonoylethanolamine) is an endogenous ligand for both the brain-type (CB1-R) and spleen-type (CB2-R) cannabinoid receptors. This investigation demonstrates that the periimplantation mouse uterus contains the highest levels of anandamide (142-1345 pmol͞ mol lipid P; 1-7 g͞g wet weight) yet discovered in a mammalian tissue. The levels f luctuate with the state of pregnancy; down-regulation of anandamide levels is associated with uterine receptivity, while up-regulation is correlated with uterine refractoriness to embryo implantation. Anandamide levels are highest during the nonreceptive phase in the pseudopregnant uterus and in the interimplantation sites, and lowest at the site of embryo implantation. The lower levels of uterine anandamide at the implantation sites may be a mechanism by which implanting embryos protect themselves from the detrimental effects of this endogenous ligand. We also observed a reduced rate of zona-hatching of blastocysts in vitro in the presence of anandamide, and inhibition of implantation by systemic administration of a synthetic cannabinoid agonist CP 55,940. These adverse effects were reversed by SR141716A, a specific CB1-R antagonist. Taken together, the results suggest that an aberrant synthesis of anandamide and͞or expression of the cannabinoid receptors in the uterus͞embryo may account for early pregnancy failure or female infertility.

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Section: Resultssupporting

confidence: 91%

supporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation

Schmid

Paria

Krebsbach

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

240

166

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“…These compounds, in particular D 9 -tetrahydrocannabinol, have been reported to have adverse effects on reproductive functions, including retarded embryo development, fetal loss and pregnancy failure [7,8]. A major endocannabinoid, anandamide (arachidonoylethanolamide), has been shown to impair pregnancy and embryo development [9]. Down-regulation of anandamide levels in mouse uterus has been associated with uterine receptivity, while up-regulation correlated with uterine refractoriness to embryo implantation [10].…”

mentioning

confidence: 99%

Down-regulation of anandamide hydrolase in mouse uterus by sex hormones

Maccarrone¹,

Felici²,

Bari³

et al. 2000

Eur J Biochem

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Endocannabinoids are an emerging class of lipid mediators, which mimic several effects of cannabinoids. Anandamide (arachidonoylethanolamide) is a major endocannabinoid, which has been shown to impair pregnancy and embryo development. The activity of anandamide is controlled by cellular uptake through a specific transporter and intracellular degradation by the enzyme anandamide hydrolase (fatty acid amide hydrolase, FAAH). We characterized FAAH in mouse uterus by radiochromatographic and immunochemical techniques, showing that the enzyme is confined to the epithelium and its activity decreases appreciably during pregnancy or pseudopregnancy because of lower gene expression at the translational level. Ovariectomy prevented the decrease in FAAH, and both progesterone and estrogen further reduced its basal levels, suggesting hormonal control of the enzyme. Anandamide was shown to induce programmed cell death in mouse blastocysts, through a pathway independent of type-1 cannabinoid receptor. Blastocysts, however, have a specific anandamide transporter and FAAH, which scavenge this lipid. Taken together, these results provide evidence of an interplay between endocannabinoids and sex hormones in pregnancy. These findings may also be relevant for human fertility, as epithelial cells from healthy human uterus showed FAAH activity and expression, which in adenocarcinoma cells was increased fivefold.Keywords: anandamide hydrolase; apoptosis; development; endocannabinoids; sex hormones.Endocannabinoids are an emerging class of lipid mediators, isolated from brain and peripheral tissues [1,2] and found also in chocolate [3] and milk [4]. They mimic the psychotropic, hypnotic, tranquilizing, antiemetic, anticonvulsive and analgesic effects of cannabinoids [5,6]. These compounds, in particular D 9 -tetrahydrocannabinol, have been reported to have adverse effects on reproductive functions, including retarded embryo development, fetal loss and pregnancy failure [7,8]. A major endocannabinoid, anandamide (arachidonoylethanolamide), has been shown to impair pregnancy and embryo development [9]. Down-regulation of anandamide levels in mouse uterus has been associated with uterine receptivity, while up-regulation correlated with uterine refractoriness to embryo implantation [10]. Remarkably, mouse uterus contains the highest levels of anandamide detected so far in mammalian tissues, and is the only tissue in which anandamide is the main component (up to 95%) of N-acylethanolamines [10]. Anandamide is an endogenous ligand for both the brain-type (CB1-R) and spleen-type (CB2-R) cannabinoid receptors, mimicking several actions of cannabinoids on the central nervous system and in peripheral tissues [11]. Mouse embryos express both CB1-R and CB2-R mRNA, the levels of the former being much higher than those found in brain [7,9,10]. CB1-R activation is detrimental for mouse preimplantation development [10,12], but appears to accelerate trophoblast differentiation [13].The effect of anandamide through CB1-R and CB2-R depends on its concent...

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Animal evidence considered in determination of cannabis smoke and Δ⁹‐tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint); Part I. Somatic development

Campbell

Iyer

Kaufman

et al. 2022

Birth Defects Research

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Objectives: On December 11, 2019, California's Developmental and Reproductive Toxicant Identification Committee (DARTIC) met to consider the addition of cannabis smoke and Δ 9 -THC to the Proposition 65 list as causing reproductive toxicity (developmental endpoint). As the lead state agency for implementing Proposition 65, the Office of Environmental Health Hazard Assessment (OEHHA) reviewed and summarized the relevant scientific literature in the form of a hazard identification document (HID). Here we provide reviews based on the HID: shortened, revised, and reformatted for a larger audience.Methods: While the HID included both human and animal data, this set of three reviews will highlight the animal-derived data pertaining to somatic development (Part I), neurodevelopmental effects (Part II), and proposed neurodevelopmental mechanisms of action (Part III).Results: Endogenous cannabinoids (eCBs) and their receptors serve many critical functions in normal development. Δ 9 -THC can interfere with these functions. Mechanistic studies employed techniques including: blocking Δ 9 -THC binding to endocannabinoid (EC) receptors, inhibiting Δ 9 -THC metabolism, and/or using animals expressing knockout mutations of EC receptors.Apical somatic effects of cannabis smoke or Δ 9 -THC reported in whole animal studies included decreases in offspring viability and growth. Mechanistic studies discussed in Part I focused on Δ 9 -THC effects on early embryos and implantation, immune development, and bone growth. Conclusions: In reaching its decision to list cannabis and Δ 9 -THC as a developmental toxicant under California's Proposition 65, the DARTIC considered biological plausibility and the consistency of mechanistic information with effects reported in human and whole animal studies.

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The uterus is a potential site for anandamide synthesis and hydrolysis: Differential profiles of anandamide synthase and hydrolase activities in the mouse uterus during the periimplantation period

Cited by 136 publications

References 33 publications

Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation

Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation

Down-regulation of anandamide hydrolase in mouse uterus by sex hormones

Animal evidence considered in determination of cannabis smoke and Δ⁹‐tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint); Part I. Somatic development

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The uterus is a potential site for anandamide synthesis and hydrolysis: Differential profiles of anandamide synthase and hydrolase activities in the mouse uterus during the periimplantation period

Cited by 136 publications

References 33 publications

Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation

Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation

Down-regulation of anandamide hydrolase in mouse uterus by sex hormones

Animal evidence considered in determination of cannabis smoke and Δ9‐tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint); Part I. Somatic development

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Animal evidence considered in determination of cannabis smoke and Δ⁹‐tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint); Part I. Somatic development