Emerging Roles of Endocannabinoids as Key Lipid Mediators for a Successful Pregnancy

Rava, Alessandro; Trezza, Viviana

doi:10.3390/ijms24065220

Cited by 4 publications

(4 citation statements)

References 255 publications

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“…For instance, the sharp increase in CB 1 during adulthood correlates to its functional endometrial role during the preimplantation stage [27]. Moreover, the modulation of NAPE-PLD, FAAH, and DAGL-α is consistent with accumulated literature data that show a key role of eCBs in the regulation of several steps during the estrous/menstrual cycle [4,28], as well as during early and late stages of pregnancy [29,30] in several mammalian species. Interestingly, the tissue localization of both NAPE-PLD and FAAH in the oviducts and uteri appears mainly in the epithelial cells facing the lumen of the organ, or glandular cells, as also reported in other species [28,29,31,32].…”

Section: Discussionsupporting

confidence: 86%

Endocannabinoid System Components of the Female Mouse Reproductive Tract Are Modulated during Reproductive Aging

Rossi

Nisio

Chiominto

et al. 2023

IJMS

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The endocannabinoid (eCB) system has gained ground as a key modulator of several female fertility-related processes, under physiological/pathological conditions. Nevertheless, its modulation during reproductive aging remains unclear. This study aimed to investigate the expression levels of the main receptors (cannabinoid receptor 1,CB1; cannabinoid receptor 2, CB2; G-protein coupled receptor, GPR55; and transient receptor potential vanilloid type 1 channel, TRPV1) and metabolic enzymes (N-acylphosphatidylethanolamine phospholipase D, NAPE-PLD; fatty acid amide hydrolase, FAAH; monoacylglycerol lipase, MAGL; and diacylglycerol lipase, DAGL-α and -β) of this system in the ovaries, oviducts, and uteri of mice at prepubertal, adult, late reproductive, and post-reproductive stages through quantitative ELISA and immunohistochemistry. The ELISA showed that among the receptors, TRPV1 had the highest expression and significantly increased during aging. Among the enzymes, NAPE-PLD, FAAH, and DAGL-β were the most expressed in these organs at all ages, and increased age-dependently. Immunohistochemistry revealed that, regardless of age, NAPE-PLD and FAAH were mainly found in the epithelial cells facing the lumen of the oviduct and uteri. Moreover, in ovaries, NAPE-PLD was predominant in the granulosa cells, while FAAH was sparse in the stromal compartment. Of note, the age-dependent increase in TRPV1 and DAGL-β could be indicative of increased inflammation, while that of NAPE-PLD and FAAH could suggest the need to tightly control the levels of the eCB anandamide at late reproductive age. These findings offer new insights into the role of the eCB system in female reproduction, with potential for therapeutic exploitation.

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Section: Discussionsupporting

confidence: 86%

Endocannabinoid System Components of the Female Mouse Reproductive Tract Are Modulated during Reproductive Aging

Rossi

Nisio

Chiominto

et al. 2023

IJMS

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“…Prolonged endocannabinoid signaling is linked to adverse pregnancy outcomes (78). Bariani et al (8) found that LPS altered AEA and related endocannabinoid-like lipid levels in the uterus, consistent with previous research (75,76). LPS-induced cytokines can affect endocannabinoid production by modulating the expression and activity of fatty acid amide hydrolase (FAAH) (79,80).…”

Section: Mechanisms Of Action: Resveratrol Targeting the Mechanism Of...mentioning

confidence: 53%

Promising benefit of resveratrol in preventing preterm birth: A systematic review

Habiburrahman,

Rakasiwi,

Putra

2024

World Acad Sci J

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Prematurity is a matter of utmost concern in pregnancies due to its associated complications, mortality, disability and significant economic burden. However, the current tocolytics used for preventing preterm birth have limitations, such as side-effects and unclear inhibitory pathway mechanisms. Hence, it is critical to explore alternative tocolytics, such as resveratrol. The present study, by performing a systematic review, aimed to investigate the potential of resveratrol in preventing prematurity and its therapeutic applications. A systematic search of the relevant literature was conducted using advanced search engines (PubMed, ProQuest, EBSCOhost and EMBASE), employing specific key words and predefined eligibility criteria to identify supporting articles, which were subsequently synthesized into the systematic review. Of note, four critical lines of evidence, supported by multiple studies, highlight the promising benefits of resveratrol in preventing preterm birth. In a mouse model of preterm birth, resveratrol has demonstrated the ability to: i) Reduce prematurity rates by 49-64%; ii) inhibit inflammatory mediators and cytokines (nitric oxide synthase, inducible nitric oxide synthase, cyclooxygenase (COX)-2 in the uterus, TNF-α, IL-1β, COX-2 in peritoneal macrophages and the cervixs; iii) decrease prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) levels in the uterus; and iv) regulate endocannabinoids (anandamide and 2-arachidonoylglycerol) and endocannabinoid-like lipids. By reducing the levels of these substances, resveratrol has the potential to prevent cervical ripening, membrane rupture and myometrial contractility associated with preterm birth. In summary, resveratrol offers multiple pathways to inhibit inflammation-induced prematurity, rendering it a promising candidate as a novel tocolytic agent.

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“…With the rise in cannabis consumption among reproductive age-women, and the increase in THC potency within cannabis preparation, it is important to further investigate how THC may interact with the ECS within the female reproductive system. The ECS has a prominent role in mammalian reproduction and is present in all female reproductive tissues [ 15 , 33 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…THC can directly modulate the ECS, which has been detected throughout the female reproductive system including the placenta, uterus, endometrium, ovary, embryo, oocyte, follicular fluid and granulosa cells (GCs) [ 15 , 37 – 40 ]. The ECS controls various aspects of reproduction, including the release of gonadotropins, steroid hormone synthesis, the production and release of male and female gametes, and pregnancy [ 15 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

DNA methylation, but not microRNA expression, is affected by in vitro THC exposure in bovine granulosa cells

Floccari,

Sabry,

Choux

et al. 2024

BMC Pharmacol Toxicol

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Background A global increase in cannabis use has led to questions about its effects on fertility. The rise in consumption amongst women of reproductive age is a growing concern, as this group is vulnerable in terms of reproductive health. Ample evidence suggests that the psychoactive component of cannabis, Δ9-Tetrahydrocannabinol (THC), interacts with the endocannabinoid system (ECS), that helps regulate mammalian reproduction. This study aimed to research the epigenetic effects of THC in bovine granulosa cells (GCs) by (1) investigating global DNA methylation via measuring 5-mC and 5-hmC levels; (2) measuring key methylation regulators, including the methylating enzymes DNMT1, DNMT3a, DNMT3b and the demethylases TDG and TET1/2/3; and (3) assessing fertility-associated miRNAs key in developmental competency, including miR-21, -155, -33b, -324 and -346. Methods Bovine GCs were used as a translational model for reproductive toxicity in humans. To determine THC effects, GCs were isolated from Cumulus-Oocyte-Complexes (COCs) from bovine ovaries, cultured in vitro for 7 days, or until confluent, and cryopreserved at passage 1 (P1). For experimentation, cells were thawed, cultured until passage 2 (P2), serum restricted for 24-h and treated for 24-h in one of five groups: control, vehicle (1:1:18 ethanol: tween: saline) and three clinically relevant THC doses (0.032, 0.32 and 3.2 μM). Global methylation was assessed by measuring 5-mC and 5-hmC levels with flow cytometry. To assess mRNA and protein expression of methylation regulators and miRNA profiles, qPCR and Western Blotting were utilized. Shapiro-Wilk test was used to determine normality within datasets. One-way ANOVA was applied to determine statistical significance using GraphPad Prism 6.0.0. Results Results indicate a significant decrease (p = 0.0435) in 5-mC levels following low THC exposure, while no changes were observed in 5-hmC levels. A significant increase in DNMT1 following high THC exposure at the RNA level (p < 0.05) and a significant increase following low THC exposure at the protein level (p = 0.0048) were also observed. No significant differences were observed in DNMT3a/3b, TDG, TET1/2/3 mRNAs or in any of the miRNAs analyzed. Conclusions This research suggests that THC mainly affects DNA methylation, but not miRNA profiles, ultimately altering gene expression and likely impairing oocyte competence, maturation, and fertilization potential.

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Emerging Roles of Endocannabinoids as Key Lipid Mediators for a Successful Pregnancy

Cited by 4 publications

References 255 publications

Endocannabinoid System Components of the Female Mouse Reproductive Tract Are Modulated during Reproductive Aging

Endocannabinoid System Components of the Female Mouse Reproductive Tract Are Modulated during Reproductive Aging

Promising benefit of resveratrol in preventing preterm birth: A systematic review

DNA methylation, but not microRNA expression, is affected by in vitro THC exposure in bovine granulosa cells

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