1. Important components of the endocannabinoid system (ECS) were isolated in the developing human fetal testis, implying that the development of this organ could be impacted by cannabinoid consumption.
2. Early testis exposure to phytocannabinoids directly and negatively impacted male gonadal development and physiology ex vivo.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Cannabis is the most commonly consumed recreational drug by women in pregnancy, and the presence of THC (Δ9-trans-tetrahydrocannabinol) and cannabidiol (CBD) in the fetal blood and/or meconium suggest that this substance crosses the placenta. While cannabis use in pregnancy has been shown to contribute to decreased birth weight, increased risk for prematurity, cognitive deficits, and behavioural and cognitive impairment, its effects on human genital development are unknown. In this randomized controlled trial, researchers investigated the expression and localization of components of the ECS with first-trimester fetuses obtained following legal abortions in France. Fetal testes were cultured, and then treated either with CBD, THC, or THC/CBD at different stages of early development. Several measures were taken to quantify and qualify the function of ECS components, hormones, proliferative and apoptotic cells, genes involved in biosynthesis ex-vivo. The study demonstrated not only that the cannabinoid receptors CB1 and CB2 as well as endocannabinoid synthesizing and degrading enzymes were present in human fetal testis, but that there were also several deleterious effects of direct exposures to THC and CBD on the developing human testis and its endocrine functions ex vivo. Although in vivo studies will be required to further elucidate the true developmental effects of cannabinoid exposure on testis development, the findings from the current study appear to corroborate the potential harms of cannabinoid exposure during pregnancy.
Click to read the study in BMC Medicine
In-Depth [randomized controlled trial]: While the effects of several other substances on pregnancy and fetal development have been elucidated, cannabis remains a relatively novel topic of study by comparison (although it is currently the most widely consumed recreational drug in pregnancy). Its effects as they relate to human gonadal development have not yet been explored. This study sought to investigate the impacts of cannabis exposure in pregnancy on the development and physiology of fetal human testis ex vivo, and to identify whether components of the endocannabinoid system (ECS) would be present in the testis. First trimester (7 to 12 week) human fetuses were obtained following legally performed abortions in France. Sections of fetal testis were cultured. Following this, varying concentrations of THC and/or CBD (concentrations of 10−7 M to 10−5 M) were added to the medium based on peak plasma concentrations for either 72 hours or 14 days at different time points during development. The first significant finding of this study was that the ECS was dynamically regulated in fetal testes in early development. mRNA for synthesizing and degrading enzymes Anandamide (AEA) and 2-Arachidonyl-glycerol (2-AG), as well as the cannabinoid receptors CB1 and CB2, were isolated. These results suggest that the first months of testis development could be impacted by components of the ECS. After a 72-hour exposure to phytocannabinoids at varying stages of early development, the density of proliferative cells was significantly decreased in extracordial cells (Leydig cells, immune cells, fibroblasts) exposed to THC or THC/CBD (Ps < 0.05), as well as intracordial cells (Sertoli and germ cells) treated with THC only (P < 0.05). There was a significant increase in the density of apoptotic intracordial cells for CBD, THC, and THC/CBD groups (Ps < 0.05). There was also significantly decreased testosterone secretion by Leydig cells when exposed to CBD between 8-10 weeks or THC between 10-12 weeks (Ps < 0.05). A dose-dependent testosterone decrease was noted with a 1:1 mixture of CBD and THC. Insulin-like factor 3, also a Leydig cell-derived hormone, was also significantly decreased in testis explants exposed to THC at 8-10 weeks. Anti-Müllerian Hormone (AMH) secretion was significantly decreased in explants treated with THC (P < 0.05) or CBD/THC (P < 0.01) for 72 hours. The relative surface area occupied by AMH-positive Sertoli cells did not change, suggesting that Sertoli cell function (rather than viability) was affected by cannabinoid exposure. When exposed to CBD, THC, or combinations thereof, the expression of 187 genes was either up- or down-regulated (compared to three genes in controls). Several of these genes were implicated in steroid biosynthesis or cellular responses to toxic substances and inorganic compounds. Finally, to mimic a chronic-use situation, a 14-day-long exposure to phytocannabinoids between 10-12 weeks of development was carried out. CBD/THC exposure visibly shrank the size of explants (p < 0.01), as did exposure to CBD or THC alone (Ps < 0.05). A massive increase in apopotic cells was observed in CBD/THC treated testis, as was a near disappearance of the cords and a drastic decrease in germ and Sertoli cells. CBD and THC treatments both significantly decreased testosterone levels at 14 days after treatment initiation. This study was the first to demonstrated the presence of ECS components in the human fetal testis and the direct negative impacts of phytocannabinoid exposure on fetal testis physiology ex vivo. A critical period of 8 to 12 weeks gestational age for testicular development and susceptibility to environmental exposures applied in this study. Further large-scale, longitudinal mother-child cohort studies should be undertaken to study how these effects translate into risk for reproductive pathologies into adulthood, and additional genetic studies should also be conducted to corroborate these results.
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