Abstract
Recent changes in legal status and public perception of cannabis have contributed to an increase use amongst women of reproductive age. Concurrently, there is inadequate evidence-based knowledge to guide clinical practice regarding cannabis and its effects on fertility and early embryonic development. This study aimed to evaluate the effects of the primary psychoactive component of cannabis, delta-9 tetrahydrocannabinol (THC), during oocyte maturation, and its impact on the developing embryo. Bovine oocytes were matured in vitro for 24 h under clinically relevant doses of THC mimicking plasma levels achieved after therapeutic (0.032 μM) and recreational (0.32 and 3.2 μM) cannabis use. THC-treated oocytes were assessed for development and quality parameters at both the oocyte and embryo level. Characteristics of oocytes treated with cannabinoid receptor antagonists were also assessed. Oocytes treated with 0.32 and 3.2 μM THC, were significantly less likely to reach metaphase II (p < 0.01) and consequently had lower cleavage rates at day 2 post-fertilization (p < 0.0001). Treatment with cannabinoid receptor antagonists restored this effect (p < 0.05). Oocytes that did reach MII showed no differences in spindle morphology. Oocytes treated with 0.032 μM THC had significantly lower connexin mRNA (p < 0.05) (correlated with decreased quality), but this was not confirmed at the protein level. At the blastocyst stage there were no significant differences in developmental rates or the proportion of trophectoderm to inner cell mass cells between the control and treatment groups. These blastocysts, however, displayed an increased level of apoptosis in the 0.32 and 3.2 μM groups (p < 0.0001). Our findings suggest a possible disruptive effect of cannabis on oocyte maturation and early embryonic development.
Highlights
Oocyte maturation ensures the oocyte has all the needed material to successfully undergo fertilization and progress through the early stages of embryonic development (De Felici et al, 2005; Sánchez and Smitz, 2012)
The cumulus oocyte complexes (COCs) were matured in serum in vitro maturation media (S-IVM) comprised of HEPES buffered TCM199 maturation media supplemented with 2% steer serum, sodium pyruvate, 1 μg/mL luteinizing hormone (LH) (NIH, Washington, DC, USA) 0.5 μg/mL follicle stimulating hormone (FSH) (Follitropin V; Vetoquinol, QC, Canada), 1 μg/mL estradiol and 10% fetal bovine serum (FBS) (Gibco)
By treating oocytes in vitro with pharmacologically relevant doses of THC, [low (THC) 0.032 μM; mid (THC) 0.32 μM; high (THC) 3.2 μM], we attempted to model the effects of cannabis use on the female reproductive system, considering the lack of information on in vivo concentrations
Summary
Oocyte maturation ensures the oocyte has all the needed material to successfully undergo fertilization and progress through the early stages of embryonic development (De Felici et al, 2005; Sánchez and Smitz, 2012) In mammals, this initial development involves a number of tightly regulated signaling and molecular pathways, many of which are not fully elucidated (Park et al, 2004; Wang et al, 2006; Correa et al, 2016; Cecconi et al, 2020). While a lot of work has been published in this regard, there still remain substances in which the available literature is inconclusive Cannabis falls into this realm of understudied, but readily available compounds, which is especially notable with its recent legalization in many countries (Chavarro, 2018; Ilnitsky and Van Uum, 2019; De Angelis et al, 2020)
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