Abstract
Type 2 cannabinoid receptor (CB2R) has been proposed to promote in vitro meiotic entry of postnatal male germ cells and to maintain the temporal progression of spermatogenesis in vivo. However, no information is presently available on the role played by CB2R in male and female fetal gonads. Here we show that in vitro pharmacological stimulation with JWH133, a CB2R agonist, induced activation of the meiotic program in both male and female fetal gonads. Upon stimulation, gonocytes initiated the meiotic program but became arrested at early stages of prophase I, while oocytes showed an increased rate of meiotic entry and progression toward more advanced stage of meiosis. Acceleration of meiosis in oocytes was accompanied by a strong increase in the percentage of γ-H2AX-positive pachytene and diplotene cells, paralleled by an increase of TUNEL-positive cells, suggesting that DNA double-strand breaks were not correctly repaired during meiosis, leading to oocyte apoptosis. Interestingly, in vivo pharmacological stimulation of CB2R in fetal germ cells through JWH133 administration to pregnant females caused a significant reduction of primordial and primary follicles in the ovaries of newborns with a consequent depletion of ovarian reserve and reduced fertility in adult life, while no alterations of spermatogenesis in the testis of the offspring were detected. Altogether our findings highlight a pro-meiotic role of CB2R in male and female germ cells and suggest that the use of cannabis in pregnant female might represent a risk for fertility and reproductive lifespan in female offspring.
Highlights
Meiosis is a crucial event in mammalian reproduction that occurs at different developmental ages in male and female gonads
In order to extend our knowledge on the pro-meiotic role of CB2R, in the current study we investigated the function of this cannabinoid receptor in male and female fetal gonads during a developmental window in which female germ cells enter meiosis but gonocytes are still proliferating, with the additional intent of gaining insights into the role of endocannabinoid system (ECS) in oocyte maturation, a function remained unclear
We previously demonstrated that cannabinoid receptor CB2 regulated meiotic entry of postnatal spermatogonia in vitro and in vivo, and its activation induced an acceleration of the onset of spermatogenesis that disrupted the temporal dynamics of the spermatogenic cycle.[12]
Summary
Cannabinoid receptors CB1 and CB2 are expressed in male and female fetal gonads. The expression of CB1 and CB2 receptors (CB1R and CB2R) in male and female fetal gonads at different stages of development from E11.5 to E17.5 was investigated. No differences in the percentage of SCP3-positive cells nor in the distribution of the meiotic stages between treated and untreated cells were detected following stimulation of male fetal gonads with CB1R agonist ACEA, indicating that CB1R did not have a role in male germ cell differentiation (Supplementary Figures S1B and C). JWH133 treatment induced a decrease in the percentage of zygotene cells (18.3 ± 2.5% versus 25.9 ± 3.61% of control cells) concomitantly with an increase of diplotene (19.7 ± 1.53% versus 15.3 ± 0.6% of control cells) and the appearance of metaphase-like cells (12.7 ± 2.51% versus 1.3 ± 2.4% of control cells) (Figure 4c), further suggesting that CB2R stimulation promoted meiotic progression of fetal oocytes.
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