Overactive type 2 cannabinoid receptor induces meiosis in fetal gonads and impairs ovarian reserve

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.

Activation of the cannabinoid receptor type 2 by the agonist JWH133 promotes the first wave of in vitro spermatogenesis

“…Therefore, a concentration of 1 μ m of JWH133 reduced the central necrotic area at D30 and promoted a higher number of CREM‐positive cells (corresponding to late pachytene spermatocyte I and round spermatids) per healthy tissue area at D18 and D30. These data are consistent with other studies that evaluate the impact of JWH133 on culture of isolated cells with an optimal concentration of 1 μ m of JWH133 30,31,39 …”

“…Other studies evaluated the impact of JWH133 on culture of isolated cells with promising results with a concentration of 1 μ m of JWH133 30,31,39 with an expression level of CB 2 expression who remains constant until 7 d pp 39 . However, distribution of this molecule through in vitro culture system composed of agarose gel was not known.…”

Paternal activation of CB2 cannabinoid receptor impairs placental and embryonic growth via an epigenetic mechanism

“…Instead we speculate that this reduction in sperm count is determined by an apoptotic effect of the drug on CB 2 expressing germ cells. Accordingly, we previously observed a similar effect in fetal oocytes, in which activation of CB 2 induced their differentiation but concomitantly determined apoptotic cell death 30 . Although chronic exposure to JWH-133 caused a significant decrease in sperm count, mating and fertility were not impaired and no reduction of litter size nor frequency was observed.…”

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“…Embora existam poucos estudos, as variantes histonas também estão envolvidas com os efeitos de canabinóides no desenvolvimento fetal e epigenética (DE DOMENICO et al, 2017). Dentre as variações deste marcador, phospho-histone em células-tronco neurais no cérebro em desenvolvimento (XIA; JIAO, 2017).…”

“…Na metáfase, a histona-PH3 é sempre altamente fosforilada e positiva para phosphohistone + (KIM et al, 2017). O estudo de De Domenico et al (2017) é um dos poucos estudos que avaliam a ativação de CB2r por um agonista e seu efeito na condensação cromossômica em gônodas fetais utilizando a imunopositividade de PH3-histona.…”