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

Elisa Innocenzi,Michele Zampieri,Gabriele Rossi,Fabio Ciccarone,Roberta Bernardini,Rosella Cicconi,Emanuela De Domenico,Paola Grimaldi,Maurizio Mattei

doi:10.1038/s41598-019-53579-3

Abstract

The cannabinoid receptor type 2 (CB2) is the peripheral receptor for cannabinoids, involved in the homeostatic control of several physiological functions. Male mitotic germ cells express a high level of CB2, whose activation promotes their differentiation in both in vitro and in vivo experiments, controlling the correct progression of spermatogenesis. However, it remains elusive if CB2 activation in spermatogonia could affect reproductive success in terms of fertility and healthy pregnancy outcomes. In this study, we explored the effects of male CB2 activation on sperm number and quality and its influence on next generation health. We show that exposure of male mice to JWH-133, a selective CB2 agonist, decreased sperm count, impaired placental development and reduced offspring growth. These defects were associated with altered DNA methylation/hydroxymethylation levels at imprinted genes in sperm and conserved in placenta. Our findings reveal that paternal selective activation of CB2 alters the sperm epigenome and compromises offspring growth. This study demonstrates, for the first time, a new role of CB2 signaling in male gametes in causing epigenetic alterations that can be transmitted to the next generation by sperm, highlighting potential risks induced by recreational cannabinoid exposure.

Highlights

The cannabinoid receptor type 2 (CB2) is the peripheral receptor for cannabinoids, involved in the homeostatic control of several physiological functions
We previously reported that in the testis CB2 is expressed at a high level by spermatogonia and its in vivo activation, by using JWH-133, a synthetic CB2‐selective cannabinoid agonist, caused alteration of the temporal progression of spermatogenesis[5,10]
We show that overactivation of CB2 signaling in young males affected spermatogenesis by decreasing sperm count of about 30%, without altering their motility, a function instead correlated to CB1 activation[7,9]

Summary

Introduction

The cannabinoid receptor type 2 (CB2) is the peripheral receptor for cannabinoids, involved in the homeostatic control of several physiological functions. We show that exposure of male mice to JWH-133, a selective CB2 agonist, decreased sperm count, impaired placental development and reduced offspring growth These defects were associated with altered DNA methylation/hydroxymethylation levels at imprinted genes in sperm and conserved in placenta. No information has been reported on the effects of male exposure to JWH-133 on sperm number, morphology and function as well as on the potential impact on the offspring This last outcome is of Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy. We show that paternal exposure to JWH-133 reduced sperm count and caused defects in placental and embryonic development These effects were associated with altered DNA methylation and hydroxymethylation at specific imprinted genes in sperm and in placenta. Our results underline the urgent need for studies evaluating the potential risks of cannabis/cannabinoid usage for offspring development and health

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