The Epigenetics of the Endocannabinoid System.

Meccariello Meccariello,Morrone Morrone,Viggiano Viggiano,D'angelo D'Angelo,Fasano Fasano,Pierantoni Pierantoni,Santoro Santoro

doi:10.3390/ijms21031113

Abstract

The endocannabinoid system (ES) is a cell-signalling system widely distributed in biological tissues that includes endogenous ligands, receptors, and biosynthetic and hydrolysing machineries. The impairment of the ES has been associated to several pathological conditions like behavioural, neurological, or metabolic disorders and infertility, suggesting that the modulation of this system may be critical for the maintenance of health status and disease treatment. Lifestyle and environmental factors can exert long-term effects on gene expression without any change in the nucleotide sequence of DNA, affecting health maintenance and influencing both disease load and resistance. This potentially reversible “epigenetic” modulation of gene expression occurs through the chemical modification of DNA and histone protein tails or the specific production of regulatory non-coding RNA (ncRNA). Recent findings demonstrate the epigenetic modulation of the ES in biological tissues; in the same way, endocannabinoids, phytocannabinoids, and cannabinoid receptor agonists and antagonists induce widespread or gene-specific epigenetic changes with the possibility of trans-generational epigenetic inheritance in the offspring explained by the transmission of deregulated epigenetic marks in the gametes. Therefore, this review provides an update on the epigenetics of the ES, with particular attention on the emerging role in reproduction and fertility.

Highlights

The endocannabinoid system (ES) is a complex cell-signalling system identified in the early 1990s following studies on the phytocannabinoid ∆9-tetrahydrocannabinol (∆9THC), the main psychoactive constituent of the marijuana plant Cannabis sativa [1]
From the data reported, it emerges that epigenetic modifications of the ES by means of DNA methylation, histone acetylation/deacetylation at the CNR1, and FAAH genes encoding the CB1 receptor and FAAH hydrolysing enzyme may play a relevant role both in physiological processes regulating fertility and reproduction as well as in disease pathogenesis and progression including cancer
It has been documented that external epigenetic cues such as alcohol induce DNA methylation changes in the mouse model of foetal alcohol spectrum disorder, and the lack of a functional CNR1 gene protects against ethanol-induced impairments of DNMT1, DNMT3A, and DNA methylation [49]

Summary

Introduction

The endocannabinoid system (ES) is a complex cell-signalling system identified in the early 1990s following studies on the phytocannabinoid ∆9-tetrahydrocannabinol (∆9THC), the main psychoactive constituent of the marijuana plant Cannabis sativa [1]. The high expression of the ES in brain areas playing a key role in conditioning processes such as drug-seeking behaviour, smoking, and alcohol addiction, emphasises that the ES is widely sensible to environmental epigenetic cues [4,5,6]. In this respect, epigenetics can be defined as the overall biological processes changing gene expression without any change in the nucleotide DNA sequence [7]. Recent evidence revealed the transfer of epigenetic marks from gametes to the embryo [14,15] with three possibilities of epigenetic inheritance: (1) cross-generational effects or intergenerational inheritance, when the F1 generation is affected as a consequence of in utero or paternal exposure to environmental cues; (2) multigenerational inheritance when F1 and F2 generations are affected; and (3) trans-generational effects when more than three generations stably present the phenotype caused by epigenetic changes [16]

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Conclusion